Ambulatory blood pressure monitoring (ABPM) has greater predictive value than office blood pressure (BP) with respect to hypertension-related target-organ damage and morbidity. ABPM in a subset of 80 patients from the Exforge Target Achievement trial (N= 728) was used to compare the efficacy of intensive-treatment and moderate-treatment regimens of amlodipine/valsartan, and to determine whether treatment differences could be better assessed with ABPM than with office or home BP. Home BP was measured on the morning of clinic visits to minimize differences that timing might have on home versus office BP measures.
A 12-week randomized, double-blind study in which hypertensive patients earlier uncontrolled (mean sitting systolic BP≥150 and <200 mmHg) on angiotensin receptor blocker monotherapy (other than valsartan) after 28 days or more (N=728) were randomized to amlodipine/valsartan treatment [10/320mg (intensive) or 5/160mg (moderate)]. Treatment-naive patients (in previous 28 days) or patients who failed on a nonangiotensin receptor blocker agent underwent a 28-day run-in period with a 20-mg or 40-mg dose of olmesartan, respectively.
Significantly greater 24-h ABP reductions from baseline to week 4 (primary time point) were observed with intensive versus moderate treatment (least-square mean systolic/diastolic BP reduction of −16.2/ −10.1 vs. −9.5/−6.5 mmHg; P=0.0024/P=0.010 for least-square mean difference). Similarly, a significantly greater proportion of patients receiving an intensive treatment achieved ambulatory BP goal (<130/80 mmHg) at week 4 than did those receiving a moderate treatment (P=0.040). Treatment-group differences did not reach statistical significance for these end points when measured by office and home BP.
In this first randomized trial evaluating the effects of intensive versus moderate dosing of the combination of amlodipine/valsartan, our data suggest that ABPM was a better method for assessing between-treatment differences than clinic or home BP recordings, although measurement of home BP as a single recording was a limitation of our trial.
ambulatory blood pressure monitoring; amlodipine; combination therapy; hydrochlorothiazide; hypertension; valsartan
Combination therapy may reduce racial/ethnic differences in response to antihypertensives. In this post-hoc analysis, we evaluated treatment response by race/ethnicity among hypertensive adults enrolled in a 12-week, double-blind study in which patients previously uncontrolled (mean sitting systolic blood pressure [MSSBP] ≥150 and <200 mm Hg) on angiotensin receptor blocker (ARB) monotherapy (other than valsartan) for 28 days or more (n = 728) were randomized to amlodipine/valsartan 10/320 mg (intensive) or 5/160 mg (moderate). Treatment-naïve patients (in previous 28 days) or those who failed on a non-ARB first underwent a 28-day run-in period with olmesartan 20 mg or 40 mg, respectively. Hydrochlorothiazide (HCTZ) 12.5 mg was added to both arms at week 4; optional up-titration to 25 mg at week 8 (if MSSBP >140 mm Hg). Intensive treatment provided greater BP lowering versus moderate treatment throughout the study, regardless of race/ethnicity (474 white, 198 African American, 165 Hispanic individuals). Least-square mean reductions from baseline to week 4 in MSSBP (primary outcome) ranged from 20.4 to 23.5 mm Hg (intensive) versus 17.5 to 19.0 mm Hg (moderate), across racial/ethnic subgroups. Both regimens were well tolerated. Amlodipine/valsartan/HCTZ combination therapy was efficacious across racial/ethnic subgroups. Maximal efficacy was obtained with intensive treatment.
