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Logo of nihpaAbout Author manuscriptsSubmit a manuscriptHHS Public Access; Author Manuscript; Accepted for publication in peer reviewed journal;
Nitric Oxide. Author manuscript; available in PMC 2017 April 1.
Published in final edited form as:
PMCID: PMC5017793

Effect of asymmetric dimethylarginine (ADMA) on heart failure development


Asymmetric dimethylarginine (ADMA) is an endogenous inhibitor of nitric oxide synthases that limits nitric oxide bioavailability and can increase production of NOS derived reactive oxidative species. Increased plasma ADMA is a one of the strongest predictors of mortality in patients who have had a myocardial infarction or suffer from chronic left heart failure, and is also an independent risk factor for several other conditions that contribute to heart failure development, including hypertension, coronary artery disease/atherosclerosis, diabetes, and renal dysfunction. The enzyme responsible for ADMA degradation is dimethylarginine dimethylaminohydrolase-1 (DDAH1). DDAH1 plays an important role in maintaining nitric oxide bioavailability and preserving cardiovascular function in the failing heart. Here, we examine mechanisms of abnormal NO production in heart failure, with particular focus on the role of ADMA and DDAH1.

Keywords: Nitric oxide, Asymmetric dimethylarginine, dimethylarginine dimethylaminohydrolase-1, heart failure


Chronic Heart failure (CHF) is a condition in which the left heart is not able to pump out sufficient oxygen-rich blood into circulation to meet the body’s needs. The term “congestive heart failure” is often used interchangeably with “chronic left heart failure”. The common clinical symptoms of CHF include shortness of breath (dyspnea), excessive fatigue or reduced exercise capacity and swelling (edema) in legs and feet etc (32,45). The common causes of CHF include prolonged high blood pressure (chronic hypertension), myocardial infarction (heart attack) after coronary artery disease, cardiac valve disease, idiopathic cardiomyopathy, myocarditis from inflammation, and congenital heart diseases etc (32,73). The prevalence of CHF patients is ~6.6 million adults in 2010, and it is projected that additional 3 million people will have CHF by 2030 (39). CHF is the leading cause of death in United States (83).

Nitric Oxide (NO) is an endogenously produced, locally acting gas that exerts multiple actions that help preserve cardiac function in the setting of CHF (17,47, 58,85). NO synthesis is catalyzed by a family of NO synthases (NOS), which use L-arginine as the substrate to produce NO and L-citrulline. In mammals, there are at least 3 NO synthases; endothelial NOS (eNOS), neuronal NOS (nNOS) and inducible NOS (iNOS). eNOS is most stongly expressed in vascular endothelial cells, while nNOS is predominant in neuronal cells and skeletal muscle, but both forms are expressed at lower levels in many cell types (17,47). iNOS is predominantly expressed in leukocytes under normal conditions, but it is also induced in various cells in response to inflammation or other stress signals. eNOS and nNOS produce NO in response to increased cytosolic Ca++ (Ca++-dependent NOS), while iNOS is constitutively active (17,47). NO produced by eNOS, the major isoform in the endothelium, plays a critical role in vascular tone by diffusing into adjacent smooth muscle cells (17,48). NO activates soluble guanylate cyclase, promoting cGMP production, subsequent activation of cGMP dependent protein kinase or Protein Kinase G (PKG). PKG phosphorylates a number of important intracellular targets that cause smooth muscle relaxation and increased blood flow (17,33,48). During heart failure, coronary or systemic vasodilatation in response to agonists or shear stress are attenuated, in part due to decreased vascular NO bioavailability (20,22). NO-cGMP signaling also modulates other vessel related functions including angiogenesis, vascular endothelial cell growth/proliferation, platelet aggregation, and injury repair. Importantly, reduced NO bioavailability contributes to hypertension, coronary disease, atherosclerosis, diabetes, and renal dysfunction, a group of risk factors that promote or exacerbate CHF. NO production is regulated by substrate L-arginine availability (17), NOS protein content and quality, NOS cellular and subcellular distribution, tetrahydrobiopterin (BH4, an essential cofactor for the dimerization of NOS) availability (17), endogenous NOS inhibitors asymmetric dimethylarginine (ADMA) and N-monomethy L-arginine (L-NMMA) (59,77), and the enzyme activity of dimethylarginine dimethylaminohydrolase-1 (DDAH1) (Figure 1) (44,77). ADMA and L-NMMA attenuate NO production by all NOS isoforms (15,16). Here we will briefly review the role of ADMA and DDAH1 in regulating cardiovascular NO production and heart failure development.

Figure 1
ADMA attenuates nitric oxide synthase (NOS)-induced NO/cGMP/PKG signaling and increases NOS derived superoxide anion production in vascular endothelial cells.

NO/cGMP/PKG signaling and CHF development

In addition to the well-established role of NO-cGMP signaling in maintaining normal cardiovascular function, NO protects against cardiac remodeling and dysfunction under stress conditions such as aging (65), myocardial infarction, and pressure overload (58,85). For example, progressive cardiomyocyte hypertrophy, interstitial fibrosis, left ventricular dilation and dysfunction that develops in the surviving tissue after myocardial infarction, are exacerbated in eNOS KO mice as compared to wild type mice (85), while transgenic mice over-expressing eNOS are protected from myocardial infarct-induced left ventricular remodeling, cardiac death, and the development of CHF (29,58,85). eNOS KO also was shown to exacerbate left ventricular dysfunction in response to increase of systemic pressure overload produced by aortic banding (58,84), while cardiomyocyte-restricted restoration of eNOS (over-expressing eNOS in eNOS KO mice) reversed the exacerbated aortic banding-induced ventricular remodeling in eNOS KO mice (13), indicating an important role of NO in maintaining cardiomyocyte function. Over-expression of eNOS also attenuated myocardial infarction induced compensatory hypertrophy and left ventricular failure in comparison to wild type mice (56). The protective effects of NOS signaling are largely attributed to cGMP production and activation of PKG, which targets several proteins involved in cardiac contractility, hypertrophy and remodeling.

Besides promoting cGMP production, NO modulates cardiovascular function by promoting post-translational modification of proteins via S-nitrosylation. For instance, S-nitrosylation of L-type calcium channels reduces ventricular arrhythmias and mortality in mice after myocardial infarction (12), while S-nitrosylation of the ryanodine receptor can reduce diastolic calcium leak (37). S-nitrosylation also regulates G-protein coupled receptor signaling (42) and the stability of PDE5 (107), an enzyme that degrades cGMP to exacerbate heart failure development (70). Thus, NOS influences cardiac signaling and adaptation to stress through both the NO-cGMP pathway and NO dependent S-nitrosylation.

While eNOS and nNOS activity are generally considered cardioprotective, iNOS expression can be detrimental (14,38,114). This is likely due to unmitigated production of NO and superoxides by iNOS uncoupling (6,111,114) resulting in peroxynitrite formation in the inflammatory setting of heart failure and resulting tissue damage (38,78,114). Excessive NO may also promote apoptosis (38) or cardiomyocyte dysfunction (14) through aberrant S-nitrosylation. In addition, under certain conditions, such as oxidative stress (117), when levels of the cofactor tetrahydrobiopterin is limited, or when bioavailability of L-arginine is insufficient, the normally protective effects of NOS signaling can be derailed by NOS “uncoupling”. Under optimal conditions, NOS bound to the co-factor tetrahydrobiopterin forms a homodimer and produces NO using L-arginine as the substrate. In absence of tetrahydrobiopterin, which may be limited under oxidative stress conditions, NOS becomes uncoupled, and NOS monomers produce superoxide rather than NO. We found that both iNOS and eNOS monomers were increased in failing hearts from wild type mice in response to TAC, and this was associated with increased myocardial superoxide production (114). Furthermore, iNOS gene deficiency or the selective iNOS inhibitor 1400W protected the heart against TAC-induced left ventricular failure and oxidative stress (114).

