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author:("Park, sangha")
1.  The N-Glycoform of sRAGE is the Key Determinant for Its Therapeutic Efficacy to Attenuate Injury-elicited Arterial Inflammation and Neointimal Growth 
Journal of molecular medicine (Berlin, Germany)  2013;91(12):10.1007/s00109-013-1091-4.
Signaling of the receptor for advanced glycation end products (RAGE) has been implicated in the development of injury-elicited vascular complications. Soluble RAGE (sRAGE) acts as a decoy of RAGE, and has been used to treat pathological vascular conditions in animal models. However, previous studies using sRAGE produced in insect Sf9 cells (sRAGESf9) used a high dose and multiple injections to achieve the therapeutic outcome. Here, we explore whether modulation of sRAGE N-glycoform impacts its bioactivity and augments its therapeutic efficacy. We first profiled carbohydrate components of sRAGECHO to show that a majority of its N-glycans belong to sialylated complex-types that are not shared by sRAGESf9. In cell-based NF-κB activation and vascular smooth muscle cell (VSMC) migration assays, sRAGECHO exhibited a significantly higher bioactivity relative to sRAGESf9 to inhibit RAGE alarmin ligand-induced NF-κB activation and VSMC migration. We next studied whether this N-glycoform-associated bioactivity of sRAGECHO is translated to higher in vivo therapeutic efficacy in a rat carotid artery balloon injury model. Consistent with the observed higher bioactivity in cell assays, sRAGECHO significantly reduced injury-induced neointimal growth and the expression of inflammatory markers in injured vasculature. Specifically, a single dose of 3 ng/g of sRAGECHO reduced neointimal hyperplasia by over 70%, whereas the same dose of sRAGESf9 showed no effect. The administered sRAGECHO is rapidly and specifically recruited to the injured arterial locus, suggesting that early intervention of arterial injury with sRAGECHO may offset an inflammatory circuit and reduce the ensuing tissue remodeling. Our findings showed that the N-glycoform of sRAGE is the key determinant underlying its bioactivity, and thus is an important glycobioengineering target to develop a highly potent therapeutic sRAGE for future clinical applications.
PMCID: PMC3846495  PMID: 24132651
sRAGE; N-glycoform; arterial injury; arterial inflammation; neointimal hyperplasia; therapeutic window
2.  Vessel Ultrasound Sonographic Assessment of Soluble Receptor for Advanced Glycation End Products Efficacy in a Rat Balloon Injury Model 
We aimed to assess the therapeutic efficacy of differentially modified soluble receptor for advanced glycation end products (sRAGE) in vivo using vessel ultrasound sonography and to compare the sonography data with those from postmortem histomorphologic analyses to have a practical reference for future clinical applications.
Vessel ultrasound sonography was performed in a sRAGE-treated rat carotid artery balloon injury model at different time points after the surgery, and therapeutic efficacy of different doses of sRAGE produced in Chinese hamster ovary cells and with different N-glycoform modifications were assessed.
Vessel ultrasound sonography found that sRAGE produced in Chinese hamster ovary cells with complex N-glycoform modifications is highly effective, and is consistent with our recent findings in the same model assessed with histology. We also found that sonography is less sensitive than histology when a higher dose of sRAGE is administered.
Sonograph results are consistent with those obtained from histology; that is, sRAGE produced in Chinese hamster ovary cells has significantly higher efficacy than insect cell-originated sRAGE cells.
PMCID: PMC4229510  PMID: 25408789
neointima; N-glycosylationl; soluble receptor for advanced glycation end products; vascular injury; vessel sonography
3.  Gender Differences in the Association between Serum γ-Glutamyltransferase and Blood Pressure Change: A Prospective Community-Based Cohort Study 
Journal of Korean Medical Science  2014;29(10):1379-1384.