Racial differences; combination therapy
Two-thirds of adults in the U.S. are overweight or obese, and another 26 million have type 2 diabetes (T2D). Patients with diabetes and/or the metabolic syndrome have a significantly increased risk of heart attack and stroke compared with people with normal insulin sensitivity. Decreased insulin sensitivity in cardiovascular tissues as well as in traditional targets of insulin metabolic signaling, such as skeletal muscle, is an underlying abnormality in obesity, hypertension, and T2D. In the vasculature, insulin signaling plays a critical role in normal vascular function via endothelial cell nitric oxide production and modulation of Ca2+ handling and sensitivity in vascular smooth muscle cells. Available evidence suggests that impaired vascular insulin sensitivity may be an early, perhaps principal, defect of vascular function and contributor to the pathogenesis of vascular disease in persons with obesity, hypertension, and T2D. In the overweight and obese individual, as well as in persons with hypertension, systemic and vascular insulin resistance often occur in concert with elevations in plasma aldosterone. Indeed, basic and clinical studies have demonstrated that elevated plasma aldosterone levels predict the development of insulin resistance and that aldosterone directly interferes with insulin signaling in vascular tissues. Furthermore, elevated plasma aldosterone levels are associated with increased heart attack and stroke risk. Conversely, renin–angiotensin–aldosterone system and mineralocorticoid receptor (MR) antagonism reduces cardiovascular risk in these patient populations. Recent and accumulating evidence in this area has implicated excessive Ser phosphorylation and proteosomal degradation of the docking protein, insulin receptor substrate, and enhanced signaling through hybrid insulin/IGF-1 receptor as important mechanisms underlying aldosterone-mediated interruption of downstream vascular insulin signaling. Prevention or restoration of these changes via blockade of aldosterone action in the vascular wall with MR antagonists (i.e., spironolactone, eplerenone) may therefore account for the clinical benefit of these compounds in obese and diabetic patients with cardiovascular disease. This review will highlight recent evidence supporting the hypothesis that aldosterone and MR signaling represent an ideal candidate pathway linking early promoters of diabetes, especially overnutrition and obesity, to vascular insulin resistance, dysfunction, and disease.
Insulin resistance and associated reductions in cardiac insulin metabolic signaling is emerging as a major factor for the development of heart failure and assumes more importance because of an epidemic increase in obesity and the cardiorenal metabolic syndrome and our aging population. Major factors contributing to the development of cardiac insulin resistance are oxidative stress, hyperglycemia, hyperlipidemia, dysregulated secretion of adipokines/cytokines and inappropriate activation of renin-angiotensin II-aldosterone system (RAAS) and the sympathetic nervous system. The effects of cardiac insulin resistance are exacerbated by metabolic, endocrine and cytokine alterations associated with systemic insulin resistance. The aggregate of these various alterations leads to an insulin resistant phenotype with metabolic inflexibility, impaired calcium handling, mitochondrial dysfunction and oxidative stress, dysregulated myocardial-endothelial interactions resulting in energy deficiency, impaired diastolic dysfunction, myocardial cell death and cardiac fibrosis. Therefore, understanding the molecular mechanisms linking insulin resistance and heart failure may help to design new and more effective mechanism-based drugs to improve myocardial and systemic insulin resistance.
Cardiac insulin resistance; cardiorenal metabolic syndrome
A clinical trial showed comparable blood pressure (BP) lowering by valsartan/hydrochlorothiazide and amlodipine/hydrochlorothiazide in obese hypertensives. Relative to amlodipine/hydrochlorothiazide, valsartan/hydrochlorothiazide reduced the hyperglycemic response to glucose challenge. An objective of this post-hoc analysis was to determine whether this benefit extended to African Americans and Caucasians. Treatments (valsartan/hydrochlorothiazide 160/12.5 mg force-titrated to valsartan/hydrochlorothiazide 320/25 mg at Week 4 or hydrochlorothiazide 12.5 mg force-titrated to hydrochlorothiazide 25 mg at Week 4 with amlodipine 5 mg and 10 mg added at Weeks 8 and 12, respectively) were administered once daily. Both treatments reduced clinic BP from baseline to all visits (p<0.0001), regardless of race/ethnicity (126 African Americans, 212 Caucasians). In African Americans, there were no significant between-treatment differences in clinic or ambulatory BP lowering at Weeks 8 or 16. Caucasians responded better to valsartan/hydrochlorothiazide. In both racial/ethnic subgroups, the addition of valsartan but not amlodipine mitigated the hyperglycemic response to hydrochlorothiazide through enhanced insulin secretion. Valsartan/hydrochlorothiazide was as effective as amlodipine/hydrochlorothiazide in reducing BP in obese, hypertensive African Americans, and better than amlodipine/hydrochlorothiazide in Caucasians. In both racial/ethnic subgroups, addition of valsartan to hydrochlorothiazide reduced the negative metabolic effects associated with thiazide therapy.