Because NO signaling is often impaired in CHF, strategies to promote cGMP production by pharmacological activation of guanylate cyclase (27,36) or blocking cGMP degradation using cGMP specific phosphodiesterase inhibitors are being examined as potential treatments for CHF (61,70,67,95). While promising results have been obtained through these strategies in animal models, success of these approaches in human trials has been mixed or unknown (11,66). Identification and targeting of NO/cGMP/PKG signal pathway may lead to new treatments for CHF.

Cellular and subcellular localization of eNOS and DDAH1

Because NO diffusion distance is quite limited, the cellular and subcellular distribution of eNOS are important for NO signaling. eNOS is predominantly expressed in vascular endothelial cells, so that the level of eNOS expression in a particular tissue is often related to its vascularity. In the heart, eNOS is not only expressed in vascular endothelial cells, but is also expressed on sarcolemma of cardiomyocytes (17,34). In vascular endothelial cells, eNOS is mainly localized to the plasma membrane and Golgi complexes (35,69,89). Interestingly, the activity of eNOS located at cell membrane is higher than eNOS distributed in Golgi, nucleus and mitochondria (50,55,89,116). The plasma membrane localization of eNOS facilitates diffusion of NO into adjacent smooth muscle cells to regulate vascular tone. In cardiomyocytes, eNOS is predominantly localized to caveolae on the sarcolemma, and also found on Golgi complexes(7,34,114), while nNOS is localized to the sarcoplasmic reticulum. DDAH1, the critical enzyme for ADMA and L-NMMA degradation, is highly abundant in tissues with high nNOS expression such as brain, in tissue removing ADMA (such as kidney, and liver), and in tissues with high eNOS expression (such as lung) (43,101). At least in the heart, the cellular distribution of DDAH1 is similar to eNOS (20). The subcellular distribution of DDAH1 in vascular endothelial cells is not clear, but the subcellular distribution of DDAH1 in cardiomyocytes is similar to subcellular localization of eNOS (20). The similar cellular and subcellular distribution of DDAH1 and eNOS in the heart may facilitate compartmentalized NO production at the plasma membrane of endothelial cells and cardiomyocytes, and also improve overall cardiac NO bioavailability.

Effect of ADMA and L-NMMA on CHF and the common causes of CHF

Endogenous NOS inhibitors ADMA and L-NMMA compete with L-arginine for NOS binding to attenuate NO production (15). As ADMA is more abundant than L-NMMA, most of the studies have focused on the physiological or pathological effects of ADMA in various biological or clinical conditions. By preventing L-arginine binding to NOS, ADMA not only reduces NO formation, but can also promote superoxide formation, similar to L-arginine depletion.

Importantly, ADMA levels are strongly associated with CHF (Figure 2) (31,40,99,112) and the common causes for CHF (Figure 3). For examples, accumulation of ADMA occurs in hypertension (92), coronary disease (8,76,88,91), cardiac valve disease (2), idiopathic cardiomyopathy (3), congenital heart diseases (103), renal failure (54), diabetes (4,67), and atrial fibrillation (18,19) (Figure 3). Elevated plasma ADMA levels are associated with an increased risk for developing angina pectoris, myocardial infarction or cardiac death (9,10). Plasma ADMA level is the strongest predictor of mortality in patients after myocardial infarction (76,88), and a strong and independent predictor of all-cause mortality in the community (9). In addition, studies have shown that infusion of ADMA results in reduced endothelium-dependent coronary vasodilation in pacing induced heart failure dogs (23) and in mice (44) a decrease of cardiac output in normal human subjects (1), and hypertension in mice (44,63). Together, chronic ADMA accumulation may either exacerbate CHF development directly or exacerbate CHF development through increase of cardiovascular risk factors such as hypertension, diabetes, atherosclerosis, coronary disease and renal failue as summarized in Figure 3.

Figure 2
ADMA levels are independent predictors of cardiovascular events in patients with congestive heart failure and the Major Adverse Cardiac Events (MACE).
Figure 3
The proposed mechanism of DDAH1 dysfunction and accumulation of ADMA on the development of congestive heart failure through modulating various cardiovascular risk factors.

Because plasma levels of L-arginine far exceed the levels of plasma ADMA, it has been suggested that ADMA may be a feature of cardiovascular diseases, but does not reach sufficient levels to compete with L-arginine and inhibit NOS. However, ADMA appears to accumulate within cells to a concentration sufficient to impair NOS activity, despite the higher concentration of L-arginine relative to ADMA in plasma (10,15). In addition, chronic infusion of ADMA was reported to increase vascular angiotensin-converting enzyme, oxidative stress, and vessel lesions, suggesting that ADMA can cause vessel injury at least partially through modulating oxidative stress (93). Interestingly, this study also reported that chronic ADMA infusion caused similar increases of vascular angiotensin-converting enzyme, oxidative stress and vessel lesions in eNOS deficient and wild type mice, suggesting that ADMA may exert detrimental effects beyond its disruption of eNOS derived NO production. At the present time, it is unclear whether chronic ADMA accumulation observed in CHF can actually cause or exacerbate the development of myocardial dysfunction or CHF.

While the detailed molecular mechanism for increased ADMA and L-NMMA in various pathological conditions is not clear, there is some evidence that accumulation of ADMA and L-NMMA may result from depressed DDAH1 expression or activity, either through loss-of-function polymorphisms of the DDAH1 gene (104), reduced DDAH1 transcript expression (21), or post-translational modifications such as oxidation of DDAH1 protein. For example, Valkonen et al identified a mutation of the DDAH1 gene that is associated with high plasma ADMA levels and conveys an increased risk for coronary heart disease and an increased prevalence of hypertension (104). DDAH activity is also depressed by oxidized LDL and TNFα (51), high levels of homocysteine in endothelial cells (91), and high plasma glucose in diabetic rats (67). In addition, our previous study showed that mechanical unloading by left ventricular assistant device caused significant decreases of a group of pro-inflammatory cytokines and increase of myocardial DDAH1 mRNA and protein content in left ventricular tissue from patients with severe CHF (21), suggesting that mechanical stresses regulate myocardial DDAH1 protein expression in the failing heart.

ADMA and L-NMMA production and removal

Protein methylation plays an important role in many cellular functions and occurs constitutively in cells. The production of ADMA and L-NMMA is the result of proteolysis of proteins containing methylated arginines (74,81,90). L-NMMA is formed when protein-incorporated L-arginine is methylated by the enzymes protein arginine methyltransferases type I (PRMT-I) or type-II (PRMT-II) (74,81). PRMT-I can subsequently methylate L-NMMA, resulting in the formation of ADMA, whereas PRMT-II can methylate L-NMMA into symmetric dimethylarginine (SDMA) (74,81). Methylated arginines are released as unbound forms in the cytosol then transported into the circulation via system y+-carriers of the cationic amino acid transporter (CAT) family. Similar to L-arginine, ADMA, L-NMMA and SDMA can be taken up by other cells using CAT. Both ADMA and L-NMMA directly compete with L-arginine for the active site of NOS to attenuate NO production. SDMA does not directly inhibit NOS activity, but SDMA could attenuate NOS function indirectly by inhibition of the CAT (24). The strong association between increased ADMA levels and CHF suggests ADMA production may be increased or its removal may be decreased under these conditions. One possible source of increased ADMA is increased protein degradation by autophagy or proteasome activity during tissue remodeling and inflammation associated with cardiovascular diseases. Interestingly, inhibition of proteasome activity in cultured cells reduced free levels of ADMA and SDMA, while inhibition of autophagy only reduced ADMA (100) Both autophagy and proteasome activity are up-regulated during various phases of CHF (106), while protein synthesis is often increased as well, so that protein turnover and subsequent production of ADMA and L-NMMA may also be elevated. However, the contribution and significance of these pathways to ADMA production in CHF is not known.