We evaluated the gender differences in the relation of baseline serum γ-glutamyltransferase (GGT) levels to blood pressure (BP) change during 4 yr. 4,025 normotensive subjects (1,945 men and 2,080 women) who aged 40-69 yr at baseline participated in the Ansung-Ansan cohort of the Korean Genome Epidemiology Study were included. The associations of GGT with baseline BP or 4-yr change of BP were evaluated. GGT levels were associated with systolic blood pressure (SBP) and diastolic blood pressure (DBP) at baseline after adjusting for age, body mass index (BMI), HDL-cholesterol, triglyceride, C-reactive protein (CRP), current smoking status and alcohol intake (SBP, β=1.28, P<0.001; DBP, β=1.41, P<0.001). GGT levels were also associated with 4-yr change in BP after adjusting for age, BMI, HDL-cholesterol, triglyceride, CRP, current smoking status, alcohol intake and SBP (SBP, β=1.08, P=0.001; DBP, β=0.64, P=0.003). This association was statistically significant in men (SBP, β=1.82, P<0.001; DBP, β=1.05, P=0.001), but not in women (SBP, β=0.38, P=0.466; DBP, β=-0.37, P=0.304). Remarkably, this association between GGT and BP was significant in men at 40-49 yr of age. In summary, we found positive associations between GGT levels at baseline and the change of BP. The relation of GGT level and the change of BP was only significant in men, not in women, which warrants further studies to elucidate the biologic mechanisms.
Graphical Abstract
PMCID: PMC4214938  PMID: 25368491
Blood Pressure; γ-Glutamyltransferase; Gender
5.  Neck Circumference and Lowest Oxygen Saturation Are Independently Associated with High Coexistence of Hypertension in Obstructive Sleep Apnea 
Yonsei Medical Journal  2014;55(5):1310-1317.
Obstructive sleep apnea (OSA) is considered an independent risk factor for hypertension. However, it is still not clear which clinical factors are related with the presence of hypertension in OSA patients. We aimed to find different physical features and compare the sleep study results which are associated with the occurrence of hypertension in OSA patients.
Materials and Methods
Medical records were retrospectively reviewed for patients diagnosed with OSA at Severance Cardiovascular Hospital between 2010 and 2013. Males with moderate to severe OSA patients were enrolled in this study. Clinical and polysomnographic features were evaluated to assess clinical variables that are significantly associated with hypertension by statistical analysis.
Among men with moderate to severe OSA, age was negatively correlated with hypertension (odds ratio=0.956), while neck circumference was positively correlated with the presence of hypertension (odds ratio=1.363). Among the polysomnographic results, the lowest O2 saturation during sleep was significantly associated with the presence of hypertension (odds ratio=0.900).
Age and neck circumference should be considered as clinically significant features, and the lowest blood O2 saturation during sleep should be emphasized in predicting the coexistence or development of hypertension in OSA patients.
PMCID: PMC4108817  PMID: 25048490
Sleep apnea; hypertension; polysomnography; neck circumference; lowest oxygen saturation level
6.  Combination of a peroxisome proliferator‐activated receptor‐gamma agonist and an angiotensin II receptor blocker attenuates myocardial fibrosis and dysfunction in type 2 diabetic rats 
We aimed to examine the effect of an angiotensin II receptor blocker (ARB), a peroxisome proliferator‐activated receptor (PPAR)‐gamma agonist, and their combination on myocardial fibrosis and function in type 2 diabetic rats.
Materials and Methods
Five male Long‐Evans Tokushima Otsuka (LETO) rats and 20 male Otsuka Long‐Evans Tokushima Fatty (OLETF) rats were used. OLETF rats were assigned to four groups (n = 5 per group) at 28 weeks‐of‐age: untreated, losartan‐treated, rosiglitazone‐treated and combination‐treated. The ARB, losartan, was administered at a dose of 5 mg/kg/day, and the PPAR‐gamma agonist, rosiglitazone, was administered at a dose of 3 mg/kg/day by oral gavage for 12 weeks. Urine and blood samples were collected, and two‐dimensional echocardiograms and strain rate imaging were obtained at 28 and 40 weeks. Cytokines were evaluated by reverse transcriptase polymerase chain reaction, and histological analysis was carried out at 40 weeks.