valsartan; hydrochlorothiazide; diuretic; prediabetic; obesity
Cardiovascular disease, which accounts for the highest morbidity and mortality in the United States, has several major risk factors, including aging and diabetes. Overweight and obesity, especially abdominal obesity, have been increasingly implicated as independent risk factors in the development of cardiovascular disease. Metabolic and/or diabetic cardiomyopathy has been especially associated with excess body weight caused by chronic over-nutrition and high-fat feeding. In the initial stages, obesity is now understood to cause significant dysregulation of cardiac fatty acid and glucose metabolism. These abnormalities are due, in part, to increased oxidative stress, which in turn can cause deleterious effects on intracellular signaling pathways that control cellular growth and proliferation. This increase in oxidative stress is coupled with reduced anti-oxidant species and dysregulation of metabolic signaling pathways. The cardiomyopathy seen with obesity is associated with increased interstitial fibrosis and diastolic dysfunction. Over time, evolving abnormalities include hypertrophy and systolic dysfunction, eventually leading to heart failure.
insulin; metabolic; signaling; heart
Recent data implicate oxidative stress as a mediator of pulmonary hypertension (PH) and of the associated pathological changes to the pulmonary vasculature and right ventricle (RV). Increases in reactive oxygen species (ROS), altered redox state, and elevated oxidant stress have been demonstrated in the lungs and RV of several animal models of PH, including chronic hypoxia, monocrotaline toxicity, caveolin-1 knock-out mouse, and the transgenic Ren2 rat which overexpresses the mouse renin gene. Generation of ROS in these models is derived mostly from the activities of the nicotinamide adenine dinucleotide phosphate oxidases, xanthine oxidase, and uncoupled endothelial nitric oxide synthase. As disease progresses circulating monocytes and bone marrow-derived monocytic progenitor cells are attracted to and accumulate in the pulmonary vasculature. Once established, these inflammatory cells generate ROS and secrete mitogenic and fibrogenic cytokines that induce cell proliferation and fibrosis in the vascular wall resulting in progressive vascular remodeling. Deficiencies in antioxidant enzymes also contribute to pulmonary hypertensive states. Current therapies were developed to improve endothelial function, reduce pulmonary artery pressure, and slow the progression of vascular remodeling in the pulmonary vasculature by targeting deficiencies in either NO (PDE-type 5 inhibition) or PGI2 (prostacyclin analogs), or excessive synthesis of ET-1 (ET receptor blockers) with the intent to improve patient clinical status and survival. New therapies may slow disease progression to some extent, but long term management has not been achieved and mortality is still high. Although little is known concerning the effects of current pulmonary arterial hypertension treatments on RV structure and function, interest in this area is increasing. Development of therapeutic strategies that simultaneously target pathology in the pulmonary vasculature and RV may be beneficial in reducing mortality associated with RV failure.
Pulmonary arterial hypertension; Rosuvastatin; Oxidative stress; Nicotinamide adenine dinucleotide phosphate oxidase; Statins
Angiotensin receptor (type 1) blockers (ARBs) can reduce both hypertension and insulin resistance induced by local and systemic activation of the renin-angiotensin-aldosterone system. The effectiveness of azilsartan medoxomil (AZIL-M), a novel imidazole-based ARB, to facilitate metabolic improvements in conditions of angiotensin II (Ang II)-associated insulin resistance is currently unknown. The aim of this study was to determine the impact of chronic AZIL-M treatment on glucose transport activity and key insulin signaling elements in red skeletal muscle of Ang II-treated rats. Male Sprague-Dawley rats were treated for 8 weeks with or without Ang II (200 ng/kg/min) combined with either vehicle or AZIL-M (1 mg/kg/day). Ang II induced significant (p < 0.05) increases in blood pressure, which were completely prevented by AZIL-M. Furthermore, Ang II reduced insulin-mediated glucose transport activity in incubated soleus muscle, and AZIL-M co-treatment increased this parameter. Moreover, AZIL-M treatment of Ang II-infused animals increased the absolute phosphorylation of insulin signaling molecules, including Akt [both Ser473 (81%) and Thr308 (23%)] and AS160 Thr642 (42%), in red gastrocnemius muscle frozen in situ. Absolute AMPKα (Thr172) phosphorylation increased (98%) by AZIL-M treatment, and relative Thr389 phosphorylation of p70 S6K1, a negative regulator of insulin signaling, decreased (51%) with AZIL-M treatment. These results indicate that ARB AZIL-M improves the in vitro insulin action on glucose transport in red soleus muscle and the functionality of the Akt/AS160 axis in red gastrocnemius muscle in situ in Ang II-induced insulin-resistant rats, with the latter modification possibly associated with enhanced AMPKα and suppressed p70 S6K1 activation.