Once ADMA and L-NMMA are released by proteolysis, they are eliminated from the body in part through renal excretion (1). As ADMA was first isolated from human urine by Kakimoto and Akazawa in 1970 (59), renal excretion was initially recognized as the major route for ADMA elimination. However, a study from McDermott subsequently showed that the urinary recovery of L-NMMA and ADMA following intravenous injection in rabbits was only 0.14% and 5.1%, respectively, indicating that both L-NMMA and ADMA undergo extensive metabolism (75). Ogawa et al further identified an enzyme termed dimethylarginine dimethylaminohydrolase (DDAH, it is currently named as DDAH1) that catalyzes hydrolysis of L-NMMA and ADMA into L–citrulline and mono- or dimethylamine (77). A second DDAH isoform (DDAH2) was reported in 1999 (62). While early studies suggested that both DDAH1 and DDAH2 are effective in degrading ADMA and L-NMMA, we have demonstrated that DDAH1 is the essential or sole enzyme responsible for ADMA degradation in mice and in cultured human endothelial cells (44).

The critical role of DDAH1 in ADMA degradation

As stated above, two DDAH isoforms have been reported. Previous existing concepts regarding tissue or cell specific DDAH1 biology and their function in regulating NO production in various tissues are based on the reports that DDAH1 and DDAH2 have comparable activities for degrading ADMA and L-NMMA (62), as well as the report that DDAH1 is minimally expressed in the heart (62,100), vessels (62) and vascular endothelial cells (5). Accordingly, it was originally accepted that DDAH2 plays the major role in regulating ADMA and L-NMMA levels in the heart and vessels, while DDAH1 plays the major role in degrading ADMA and L-NMMA in neuronal tissues. However, we observed that DDAH activity was totally abolished in all tissues obtained from global DDAH1 deficient mice while the expression of DDAH2 was unaffected in these tissues (43). In other words, tissues obtained from global DDAH1 KO mice are unable to degrade ADMA or NMMA even though DDAH2 expression is not affected (43). Consistent with our findings, Dr. Leiper et al. also demonstrated that DDAH activity was reduced ~50% in tissues obtained from heterozygous DDAH1 KO mice (63). Furthermore, selective gene silencing of DDAH1 (but not DDAH2) caused accumulation of ADMA and decreased NO production in cultured human endothelial cells (43), while over-expression of DDAH1 (but not DDAH2) decreased ADMA content in cultured human endothelial cells (113). These findings clearly indicate that DDAH1 is the critical enzyme for ADMA degradation, while DDAH2 has no detectable role in ADMA degradation in both mouse tissues and human cells.

The important role of DDAH1 in cardiovascular function

DDAH1 plays an important role in regulating cardiovascular function and risk factors of CHF by degrading endogenous NOS inhibitors ADMA and L-NMMA. Thus, DDAH1 gene deficiency causes increases of plasma and tissue ADMA and L-NMMA, which is associated with reduced NO production, moderate hypertension, and endothelial dysfunction (43,44,63). DDAH1 gene deficiency also limits angiogenesis and impairs vascular injury repair (30,113,115). Conversely, over-expression of DDAH1 results in decreases of plasma and tissue ADMA levels, which was associated decrease of systemic blood pressure (28), increase of insulin sensitivity (94), increase of angiogenesis (53,113,115), reduced high fat diet induced atherosclerosis (52,108) and graft coronary artery disease (98). These findings indicate that endogenous ADMA levels are sufficient to alter vascular tone and other tissue functions, and suggest that elevating DDAH1 activity to eliminate ADMA could be a promising strategy for restoring NOS function and increasing NO bioavailability in CHF and other cardiovascular diseases.

While the recent studies clearly show DDAH1 plays the critical role for ADMA and L-NMMA degradation, the significance of endothelial DDAH1 in regulating cardiovascular NO signaling is not totally clear. Using the Tie-2 Cre system, we found that endothelial specific DDAH1 gene deletion caused significant decreases of DDAH1 in vascular tissues, increased tissue and plasma ADMA, reduced acetylcholine induced NO production and vessel dilatation, and resulted in systemic hypertension (43,44), abnormal angiogenesis, and impaired endothelial injury repair (113,115). However, using a similar Tie-2 Cre system, a new endothelial specific DDAH1 strain was shown to have no major effect on systemic ADMA content (30), but significantly attenuated angiogenesis (30). While endothelial specific DDAH1 gene deletion using Tie-2 Cre system attenuated endothelial injury repairs and angiogenesis in both mouse strains, the effect of endothelial DDAH1 gene deletion on systemic blood ADMA was different in these mouse strains. Unfortunately, the causes of the discrepancy of endothelial DDAH1 on systemic blood ADMA between these two endothelial DDAH1 gene deficient strains are not clear at this point.

An important role of kidneys in ADMA metabolism

Kidneys are the organs with highest DDAH1 expression and play an important role in regulating systemic ADMA and L-NMMA. It was reported that less than 20% ADMA was excreted via urine in humans, indicating that over 80% of ADMA is metabolized by DDAH (1). Thus, it is generally believed that ADMA and L-NMMA are eliminated principally by DDAH with a small contribution from renal excretion at least in human. However, gene deletion of DDAH1 (DDAH1 knockout mice has no detectable tissue DDAH activity) causes only ~2 fold increase of plasma ADMA and L-NMMA in mice under control conditions (44), while plasma ADMA and L-NMMA generally increases over 4 fold (increases up to 10 fold) in patients with severe renal failure (10,54). While the dramatic increase of plasma ADMA and L-NMMA in renal failure is likely a combined result of diminished renal ADMA and L-NMMA excretion and decreased degradation by renal DDAH1, these findings clearly indicate that kidneys play a greater role in ADMA and L-NMMA elimination than previously thought. In addition, these data suggest that kidneys may be able to dramatically increase excretion of ADMA and L-NMMA when ADMA and L-NMMA are overloaded in response to DDAH1 dysfunction. Thus, the important role of the kidneys in ADMA and L-NMMA metabolism under stress conditions may have been underestimated by the field.

ADMA enhances NOS-derived O2 and peroxynitrite (ONOO)

Although the most obvious consequence of increased levels of ADMA and L-NMMA is to inhibit NO production, recent reports indicate that the endogenous NOS inhibitors may also cause NOS to generate O2 and peroxynitrite rather than NO (Figure 1). Normally, NOS transfers electrons from NADPH, via the flavins FAD and FMN in the carboxy-terminal reductase domain, to the heme in the amino-terminal oxygenase domain, where the substrate L-arginine is oxidized to L-citrulline and NO. The flow of electrons within NOS is normally tightly regulated. However, when this flow is disrupted, oxygen reduction and NO generation can become uncoupled so that O2 is generated by the oxygenase domain. This uncoupling can occur when NOS is exposed to oxidant stress (including peroxynitrite), when it is deficient in the reducing cofactor BH4 (25,60), or when it is deprived of its substrate L-arginine (110). BH4 is required for iNOS dimerization (6,26) and stabilizes the dimeric forms of eNOS, nNOS and iNOS (6). Thus, BH4 depletion (or oxidation of BH4 to BH2) can induce NOS-derived O2 generation (6,25,96). Deprivation of the substrate L-arginine can also induce NOS to generate O2 and ONOO (110,111,117). Similar to substrate deficiency, several in vitro studies have demonstrated that addition of ADMA or L-NMMA caused O2 generation by purified NOS protein (16,67,78), and also in cultured human endothelial cells (16), isolated arterioles from rat gracilis muscle (100), and in a murine lung epithelial cell line LA-4 (109). In vitro studies have demonstrated that the NOS inhibitor N-monomethyl-L-arginine (L-NMMA) is also capable of inducing NOS uncoupling through multiple mechanisms such as heme loss (78). Importantly, elevated superoxide in cardiomyocytes or endothelial cells can interact with and scavenge NO before it can activate guanylate cyclase to produce cGMP or be utilized for S-nitrosylation, thereby further impairing NO signaling. Reduced NO bioavailability or increased ROS is also known to increase PDE5 activity (70) partially through attenuating PDE5 nitrosylation (107), suggesting further indirect effects of NOS uncoupling on reducing cGMP signaling. ADMA inhibition of NOS, through inhibition of NO production as well as NOS uncoupling and superoxide production, thus acts as a double edged sword in endothelial and cardiomyocyte pathophysiology. Importantly, administration of tetrahydrobiopterin, which prevents NOS uncoupling, can significantly attenuate ROS production, pressure overload induced cardiac hypertrophy and heart failure, indicating that the loss of NO production, as well as increased ROS production that results from NOS uncoupling contributes to CHF (17,57). It is possible that strategies to reduce ADMA levels in conjunction with increasing BH4 may further alleviate NOS dysfunction during CHF. Therefore, identifying methods to increase DDAH1 activity and reduce ADMA levels may be clinically important.