At 40 weeks, the global radial strains of the losartan‐treated (55.7 ± 4.5%, P = 0.021) and combination‐treated groups (59.3 ± 6.7%, P = 0.001) were significantly higher compared with the untreated OLETFs (44.3 ± 10.5%). No difference was observed when compared with LETO rats. Although the rosiglitazone‐treated group showed a better metabolic profile than the untreated OLETF group, there was no difference in the global radial strain (49.8 ± 6.0 vs 44.3 ± 10.5, P = 0.402). The expression of pro‐inflammatory cytokines, and collagen type I and III were consistently attenuated in the losartan‐treated and combination‐treated OLETF groups, but not in the rosiglitazone‐treated group.
A combination of rosiglitazone and losartan attenuates myocardial fibrosis and dysfunction in type 2 diabetic rats.
PMCID: PMC4210065  PMID: 25411595
Angiotensin II receptor blocker; Diabetic cardiomyopathy; Peroxisome proliferator‐activated receptor‐gamma agonist
7.  C-Reactive Protein Inhibits Survivin Expression via Akt/mTOR Pathway Downregulation by PTEN Expression in Cardiac Myocytes 
PLoS ONE  2014;9(5):e98113.
C-reactive protein (CRP) is one of the most important biomarkers for arteriosclerosis and cardiovascular disease. Recent studies have shown that CRP affects cell cycle and inflammatory process in cardiac myocytes. Survivin is also involved in cardiac myocytes replication and apoptosis. Reduction of survivin expression is associated with less favorable cardiac remodeling in animal models. However, the effect of CRP on survivin expression and its cellular mechanism has not yet been studied. We demonstrated that treatment of CRP resulted in a significant decrease of survivin protein expression in a concentration-dependent manner in cardiac myocytes. The upstream signaling proteins of survivin, such as Akt, mTOR and p70S6K, were also downregulated by CRP treatment. In addition, CRP increased the protein and mRNA levels of PTEN. The siRNA transfection or specific inhibitor treatment for PTEN restored the CRP-induced downregulation of Akt/mTOR/p70S6K pathway and survivin protein expression. Moreover, pretreatment with a specific p53 inhibitor decreased the CRP-induced PTEN expression. ERK-specific inhibitor also blocked the p53 phosphorylation and PTEN expression induced by CRP. Our study provides a novel insight into CRP-induced downregulation of survivin protein expression in cardiac myocytes through mechanisms that involved in downregulation of Akt/mTOR/p70S6K pathway by expression of PTEN.
PMCID: PMC4035334  PMID: 24866016
8.  Red Cell Distribution Width as an Independent Predictor of Exercise Intolerance and Ventilatory Inefficiency in Patients with Chronic Heart Failure 
Yonsei Medical Journal  2014;55(3):635-643.
Peak oxygen uptake (peak VO2) and ventilatory inefficiency (VE/VCO2 slope) have proven to be strong prognostic markers in patients with chronic heart failure (CHF). Recently increased red cell distribution width (RDW) has emerged as an additional predictor of poor outcome in CHF. We sought to evaluate the relationship between RDW and cardiopulmonary exercise test (CPET) parameters in CHF patients and healthy controls.
Materials and Methods
85 ambulatory CHF patients (68 men, 54±10 years) and 107 healthy controls, who underwent a symptom-limited CPET on a treadmill according to the modified Bruce ramp protocol, were enrolled. CHF patients and healthy controls were divided into RDW tertile groups and laboratory, echocardiographic, and CPET results were analyzed.
For patients with CHF, compared with patients in the lowest RDW tertile, those in the highest tertile had lower peak VO2 (22 mL/kg/min vs. 28 mL/kg/min, p<0.001) and higher VE/VCO2 slope (31 vs. 25, p=0.004). Multivariate regression analysis revealed RDW to be an independent predictor for peak VO2 (β=-0.247, p=0.035) and VE/VCO2 slope (β=0.366, p=0.004). The optimal cutoff value of RDW for predicting peak VO2 ≤20 mL/kg/min and VE/VCO2 slope ≥34 was 13.6% (sensitivity 53%, specificity 89%) and 13.4% (sensitivity 75%, specificity 82%), respectively. In contrast, for healthy controls, RDW was not related to both peak VO2 and VE/VCO2 slope.