Angiotensin II; Glucose transport; Red skeletal muscle; Akt; AS160; AMPK; p70 S6K1
Many angiotensin receptor blocker (ARB) monotherapy patients need at least two agents to control blood pressure (BP). We investigated whether initiating intensive treatment with combination amlodipine/valsartan was superior to moderate treatment with amlodipine/valsartan in patients previously uncontrolled on ARB monotherapy.
In this 12-week study, patients aged at least 18 years on ARB (other than valsartan) for at least 28 days (with treatment-naïve patients or those not controlled on agents other than an ARB treated with open-label olmesartan 20 or 40 mg, respectively, for 28 days) and with uncontrolled mean sitting systolic blood pressure (MSSBP; ≥150–<200 mmHg) were randomized to amlodipine/valsartan 5/320 mg (n = 369) or 5/160 mg (n = 359). At week 2, the dose was increased to 10/320 mg in the intensive arm. Hydrochlorothiazide 12.5 mg was added to both arms at week 4. Optional up-titration with hydrochlorothiazide 12.5 mg at week 8 was allowed if MSSBP was more than 140 mmHg.
At baseline, mean office sitting BP was comparable in the intensive (163.9/95.5 mmHg) and moderate (163.3/95.0 mmHg) groups. Intensive treatment provided greater BP reductions versus moderate treatment (P<0.05) from week 4 (−23.0/−10.4 versus −19.2/−8.7 mmHg; primary endpoint) to week 12 (−29.0/−14.8 versus −25.3/−12.3 mmHg). Adverse events were reported by a similar percentage of patients in both groups (36.3% intensive, 37.6% moderate); peripheral edema was more common with intensive versus moderate treatment (8.7 versus 4.5%; P=0.025).
Initiating treatment with an intensive dose of amlodipine/valsartan provides significantly greater BP lowering versus moderate treatment in hypertensive patients unresponsive to ARB monotherapy. Both treatment regimens were generally well tolerated based on adverse event reports, but the lack of routine laboratory testing after screening limits conclusions on tolerability.
amlodipine; blood pressure; efficacy; hydrochlorothiazide; hypertension; safety; valsartan
Enhanced renin-angiotensin-aldosterone system (RAAS) activation contributes to proteinuria and chronic kidney disease by increasing glomerular and tubulointerstitial oxidative stress, promotion of fibrosis. Renin activation is the rate limiting step in angiotensin (Ang II) and aldosterone generation, and recent work suggests direct renin inhibition improves proteinuria comparable to that seen with Ang type 1 receptor (AT1R) blockade. This is important as, even with contemporary use of AT1R blockade, the burden of kidney disease remains high. Thereby, we sought to determine if combination direct renin inhibition with AT1R blockade in vivo, via greater attenuation of kidney oxidative stress, would attenuate glomerular and proximal tubule injury to a greater extent than either intervention alone. We utilized the transgenic Ren2 rat with increased tissue RAS activity and higher serum levels of aldosterone, which manifests hypertension and proteinuria. Ren2 rats were treated with renin inhibition (aliskiren), AT1R blockade (valsartan), the combination (aliskiren+valsartan), or vehicle for 21 days. Compared to Sprague-Dawley controls, Ren2 rats displayed increased systolic pressure (SBP), circulating aldosterone, proteinuria and greater urine levels of the proximal tubule protein excretory marker beta-N-acetylglucosaminidase (β-NAG). These functional and biochemical alterations were accompanied by increases in kidney tissue NADPH oxidase subunit Rac1 and 3-nitrotyrosine (3-NT) content as well as fibronectin and collagen type III. These findings occurred in conjunction with reductions in the podocyte-specific protein podocin as well as the proximal tubule-specific megalin. Further, in transgenic animals there was increased tubulointerstitial fibrosis on light microscopy as well as ultrastructural findings of glomerular podocyte foot-process effacement and reduced tubular apical endosomal/lysosomal activity. Combination therapy led to greater reductions in SBP and serum aldosterone, but did not result in greater improvement in markers of glomerular and tubular injury (ie. β-NAG) compared to either intervention alone. Further, combination therapy did not improve markers of oxidative stress and podocyte and proximal tubule integrity in this transgenic model of RAAS-mediated kidney damage despite greater reductions in serum aldosterone and BP levels.