Regulation of DDAH1 expression by farnesoid X receptors (FXR) agonists and ursodeoxycholic acid (UDCA)

UDCA is a major component of bear bile, which has been used for thousands of years in traditional Chinese medicine to treat a variety of illnesses. Endogenous bile acids are produced in the liver and are essential for cholesterol catabolism and intestinal lipid emulsification. In addition to their role as detergents, bile acids play an important role in maintaining lipid and glucose homeostasis through activation of FXR (102) and pregnane X receptors (46). Currently, UDCA is approved by the FDA for treatment of primary biliary cirrhosis (97) and other liver diseases. Importantly, a recent report demonstrated that UDCA, as well as the FXR agonist GW4064 dose dependently increased DDAH1 expression in the liver and lowered plasma ADMA levels through an FXR response element located within the first exon of the DDAH1 gene (41). A separate study by a different group also demonstrated that activation of FXR with GW4064 increased DDAH1 gene expression in the liver and kidney, and decreased plasma ADMA (64). Interestingly, 6 weeks’ UDCA therapy was found to improve endothelium-dependent vasodilatation and arterial blood flow in patients with CHF under conditions of impaired nitric oxide production (91). In addition, a randomized, placebo-controlled clinical trial demonstrated that UDCA significantly improved peak post-ischemic blood flow in the arm (105). It will be important to find out if increased endothelial DDAH1 expression and/or reduction of ADMA levels played a role in the beneficial effects of UDCA observed in these clinical studies.

Bile acids, GW4064, or hepatic expression of constitutively active FXR, have previously been found to significantly lower plasma triglyceride, cholesterol and glucose levels (71,72). Interestingly, genetic disruption of eNOS or nNOS has also been shown to alter lipid metabolism, resulting in increased fat deposition in the liver (86,87). Similarly, FXR gene deletion increased plasma lipid levels (80). While the effects of UDCA on cardiomyocyte DDAH1 expression and NO signaling are unknown, there is evidence that UDCA can attenuate ER stress (79), and apoptosis, which are commonly observed in CHF (68,106). UDCA was also shown to protect against apoptosis in a myocardial ischemia reperfusion injury model (82). These findings suggest UDCA or other FXR agonists could provide a novel approach to increase DDAH1 expression to restore NO signaling in cardiovascular diseases. It will therefore be important to find out whether UDCA activation of FXR induces DDAH1 gene expression in the cardiovascular system or whether this effect is restricted to liver and kidney.


The current scientific literature in the field indicates that the NO/cGMP/PKG signaling pathway plays an important role in attenuating CHF development and/or progression through modulating cardiac perfusion, myocardial contractility and myocardial energy efficiency. ADMA attenuates vascular NO bioavailability in the cardiovascular system, and DDAH1 plays the major role in ADMA degradation to maintain cardiovascular NO/cGMP/PKG signaling. Increased plasma ADMA is one of the strongest predictors of mortality in patients who have had a myocardial infarction or suffer from CHF, and is also an independent risk factor for several other conditions that contribute to CHF development, including hypertension, coronary artery disease/atherosclerosis, diabetes, and renal dysfunction. Together these findings suggest that increasing or maintaining normal DDAH1 expression and/or activity could be an important therapeutic target for improving NO bioavailability in CHF and other cardiovascular diseases.


  • ADMA may exacerbate heart failure development directly.
  • ADMA may exacerbate heart failure through increase of cardiovascular risk factors.
  • DDAH1 plays a critical role in ADMA degradation.


Sources of funding: This study was supported by U.S. Public Health Service Grants HL021872, HL098669, HL098719, HL102597, HL089249, R01HL105406 from the National Institutes of Health, and Research Grants 30500681, 30973845 from National Natural Science Foundation of China.


chronic Heart failure
Asymmetric dimethylarginine
dimethylarginine dimethylaminohydrolase 1
type 1 protein arginine N-methyltransferase
nitric oxide synthesis
inducible NOS
endothelial NOS
protein kinase G
reactive oxygen species
N-monomethy L-arginine
symmetric dimethylarginine
cationic amino acid transporter
farnesoid X receptors
ursodeoxycholic acid


Disclosures: None.

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1. Achan V, Broadhead M, Malaki M, Whitley G, Leiper J, MacAllister R, Vallance P. Asymmetric dimethylarginine causes hypertension and cardiac dysfunction in humans and is actively metabolized by dimethylarginine dimethylaminohydrolase. Arterioscler Thromb Vasc Biol. 2003;23:1455–9. [PubMed]
2. Ali OA, Chapman M, Nguyen TH, Chirkov YY, Heresztyn T, Mundisugih J, Horowitz JD. Interactions between inflammatory activation and endothelial dysfunction selectively modulate valve disease progression in patients with bicuspid aortic valve. Heart. 2014;100:800–5. [PubMed]
3. Anderssohn M, Rosenberg M, Schwedhelm E, Zugck C, Lutz M, Lüneburg N, Frey N, Böger RH. The L-Arginine-asymmetric dimethylarginine ratio is an independent predictor of mortality in dilated cardiomyopathy. J Card Fail. 2012;18:904–11. [PubMed]
4. Anderssohn M, Schwedhelm E, Lüneburg N, Vasan RS, Böger RH. Asymmetric dimethylarginine as a mediator of vascular dysfunction and a marker of cardiovascular disease and mortality: an intriguing interaction with diabetes mellitus. Diab Vasc Dis Res. 2010;7:105–18. [PubMed]
5. Arrigoni FI, Vallance P, Haworth SG, Leiper JM. Metabolism of asymmetric dimethylarginines is regulated in the lung developmentally and with pulmonary hypertension induced by hypobaric hypoxia. Circulation. 2003;107:1195–201. [PubMed]
6. Baek KJ, Thiel BA, Lucas S, Stuehr DJ. Macrophage nitric oxide synthase subunits. Purification, characterization, and role of prosthetic groups and substrate in regulating their association into a dimeric enzyme. J Biol Chem. 1993;268:21120–9. [PubMed]
7. Barouch LA, Harrison RW, Skaf MW, Rosas GO, Cappola TP, Kobeissi ZA, Hobai IA, Lemmon CA, Burnett AL, O’Rourke B, Rodriguez ER, Huang PL, Lima JA, Berkowitz DE, Hare JM. Nitric oxide regulates the heart by spatial confinement of nitric oxide synthase isoforms. Nature. 2002;416:337–9. [PubMed]
8. Boger RH, Bode-Boger SM, Tsao PS, Lin PS, Chan JR, Cooke JP. An endogenous inhibitor of nitric oxide synthase regulates endothelial adhesiveness for monocytes. Journal of the American College of Cardiology. 2000;36:2287–95. [PubMed]
9. Böger RH, Sullivan LM, Schwedhelm E, Wang TJ, Maas R, Benjamin EJ, Schulze F, Xanthakis V, Benndorf RA, Vasan RS. Plasma asymmetric dimethylarginine and incidence of cardiovascular disease and death in the community. Circulation. 2009;119:1592–600. [PMC free article] [PubMed]
10. Böger RH. Asymmetric dimethylarginine, an endogenous inhibitor of nitric oxide synthase, explains the “L-arginine paradox” and acts as a novel cardiovascular risk factor. J Nutr. 2004;134:2842S–7S. [PubMed]
11. Borlaug BA, Lewis GD, McNulty SE, Semigran MJ, LeWinter M, Chen H, Lin G, Deswal A, Margulies KB, Redfield MM. Effects of sildenafil on ventricular and vascular function in heart failure with preserved ejection fraction. Circ Heart Fail. 2015;8:533–41. [PMC free article] [PubMed]
12. Burger DE, Lu X, Lei M, Xiang FL, Hammoud L, Jiang M, Wang H, Jones DL, Sims SM, Feng Q. Neuronal nitric oxide synthase protects against myocardial infarction-induced ventricular arrhythmia and mortality in mice. Circulation. 2009;120:1345–54. [PubMed]
13. Buys ES, Raher MJ, Blake SL, Neilan TG, Graveline AR, Passeri JJ, Llano M, Perez-Sanz TM, Ichinose F, Janssens S, Zapol WM, Picard MH, Bloch KD, Scherrer-Crosbie M. Cardiomyocyte-restricted restoration of nitric oxide synthase 3 attenuates left ventricular remodeling after chronic pressure overload. Am J Physiol Heart Circ Physiol. 2007;293:H620–7. [PubMed]
14. Canton M, Menazza S, Sheeran FL, Polverino de Laureto P, Di Lisa F, Pepe S. Oxidation of myofibrillar proteins in human heart failure. J Am Coll Cardiol. 2011;57:300–9. [PubMed]
15. Cardounel AJ, Cui H, Samouilov A, Johnson W, Kearns P, Tsai AL, Berka V, Zweier JL. Evidence for the pathophysiological role of endogenous methylarginines in regulation of endothelial NO production and vascular function. J Biol Chem. 2007;282:879–87. [PubMed]
16. Cardounel AJ, Xia Y, Zweier JL. Endogenous Methylarginine Modulate Superoxide as Well as Nitric Oxide Generation from Neuronal Nitric-oxide Synthase: Differences In The Effects Of Monomethyl-And Dimethylarginine In The Presence And Absence Of Tetrahydrobiopterin. J Biol Chem. 2005;280:7540–9. [PubMed]
17. Carnicer R, Crabtree MJ, Sivakumaran V, Casadei B, Kass DA. Nitric oxide synthases in heart failure. Antioxid Redox Signal. 2013;18:1078–99. [PMC free article] [PubMed]
18. Cengel A, Sahinarslan A, Biberoğlu G, Hasanoğlu A, Tavil Y, Tulmaç M, Ozdemir M. Asymmetrical dimethylarginine level in atrial fibrillation. Acta Cardiol. 2008;63:33–7. [PubMed]
19. Chao TF, Lu TM, Lin YJ, Tsao HM, Chang SL, Lo LW, Hu YF, Tuan TC, Hsieh MH, Chen SA. Plasma asymmetric dimethylarginine and adverse events in patients with atrial fibrillation referred for coronary angiogram. PLoS One. 2013;8:e71675. [PMC free article] [PubMed]
20. Chen Y, Li Y, Zhang P, Traverse JH, Hou M, Xu X, Kimoto M, Bache RJ. Dimethylarginine dimethylaminohydrolase and endothelial dysfunction in failing hearts. Am J Physiol Heart Circ Physiol. 2005;289:H2212–9. [PubMed]
21. Chen Y, Park S, Li Y, Missov E, Hou M, Han X, Hall JL, Miller LW, Bache RJ. Alterations of gene expression in failing myocardium following left ventricular assist device support. Physiological Genomics. 2003;14:251–260. [PubMed]
22. Chen Y, Traverse JH, Du R, Hou M, Bache RJ. Nitric oxide modulates myocardial oxygen consumption in the failing heart. Circulation. 2002;106:273–9. [PubMed]
23. Chen Y, Traverse JH, Hou M, Li Y, Du R, Bache RJ. Effect of PDE5 inhibition on coronary hemodynamics in pacing-induced heart failure. Am J Physiol Heart Circ Physiol. 2003;284:H1513–20. [PubMed]
24. Closs EI, Basha FZ, Habermeier A, et al. Interference of l-arginine analogues with l-arginine transport mediated by the y + carrier hCAT-2B. Nitric Oxide. 1997;1:65–73. [PubMed]
25. Cosentino F, Patton S, d’Uscio LV, Werner ER, Werner-Felmayer G, Moreau P, Malinski T, Luscher TF. Tetrahydrobiopterin alters superoxide and nitric oxide release in prehypertensiverats. J Clin Invest. 1998;101:1530–7. [PMC free article] [PubMed]
26. Crane BR, Arvai AS, Ghosh DK, Wu C, Getzoff ED, Stuehr DJ, Tainer JA. Structure of nitric oxide synthase oxygenase dimer with pterin and substrate. Science. 1998;279:2121–6. [PubMed]
27. Dasgupta A, Bowman L, D’Arsigny CL, Archer SL. Soluble guanylate cyclase: a new therapeutic target for pulmonary arterial hypertension and chronic thromboembolic pulmonary hypertension. Clin Pharmacol Ther. 2015;97:88–102. [PMC free article] [PubMed]
28. Dayoub H, Achan V, Adimoolam S, Jacobi J, Stuehlinger MC, Wang BY, Tsao PS, Kimoto M, Vallance P, Patterson AJ, Cooke JP. Dimethylargininedimethylaminohydrolase regulates nitric oxide synthesis: genetic and physiological evidence. Circulation. 2003;108:3042–7. [PubMed]
29. deWaard MC, van der Velden J, Boontje NM, Dekkers DH, van Haperen R, Kuster DW, Lamers JM, de Crom R, Duncker DJ. Detrimental effect of combined exercise training and eNOS overexpression on cardiac function after myocardial infarction. Am J Physiol Heart Circ Physiol. 2009;296:H1513–23. [PubMed]