Aldosterone; Combination; Renin inhibition; AT1R blockade; Podocyte; β-NAG; Oxidative Stress
Spinal muscular atrophy (SMA) is a leading genetic cause of infantile death. Loss of a gene called Survival Motor Neuron 1 (SMN1) and, as a result, reduced levels of the Survival Motor Neuron (SMN) protein leads to SMA development. SMA is characterized by the loss of functional motor neurons in the spinal cord. However, accumulating evidence suggest the contribution of other organs to the composite SMA phenotype and disease progression. A growing number of congenital heart defects have been identified in severe SMA patients. Consistent with the clinical cases, we have recently identified developmental and functional heart defects in two SMA mouse models, occurring at embryonic stage in a severe SMA model and shortly after birth in a less severe model (SMNΔ7). Our goal was to examine the late stage cardiac abnormalities in untreated SMNΔ7 mice and to determine whether gene replacement therapy restores cardiac structure/function in rescued SMNΔ7 model. To reveal the extent of the cardiac structural/functional repair in the rescued mice, we analyzed the heart of untreated and treated SMNΔ7 model using self-complementary Adeno-associated virus (serotype 9) expressing the full-length SMN cDNA. We examined the characteristics of the heart failure such as remodeling, fibrosis, oxidative stress, and vascular integrity in both groups. Our results clearly indicate that fibrosis, oxidative stress activation, vascular remodeling, and a significant decrease in the number of capillaries exist in the SMA heart. The cardiac structural defects were improved drastically in the rescued animals, however, the level of impairment was still significant compared to the age-matched wildtype littermates. Furthermore, functional analysis by in vivo cardiac magnetic resonance imaging (MRI) revealed that the heart of the treated SMA mice still exhibit functional defects. In conclusion, cardiac abnormalities are only partially rescued in post-birth treated SMA animals and these abnormalities may contribute to the premature death of vector-treated SMA animals with seemingly rescued motor function but an average life span of less than 70 days as reported in several studies.
SMA; scAAV9; Cardiac function; Oxidative stress; Vascular remodeling; MRI
Numerous epidemiological studies confirm that the prevalence of obesity and the cardiorenal metabolic syndrome (CRS) is extraordinarily high and that the rates have increased dramatically in the last three decades. In addition, epidemiological data demonstrate that obesity, the CRS, and diabetes are inextricably linked and are all associated with an increased incidence of a number of solid tissue cancers. The mechanisms for this association have been examined, including, but not limited to, higher levels of insulin and free levels of insulin-like growth factor and insulin resistance in obesity and the CRS. Mortality, morbidity, and the associated health care costs which are the link between obesity, the CRS, and diabetes are just beginning to be examined. In addition, we review the advantages of implementing lifestyle and surgical changes to modify obesity, lessening the development of the CRS, diabetes, and associated cancers. Epidemiological data regarding the general mechanisms of the pathogenesis of cancers associated with obesity, the CRS, and diabetes (specifically colon, pancreas, esophageal, liver, breast, prostate, thyroid, and renal carcinomas) are reviewed. The mechanisms by which obesity and other components of the CRS contribute to the pathogenesis of these cancers, such as hormone alterations and insulin- and insulin-like growth factor-dependent pathways of tumor pathogenesis, include the attending roles of inflammation and oxidative stress. Emphasis has been placed on obesity as a modifiable risk factor which, when addressed, provides a reduction in the rate of cancer deaths. In a second part to be published in the next issue of this journal, the relationship between diabetes and cancer will be reviewed in detail.
Insulin resistance; Cancer; Inflammation; Oxidative stress
The prevalence of obesity and diabetes continues to rise in the United States and worldwide. These findings parallel the expansion of childhood obesity and diabetes. Obesity is a central component of the cardiorenal metabolic syndrome (CRS) which increases the risk for cardiovascular disease (CVD) and chronic kidney disease (CKD). The hallmark of obesity, CRS, and early type 2 diabetes is insulin resistance, a result of decreased insulin metabolic signaling due, in part, to enhanced serine phosphorylation and/or proteasome-mediated degradation of the insulin receptor substrate. Cardiovascular and renal insulin resistance significantly contributes to endothelial dysfunction, impaired cardiac diastolic and vascular relaxation, glomerular injury, and tubular dysfunction. In this context, multiple factors including oxidative stress, increased inflammation, and inappropriate activation of the renin-angiotensin-aldosterone and the sympathetic nervous system contribute to overweight- and obesity-induced systemic and tissue insulin resistance. One common link between obesity and the development of insulin resistance appears to be a low-grade inflammatory response resulting from dysfunctional innate and adaptive immunity. In this regard, there has been recent work on the role of dipeptidyl peptidase-4 (DPP-4) in modulating innate and adaptive immunity. The direct effects of DPP-4 on immune cells and the indirect effects through GLP-1-dependent and -independent pathways suggest effects of DPP-4 inhibition may have beneficial effects beyond glycemic control in improving CVD and renal outcomes. Accordingly, this review addresses new insights into the role of DPP-4 in immune modulation and the potential beneficial effects of DPP-4 inhibitors in insulin resistance and associated CVD and CKD prevention.