30. Dowsett L, Piper S, Slaviero A, Dufton N, Wang Z, Boruc O, Delahaye M, Colman L, Kalk E, Tomlinson J, Birdsey G, Randi AM, Leiper J. Endothelial DDAH1 is an Important Regulator of Angiogenesis but Does Not Regulate Vascular Reactivity or Hemodynamic Homeostasis. Circulation. 2015;131:2217–25. [PubMed]
31. Dückelmann C, Mittermayer F, Haider DG, Altenberger J, Eichinger J, Wolzt M. Asymmetric dimethylarginine enhances cardiovascular risk prediction in patients with chronic heart failure. Arterioscler Thromb Vasc Biol. 2007;27:2037–42. [PubMed]
32. Emanuel LL, Bonow RO. Care of patients with end-stage heart disease. In: Bonow RO, Mann DL, Zipes DP, Libby P, editors. Braunwald’s Heart Disease: A Textbook of Cardiovascular Medicine. 9. Philadelphia, Pa: Saunders Elsevier; 2011.
33. Feil R, Lohmann SM, de Jonge H, Walter U, Hofmann F. Cyclic GMP-dependent protein kinases and the cardiovascular system: insights from genetically modified mice. Circ Res. 2003;93:907–16. [PubMed]
34. Feron O, Belhassen L, Kobzik L, Smith TW, Kelly RA, Michel T. Endothelial nitric oxide synthase targeting to caveolae. Specific interactions with caveolin isoforms in cardiac myocytes and endothelial cells. J Biol Chem. 1996;271:22810–4. [PubMed]
35. García-Cardeña G, Oh P, Liu J, Schnitzer JE, Sessa WC. Targeting of nitric oxide synthase to endothelial cell caveolae via palmitoylation: implications for nitric oxide signaling. Proc Natl Acad Sci U S A. 1996;93:6448–53. [PubMed]
36. Gheorghiade M, Marti CN, Sabbah H, et al. Soluble guanylate cyclase: a potential therapeutic target for heart failure. Heart Fail Rev. 2013;18:123–34. [PubMed]
37. Gonzalez DR, Treuer AV, Castellanos J, Dulce RA, Hare JM. Impaired S-nitrosylation of the ryanodine receptor caused by xanthine oxidase activity contributes to calcium leak in heart failure. J Biol Chem. 2010;285:28938–45. [PMC free article] [PubMed]
38. Habib FM, Springall DR, Davies GJ, Oakley CM, Yacoub MH, Polak JM. Tumour necrosis factor and inducible nitric oxide synthase in dilated cardiomyopathy. Lancet. 1996;347:1151–5. [PubMed]
39. Heidenreich PA, et al. Forecasting the future of cardiovascular disease in the United States: a policy statement from the American Heart Association. Circulation. 2011;123:933–944. [PubMed]
40. Hsu CP, Lin SJ, Chung MY, Lu TM. Asymmetric dimethylarginine predicts clinical outcomes in ischemic chronic heart failure. Atherosclerosis. 2012;225:504–10. [PubMed]
41. Hu T, Chouinard M, Cox AL, Sipes P, Marcelo M, Ficorilli J, Li S, Gao H, Ryan TP, Michael MD, Michael LF. Farnesoid X receptor agonist reduces serum asymmetric dimethylarginine levels through hepatic dimethylarginine dimethylaminohydrolase-1 gene regulation. J Biol Chem. 2006;281:39831–8. [PubMed]
42. Huang ZM, Gao E, Fonseca FV, Hayashi H, Shang X, Hoffman NE, Chuprun JK, Tian X, Tilley DG, Madesh M, Lefer DJ, Stamler JS, Koch WJ. Convergence of G protein-coupled receptor and S-nitrosylation signaling determines the outcome to cardiac ischemic injury. Sci Signal. 2013;6:ra95. [PMC free article] [PubMed]
43. Hu XL, Atzler D, Xu X, Zhang P, Guo HP, Lu ZB, Fassett J, Schwedhelm E, Böger RH, Bache RJ, Chen YJ. Global Dimethylarginine Dimethylaminohydrolase-1 (DDAH1) Gene-Deficient Mice Reveal That DDAH1 Is the Critical Enzyme for Degrading the Cardiovascular Risk Factor Asymmetrical Dimethylarginine. Arterioscler Thromb Vasc Biol. 2011;31:1540–6. [PMC free article] [PubMed]
44. Hu XL, Xu X, Zhu GB, Atzler D, Kimoto M, Chen J, Schwedhelm E, Luneburg N, Boger RH, Zhang P, Chen YJ. Vascular Endothelial-Specific DimethylarginineDimethylaminohydrolase 1 Deficient Mice Reveal That Vascular Endothelium Plays an Important Role in Removing Asymmetric Dimethylarginine. Circulation. 2009;120:2222–9. [PMC free article] [PubMed]
45. Hunt SA, Abraham WT, Chin MH, et al. ACC/AHA 2005 Guideline Update for the Diagnosis and Management of Chronic Heart Failure in the Adult. Circulation. 2005;112:e154–235. [PubMed]
46. Hylemon PB, Zhou H, Pandak WM, Ren S, Gil G, Dent P. Bile acids as regulatory molecules. J Lipid Res. 2009;50:1509–20. [PMC free article] [PubMed]
47. Ignarro LJ, Napoli C, Loscalzo J. Nitric oxide donors and cardiovascular agents modulating the bioactivity of nitric oxide: an overview. Circ Res. 2002;90:21–8. [PubMed]
48. Ignarro LJ. Nitric oxide as a unique signaling molecule in the vascular system: a historical overview. J Physiol Pharmacol. 2002;53(4 Pt 1):503–14. [PubMed]
49. Ikegami T, Matsuzaki Y. Ursodeoxycholic acid: mechanism of action and novel clinical applications. Hepatol Res. 2008;38:123–31. [PubMed]
50. Iwakiri Y, Satoh A, Chatterjee S, Toomre DK, Chalouni CM, Fulton D, Groszmann RJ, Shah VH, Sessa WC. Nitric oxide synthase generates nitric oxide locally to regulate compartmentalized protein S-nitrosylation and protein trafficking. Proc Natl Acad Sci U S A. 2006;103:19777–82. [PubMed]
51. Ito A, Tsao PS, Adimoolam S, Kimoto M, Ogawa T, Cooke JP. Novel mechanism for endothelial dysfunction: dysregulation of dimethylarginine dimethylaminohydrolase. Circulation. 1999;99:3092–5. [PubMed]
52. Jacobi J, Maas R, Cardounel AJ, Arend M, Pope AJ, Cordasic N, Heusinger-Ribeiro J, Atzler D, Strobel J, Schwedhelm E, Böger RH, Hilgers KF. Dimethylarginine dimethylaminohydrolase overexpression ameliorates atherosclerosis in apolipoprotein E-deficient mice by lowering asymmetric dimethylarginine. Am J Pathol. 2010;176:2559–70. [PubMed]
53. Jacobi J, Sydow K, von Degenfeld G, Zhang Y, Dayoub H, Wang B, Patterson AJ, Kimoto M, Blau HM, Cooke JP. Overexpression of dimethylarginine dimethylaminohydrolase reduces tissue asymmetric dimethylarginine levels and enhances angiogenesis. Circulation. 2005;111:1431–8. [PubMed]
54. Jacobi J, Tsao PS. Asymmetrical dimethylarginine in renal disease: limits of variation or variation limits? A systematic review. Am J Nephrol. 2008;28:224–37. [PMC free article] [PubMed]
55. Jagnandan D, Sessa WC, Fulton D. Intracellular location regulates calcium-calmodulin-dependent activation of organelle-restricted eNOS. Am J Physiol Cell Physiol. 2005;289:C1024–33. [PubMed]
56. Janssens S, Pokreisz P, Schoonjans L, Pellens M, Vermeersch P, Tjwa M, Jans P, Scherrer-Crosbie M, Picard MH, Szelid Z, Gillijns H, Van de Werf F, Collen D, Bloch KD. Cardiomyocyte-specific overexpression of nitric oxide synthase 3 improves left ventricular performance and reduces compensatory hypertrophy after myocardial infarction. Circ Res. 2004;94:1256–62. [PubMed]
57. Jeong EM, Monasky MM, Gu L, Taglieri DM, Patel BG, Liu H, Wang Q, Greener I, Dudley SC, Jr, Solaro RJ. Tetrahydrobiopterin improves diastolic dysfunction by reversing changes in myofilament properties. J Mol Cell Cardiol. 2013;56:44–54. [PMC free article] [PubMed]
58. Jones SP, Greer JJ, van Haperen R, Duncker DJ, de Crom R, Lefer DJ. Endothelial nitric oxide synthase overexpression attenuates congestive heart failure in mice. Proc Natl Acad Sci U S A. 2003;100:4891–6. [PubMed]