DPP-4; Cardiorenal syndrome; Obesity; Diabetes; Insulin resistance
Increased sympathetic outflow, renin–angiotensin system (RAS) activity, and oxidative stress are critical mechanisms underlying the adverse cardiovascular effects of dietary salt excess. Nebivolol is a third-generation, highly selective β1-receptor blocker with RAS-reducing effects and additional antioxidant properties. This study evaluated the hypothesis that nebivolol reduces salt-induced cardiac remodeling and dysfunction in spontaneous hypertensive rats (SHRs) by suppressing cardiac RAS and oxidative stress.
Male SHRs (8 weeks of age) were given an 8% high salt diet (HSD; n = 22), whereas their age-matched controls (n = 10) received standard chow. In a subgroup of HSD rats (n = 11), nebivolol was given at a dose of 10 mg/kg per day by gastric gavage.
After 5 weeks, HSD exacerbated hypertension as well as increased left-ventricular weight and collagen deposition while impairing left-ventricular relaxation. Salt-induced cardiac remodeling and dysfunction were associated with increased plasma renin concentration (PRC), cardiac angiotensin II immunostaining, and angiotensin-converting enzyme (ACE)/ACE2 mRNA and activity ratio. HSD also increased cardiac 3-nitrotyrosine staining indicating enhanced oxidative stress. Nebivolol treatment did not alter the salt-induced increase in arterial pressure, left-ventricular weight, and cardiac dysfunction but reduced PRC, cardiac angiotensin II immunostaining, ACE/ACE2 ratio, oxidative stress, and fibrosis.
Our data suggest that nebivolol, in a blood pressure-independent manner, ameliorated cardiac oxidative stress and associated fibrosis in salt-loaded SHRs. The beneficial effects of nebivolol may be attributed, at least in part, to the decreased ACE/ACE2 ratio and consequent reduction of cardiac angiotensin II levels.
β1-adrenergic receptors; angiotensin II; blood pressure; cardiac fibrosis; nebivolol; salt
Hypertension; Diabetes; Microalbuminuria
Epidemiological studies support the notion that arterial stiffness is an independent predictor of adverse cardiovascular events contributing significantly to systolic hypertension, impaired ventricular-arterial coupling and diastolic dysfunction, impairment in myocardial oxygen supply and demand, and progression of kidney disease. Although arterial stiffness is associated with aging, it is accelerated in the presence of obesity and diabetes. The prevalence of arterial stiffness parallels the increase of obesity that is occurring in epidemic proportions and is partly driven by a sedentary life style and consumption of a high fructose, high salt, and high fat western diet. Although the underlying mechanisms and mediators of arterial stiffness are not well understood, accumulating evidence supports the role of insulin resistance and endothelial dysfunction. The local tissue renin-angiotensin-aldosterone system (RAAS) in the vascular tissue and immune cells and perivascular adipose tissue is recognized as an important element involved in endothelial dysfunction which contributes significantly to arterial stiffness. Activation of vascular RAAS is seen in humans and animal models of obesity and diabetes, and associated with enhanced oxidative stress and inflammation in the vascular tissue. The cross talk between angiotensin and aldosterone underscores the importance of mineralocorticoid receptors in modulation of insulin resistance, decreased bioavailability of nitric oxide, endothelial dysfunction, and arterial stiffness. In addition, both innate and adaptive immunity are involved in this local tissue activation of RAAS. In this review we will attempt to present a unifying mechanism of how environmental and immunological factors are involved in this local tissue RAAS activation, and the role of this process in the development of endothelial dysfunction and arterial stiffness and targeting tissue RAAS activation.
renin-angiotensin-aldosterone system; arterial stiffness; insulin resistance; endothelial dysfunction; obesity; diabetes
The prevalence of diabetes, hypertension, and cardiovascular disease (CVD) and chronic kidney disease (CKD) is increasing in concert with obesity. Insulin resistance, metabolic dyslipidemia, central obesity, albuminuria and hypertension commonly cluster to comprise the cardiometabolic syndrome. Emerging evidence supports a shift in our understanding of the crucial role of elevated serum aldosterone in promoting insulin resistance and resistant hypertension. Aldosterone enhances tissue generation of oxygen free radicals and systemic inflammation. This increase in oxidative stress and inflammation, in turn, contributes to impaired insulin metabolic signaling, reduced endothelial-mediated vasorelaxation and associated cardiovascular and renal structural and functional abnormalities. In this context, recent investigation indicates that hyperaldosteronism, which is often associated with obesity, contributes to impaired pancreatic beta-cell function as well as diminished skeletal muscle insulin metabolic signaling. Accumulating evidence indicates that the cardiovascular and renal abnormalities associated with insulin resistance are mediated, in part, by aldosterone's non-genomic as well as genomic signaling through the mineralocorticoid receptor (MR). In the cardiometabolic syndrome there are increased circulating levels of glucocorticoids, which can also activate MR signaling in cardiovascular, adipose, skeletal muscle, neuronal, and liver tissue. Further, there is increasing evidence that fat tissue produces a lipid soluble factor that stimulates aldosterone production from the adrenal zona glomerulosa. Recently, have we learned that MR blockade improves pancreatic insulin release, insulin-mediated glucose utilization, endothelium-dependent vasorelaxation as well as reducing the progression of CVD and CKD. In summary, aldosterone excess exerts detrimental metabolic effects that contribute to the development of the CMS and resistant hypertension as well as CVD and CKD.
Aldosterone; Insulin Resistance; Hypertension; Cardiometabolic Syndrome
Hypertension is often associated with increased oxidative stress and systemic insulin resistance. Use of β adrenergic receptor blockers in hypertension is limited due to potential negative influence on insulin sensitivity and glucose homeostasis. We sought to determine the impact of nebivolol, a selective vasodilatory β1adrenergic blocker, on whole-body insulin sensitivity, skeletal muscle oxidative stress, insulin signaling and glucose transport in the transgenic TG(mRen2)27rat (Ren2). This rodent model manifests increased tissue renin angiotensin expression, excess oxidative stress, and whole-body insulin resistance.
Research design and methods
Young (age 6-9 wks) Ren2 and age-matched Sprague-Dawley control rats were treated with nebivolol 10 mg/kg/day or placebo for 21 days. Basal measurements were obtained for glucose and insulin to calculate the Homeostasis Model Assessment (HOMA–IR). Additionally, insulin metabolic signaling, NADPH oxidase activity, reactive oxygen species (ROS), and ultrastructural changes as evaluated by transmission electron microscopy were examined ex vivo in skeletal muscle tissue.
The Ren2 rat demonstrated systemic insulin resistance as examined by HOMA-IR, along with impaired insulin metabolic signaling in skeletal muscle. This was associated with increased oxidative stress and mitochondrial remodeling. Treatment with nebivolol was associated with improvement in insulin resistance and decreased NADPH oxidase activity/levels ROS in skeletal muscle tissue.
Nebivolol treatment for 3 weeks reduces NADPH oxidase activity and improves systemic insulin resistance, in concert with reduced oxidative stress in skeletal muscle in a young rodent model of hypertension, insulin resistance and enhanced tissue RAS expression.
Insulin resistance; oxidative stress; skeletal muscle
The prevalence of obesity has increased rapidly in the United States. Obesity affects about one third of the adult population and, even though it is attributed to excess calorie intake and inadequate physical activity, its etiopathogenesis is much more complex and is an area of active study. Lifestyle modifications (with a focus on increased activity and decreased calorie intake) have modest efficacy in the treatment of obesity. There is a dearth of safe and effective therapeutic modalities to treat obesity. In this review, we discuss the role of different treatment options in the management of obesity and its comorbidities, with a focus on recently approved drugs and the emerging role of bariatric surgery.
Obesity; Cardiorenal metabolic syndrome; Cardiovascular disease; Kidney