59. Kakimoto Y, Akazawa S. Isolation and identification of N-G,N-G- and N-G,N’-G-dimethyl-arginine, N-epsilon-mono-, di-, and trimethyllysine, and glucosylgalactosyl- and galactosyl-delta-hydroxylysine from human urine. J Biol Chem. 1970;245:5751–8. [PubMed]
60. Landmesser U, Dikalov S, Price SR, McCann L, Fukai T, Holland SM, Mitch WE, Harrison DG. Oxidation of tetrahydrobiopterin leads to uncoupling of endothelial cell nitric oxide synthase in hypertension. J Clin Invest. 2003;111:1201–9. [PMC free article] [PubMed]
61. Lee DI, Zhu G, Sasaki T, Cho GS, Hamdani N, Holewinski R, Jo SH, Danner T, Zhang M, Rainer PP, Bedja D, Kirk JA, Ranek MJ, Dostmann WR, Kwon C, Margulies KB, Van Eyk JE, Paulus WJ, Takimoto E, Kass DA. Phosphodiesterase 9A controls nitric-oxide-independent cGMP and hypertrophic heart disease. Nature. 2015;519:472–6. [PMC free article] [PubMed]
62. Leiper JM, Santa Maria J, Chubb A, MacAllister RJ, Charles IG, Whitley GS, Vallance P. Identification of two human dimethylarginine dimethylaminohydrolases with distinct tissue distributions and homology with microbial arginine deiminases. Biochem J. 1999;343:209–214. [PubMed]
63. Leiper J, Nandi M, Torondel B, Murray-Rust J, Malaki M, O’hara B, Rossiter S, Anthony S, Madhani M, Selwood D, Smith C, Wojciak-Stothard B, Rudiger A, Stidwill R, McDonald NQ, Vallance P. Disruption of methylarginine metabolism impairs vascular homeostasis. Nat Med. 2007;13:198–203. [PubMed]
64. Li J, Wilson A, Gao X, Kuruba R, Liu Y, Poloyac S, Pitt B, Xie W, Li S. Coordinated Regulation of Dimethylarginine Dimethylaminohydrolase-1 and Cationic Amino Acid Transporter-1 by Farnesoid X Receptor in Mouse Liver and Kidney and Its Implication in the Control of Blood Levels of Asymmetric Dimethylarginine. J Pharmacol Exp Ther. 2009;331:234–43. [PubMed]
65. Li W, Mital S, Ojaimi C, Csiszar A, Kaley G, Hintze TH. Premature death and age-related cardiac dysfunction in male eNOS-knockout mice. J Mol CellCardiol. 2004;37:671–80. [PubMed]
66. Lindman BR, Dávila-Román VG, Mann DL, McNulty S, Semigran MJ, Lewis GD, de las Fuentes L, Joseph SM, Vader J, Hernandez AF, Redfield MM. Cardiovascular phenotype in HFpEF patients with or without diabetes: a RELAX trial ancillary study. J Am Coll Cardiol. 2014;64:541–9. [PMC free article] [PubMed]
67. Lin KY, Ito A, Asagami T, Tsao PS, Adimoolam S, Kimoto M, Tsuji H, Reaven GM, Cooke JP. Impaired nitric oxide synthase pathway in diabetes mellitus: role of asymmetric dimethylarginine and dimethylarginine dimethylaminohydrolase. Circulation. 2002;106:987–92. [PubMed]
68. Liu X, Kwak D, Lu Z, Xu X, Fassett J, Wang H, Wei Y, Cavener DR, Hu X, Hall J, Bache RJ, Chen Y. Endoplasmic reticulum stress sensor protein kinase R-like endoplasmic reticulum kinase (PERK) protects against pressure overload-induced heart failure and lung remodeling. Hypertension. 2014;64:738–44. [PMC free article] [PubMed]
69. Liu J, García-Cardeña G, Sessa WC. Palmitoylation of endothelial nitric oxide synthase is necessary for optimal stimulated release of nitric oxide: implications for caveolae localization. Biochemistry. 1996;35:13277–81. [PubMed]
70. Lu Z, Xu X, Hu X, Lee S, Traverse JH, Zhu G, Fassett J, Tao Y, Zhang P, Hall JL, dos Remedios C, Garry DJ, Chen Y. Oxidative stress regulates left ventricular PDE5 expression in the failing heart. Circulation. 2010;121:1474–83. [PMC free article] [PubMed]
71. Ma K, Saha PK, Chan L, Moore DD. Farnesoid X receptor is essential for normal glucose homeostasis. J Clin Invest. 2006;116:1102–09. [PubMed]
72. Maloney PR, Parks DJ, Haffner CD, Fivush AM, Chandra G, Plunket KD, Creech KL, Moore LB, Wilson JG, Lewis MC, Jones SA, Willson TM. Identification of a chemical tool for the orphan nuclear receptor FXR. Journal of Medicinal Chemistry. 2000;43:2971–4. [PubMed]
73. Mant J, Al-Mohammad A, Swain S, Laramée P. Guideline Development Group. Management of chronic heart failure in adults: synopsis of the National Institute For Health and clinical excellence guideline. Ann Intern Med. 2011;155(4):252–9. [PubMed]
74. McBride AE, Silver PA. State of the arg: protein methylation at arginine comes of age. Cell. 2001;106:5–8. [PubMed]
75. McDermott JR. Studies on the catabolism of Ng-methylarginine, Ng, Ng-dimethylarginine and Ng, Ng-dimethylarginine in the rabbit. Biochem J. 1976;154:179–84. [PubMed]
76. Nicholls SJ, Wang Z, Koeth R, Levison B, DelFraino B, Dzavik V, Griffith OW, Hathaway D, Panza JA, Nissen SE, Hochman JS, Hazen SL. Metabolic profiling of arginine and nitric oxide pathways predicts hemodynamic abnormalities and mortality in patients with cardiogenic shock after acute myocardial infarction. Circulation. 2007;116:2315–24. [PubMed]
77. Ogawa T, Kimoto M, Sasaoka K. Occurrence of a new enzyme catalyzing the direct conversion of NG,NG-dimethyl-L-arginine to L-citrulline in rats. Biochem Biophys Res Commun. 1987;148:671–7. [PubMed]
78. Olken NM, Osawa Y, Marletta MA. Characterization of the inactivation of nitric oxide synthase by NG-methyl-L-arginine: evidence for heme loss. Biochemistry. 1994;33:14784–91. [PubMed]
79. Ozcan U, Yilmaz E, Ozcan L, Furuhashi M, Vaillancourt E, Smith RO, Gorgun CZ, Hotamisligil GS. Chemical chaperones reduce ER stress and restore glucose homeostasis in a mouse model of type 2 diabetes. Science. 2006;313:1137–40. [PMC free article] [PubMed]
80. Parks DJ, Blanchard SG, Bledsoe RK, Chandra G, Consler TG, Kliewer SA, Stimmel JB, Willson TM, Zavacki AM, Moore DD, Lehmann JM. Bile acids: natural ligands for an orphan nuclear receptor. Science. 1999;284:1365–8. [PubMed]
81. Pope AJ, Karuppiah K, Cardounel AJ. Role of the PRMT-DDAH-ADMA axis in the regulation of endothelial nitric oxide production. Pharmacol Res. 2009;60:461–5. [PMC free article] [PubMed]
82. Rajesh KG, Suzuki R, Maeda H, Yamamoto M, Yutong X, Sasaguri S. Hydrophilic bile salt ursodeoxycholic acid protects myocardium against reperfusion injury in a PI3K/Akt dependent pathway. J Mol Cell Cardiol. 2005;39:766–76. [PubMed]
83. Roger VL, et al. Heart disease and stroke statistics--2012 update: a report from the American Heart Association. Circulation. 2012;125:e2–e220. [PMC free article] [PubMed]
84. Ruetten H, Dimmeler S, Gehring D, Ihling C, Zeiher AM. Concentric left ventricular remodeling in endothelial nitric oxide synthase knockout mice by chronic pressure overload. Cardiovascular research. 2005;66:444–53. [PubMed]
85. Scherrer-Crosbie M, Ullrich R, Bloch KD, Nakajima H, Nasseri B, Aretz HT, Lindsey ML, Vançon AC, Huang PL, Lee RT, Zapol WM, Picard MH. Endothelial nitric oxide synthase limits left ventricular remodeling after myocardial infarction in mice. Circulation. 2001;104:1286–91. [PubMed]
86. Schild L, Dombrowski F, Lendeckel U, Schulz C, Gardemann A, Keilhoff G. Impairment of endothelial nitric oxide synthase causes abnormal fat and glycogen deposition in liver. Biochim Biophys Acta. 2008;1782:180–7. [PubMed]
87. Schild L, Jaroscakova I, Lendeckel U, Wolf G, Keilhoff G. Neuronal nitric oxide synthase controls enzyme activity pattern of mitochondria and lipid metabolism. FASEB J. 2006;20:145–7. [PubMed]
88. Schnabel R, Blankenberg S, Lubos E, Lackner KJ, Rupprecht HJ, Espinola-Klein C, Jachmann N, Post F, Peetz D, Bickel C, Cambien F, Tiret L, Münzel T. Asymmetric dimethylarginine and the risk of cardiovascular events and death in patients with coronary artery disease: results from the Athero Gene Study. Circ Res. 2005;97:e53–9. [PubMed]
89. Sessa WC, García-Cardeña G, Liu J, Keh A, Pollock JS, Bradley J, Thiru S, Braverman IM, Desai KM. The Golgi association of endothelial nitric oxide synthase is necessary for the efficient synthesis of nitric oxide. J Biol Chem. 1995;270:17641–4. [PubMed]
90. Shirakawa T, Kako K, Shimada T, Nagashima Y, Nakamura A, Ishida J, Fukamizu A. Production of free methylarginines via the proteasome and autophagy pathways in cultured cells. Mol Med Rep. 2011;4:615–20. [PubMed]
91. Sinisalo J, Vanhanen H, Pajunen P, Vapaatalo H, Nieminen MS. Ursodeoxycholic acid and endothelial-dependent, nitric oxide-independent vasodilatation of forearm resistance arteries in patients with coronary heart disease. Br J Clin Pharmacol. 1999;47:661–5. [PMC free article] [PubMed]
92. Surdacki A, Nowicki M, Sandmann J, Tsikas D, Boeger RH, Bode-Boeger SM, Kruszelnicka-Kwiatkowska O, Kokot F, Dubiel JS, Froelich JC. Reduced urinary excretion of nitric oxide metabolites and increased plasma levels of asymmetric dimethylarginine in men with essential hypertension. J Cardiovasc Pharmacol. 1999;33:652–8. [PubMed]
93. Suda O, Tsutsui M, Morishita T, Tasaki H, Ueno S, Nakata S, Tsujimoto T, Toyohira Y, Hayashida Y, Sasaguri Y, Ueta Y, Nakashima Y, Yanagihara N. Asymmetric dimethylarginine produces vascular lesions in endothelial nitric oxide synthase-deficient mice: involvement of renin-angiotensin system and oxidative stress. Arterioscler Thromb Vasc Biol. 2004;24:1682–8. [PubMed]
94. Sydow K, Mondon CE, Schrader J, Konishi H, Cooke JP. Dimethylargininedimethylaminohydrolase overexpression enhances insulin sensitivity. Arterioscler Thromb Vasc Biol. 2008;28:692–7. [PMC free article] [PubMed]
95. Takimoto E, Champion HC, Li M, Belardi D, Ren S, Rodriguez ER, Bedja D, Gabrielson KL, Wang Y, Kass DA. Chronic inhibition of cyclic GMP phosphodiesterase 5A prevents and reverses cardiac hypertrophy. Nat Med. 2005;11:214–22. [PubMed]
96. Takimoto E, Champion HC, Li M, Ren S, Rodriguez ER, Tavazzi B, Lazzarino G, Paolocci N, Gabrielson KL, Wang Y, Kass DA. Oxidant stress from nitric oxide synthase-3 uncoupling stimulates cardiac pathologic remodeling from chronic pressure load. J Clin Invest. 2005;115:1221–31. [PubMed]
97. Talwalkar JA, Lindor KD. Primary biliary cirrhosis. Lancet. 2003;362:53–61. [PubMed]
98. Tanaka M, Sydow K, Gunawan F, Jacobi J, Tsao PS, Robbins RC, Cooke JP. Dimethylarginine dimethylaminohydrolase overexpression suppresses graft coronary artery disease. Circulation. 2005;112:1549–56. [PubMed]
99. Tang WH, Tong W, Shrestha K, Wang Z, Levison BS, Delfraino B, Hu B, Troughton RW, Klein AL, Hazen SL. Differential effects of arginine methylation on diastolic dysfunction and disease progression in patients with chronic systolic heart failure. Eur Heart J. 2008;29:2506–13. [PMC free article] [PubMed]
100. Toth J, Racz A, Kaminski PM, Wolin MS, Bagi Z, Koller A. Asymmetrical Dimethylarginine Inhibits Shear Stress-Induced Nitric Oxide Release and Dilation and Elicits Superoxide-Mediated Increase in Arteriolar Tone. Hypertension. 2007;49:563–8. [PubMed]
101. Tran CT, Fox MF, Vallance P, Leiper JM. Chromosomal localization, gene structure, and expression pattern of DDAH1: comparison with DDAH2 and implications for evolutionary origins. Genomics. 2000;68:101–105. [PubMed]
102. Trauner M, Claudel T, Fickert P, Moustafa T, Wagner M. Bile acids as regulators of hepatic lipid and glucose metabolism. Dig Dis. 2010;28:220–4. [PubMed]
103. Tutarel O, Denecke A, Bode-Böger SM, Martens-Lobenhoffer J, Lovric S, Bauersachs J, Schieffer B, Westhoff-Bleck M, Kielstein JT. Asymmetrical dimethylarginine--more sensitive than NT-proBNP to diagnose heart failure in adults with congenital heart disease. PLoS One. 2012;7:e33795. [PMC free article] [PubMed]
104. Valkonen V-P, Tuomainen T-P, Laaksonen R. DDAH gene and cardiovascular risk. Vascular Medicine. 2005;10:45–8. [PubMed]
105. vonHaehling S, Schefold JC, Jankowska EA, Springer J, Vazir A, Kalra PR, Sandek A, Fauler G, Stojakovic T, Trauner M, Ponikowski P, Volk HD, Doehner W, Coats AJ, Poole-Wilson PA, Anker SD. Ursodeoxycholic acid in patients with chronic heart failure: a double-blind, randomized, placebo-controlled, crossover trial. J Am Coll Cardiol. 2012;59:585–92. [PubMed]
106. Wang X, Robbins J. Proteasomal and lysosomal protein degradation and heart disease. J Mol Cell Cardiol. 2014;71:16–24. [PMC free article] [PubMed]
107. Wang Y, Zhang P, Xu Z, Yue W, Zhuang Y, Chen Y, Lu Z. S-nitrosylation of PDE5 increases its ubiquitin-proteasomal degradation. Free Radic Biol Med. 2015;86:343–51. [PubMed]
108. Weis M, Kledal TN, Lin KY, Panchal SN, Gao SZ, Valantine HA, Mocarski ES, Cooke JP. Cytomegalovirus infection impairs the nitric oxide synthase pathway: role of asymmetric dimethylarginine in transplant arteriosclerosis. Circulation. 2004;109:500–5. [PubMed]
109. Wells SM, Holian A. Asymmetric dimethylarginine induces oxidative and nitrosative stress in murine lung epithelial cells. Am J Respir Cell Mol Biol. 2007;36:520–8. [PMC free article] [PubMed]
110. Xia Y, Dawson VL, Dawson TM, Snyder SH, Zweier JL. Nitric oxide synthase generates superoxide and nitric oxide in arginine-depleted cells leading to peroxynitrite-mediated cellular injury. Proc Natl Acad Sci U S A. 1996;93:6770–4. [PubMed]
111. Xia Y, Zweier JL. Superoxide and peroxynitrite generation from inducible nitric oxide synthase in macrophages. Proc Natl Acad Sci U S A. 1997;94:6954–8. [PubMed]
112. Zairis MN, Patsourakos NG, Tsiaousis GZ, TheodossisGeorgilas A, Melidonis A, Makrygiannis SS, Velissaris D, Batika PC, Argyrakis KS, Tzerefos SP, Prekates AA, Foussas SG. Plasma asymmetric dimethylarginine and mortality in patients with acute decompensation of chronic heart failure. Heart. 2012;98:860–4. [PubMed]
113. Zhang P, Xu X, Hu X, Wang H, Fassett J, Huo Y, Chen Y, Bache RJ. DDAH1 deficiency attenuates endothelial cell cycle progression and angiogenesis. PLoS One. 2013;8:e79444. [PMC free article] [PubMed]
114. Zhang P, Xu X, Hu X, van Deel ED, Zhu G, Chen Y. Inducible nitric oxide synthase deficiency protects the heart from systolic overload-induced ventricular hypertrophy and congestive heart failure. Circ Res. 2007;100:1089–98. [PMC free article] [PubMed]
115. Zhang P, Hu XL, Xu X, Chen YJ, Bache RJ. Dimethylarginine dimethylaminohydrolase 1 modulates endothelial cell growth through nitric oxide and Akt. Arterioscler Thromb Vasc Biol. 2011;31:890–7. [PMC free article] [PubMed]
116. Zhang Q, Church JE, Jagnandan D, Catravas JD, Sessa WC, Fulton D. Functional relevance of Golgi- and plasma membrane-localized endothelial NO synthase in reconstituted endothelial cells. Arterioscler Thromb Vasc Biol. 2006;26:1015–21. [PubMed]
117. Zou MH, Shi C, Cohen RA. Oxidation of the zinc-thiolate complex and uncoupling of endothelial nitric oxide synthase by peroxynitrite. J Clin Invest. 2002;109:817–26. [PMC free article] [PubMed]