Higher RDW is independently related to peak VO2 and VE/VCO2 slope only in patients with CHF. RDW assessment, an inexpensive and simple method, might help predict functional capacity and ventilatory efficiency in these patients.
PMCID: PMC3990060  PMID: 24719129
Cardiopulmonary exercise test; heart failure; red cell distribution width
9.  The Role of Carotid Ultrasound for Cardiovascular Risk Stratification beyond Traditional Risk Factors 
Yonsei Medical Journal  2014;55(3):551-557.
Primary prevention and early detection of cardiovascular disease is important, as it is the leading cause of death throughout world. Risk stratification algorithms, such as Framingham Risk Score and European Systematic Coronary Risk Evaluation, that utilize a combination of various traditional risk factors have been developed to improve primary prevention. However, the accuracy of these algorithms for screening high risk patients is moderate at best. Accordingly, the use of biomarkers or imaging studies may improve risk stratification. Carotid ultrasound, which measures both carotid intima-media thichkness (cIMT) and carotid plaque, is useful in detecting the degree of subclinical carotid atherosclerosis, and has the advantage of being noninvasive and safe. Several large epidemiologic studies have indicated that cIMT and carotid plaque are closely related with other cardiovascular risk factors and may be useful for risk reclassification in subjects deemed to be at intermediate risk by traditional risk scores. Moreover, recent clinical guidelines for management of hypertension or dyslipidemia highlight the usefulness of cIMT in high risk patients. In this article, we review evidence for the usefulness of measurement of cIMT and carotid plaque for cardiovascular risk stratification.
PMCID: PMC3990091  PMID: 24719118
Carotid intima-media thickness; carotid plaque; cardiovascular diseases; primary prevention; atherosclerosis
10.  Role of vascular smooth muscle cell in the inflammation of atherosclerosis 
BMB Reports  2014;47(1):1-7.
Atherosclerosis is a pathologic process occurring within the artery, in which many cell types, including T cell, macrophages, endothelial cells, and smooth muscle cells, interact, and cause chronic inflammation, in response to various inner- or outer-cellular stimuli. Atherosclerosis is characterized by a complex interaction of inflammation, lipid deposition, vascular smooth muscle cell proliferation, endothelial dysfunction, and extracellular matrix remodeling, which will result in the formation of an intimal plaque. Although the regulation and function of vascular smooth muscle cells are important in the progression of atherosclerosis, the roles of smooth muscle cells in regulating vascular inflammation are rarely focused upon, compared to those of endothelial cells or inflammatory cells. Therefore, in this review, we will discuss here how smooth muscle cells contribute or regulate the inflammatory reaction in the progression of atherosclerosis, especially in the context of the activation of various membrane receptors, and how they may regulate vascular inflammation. [BMB Reports 2014; 47(1): 1-7]
PMCID: PMC4163848  PMID: 24388105
Atherosclerosis; Membrane receptor; Smooth muscle cell; Vascular inflammation
11.  Arterial stiffness, fatty liver and the presence of coronary artery calcium in a large population cohort 
We tested whether fatty liver, brachial-ankle pulse wave velocity (baPWV) and conventional cardiovascular risk factors were associated with a coronary artery calcium (CAC) score > 0 (as a marker of the presence of early atherosclerosis) in a cohort of healthy Korean adults.
The study population consisted of individuals who underwent a comprehensive health examination in 2010 at Kangbuk Samsung Hospital, College of Medicine, Sungkyunkwan University in South Korea. The 6009 subjects of total 7371 participants who had an assigned CAC score following coronary computed tomography (CT) scanning and baPWV were analyzed.
Among the study subjects, 39.2% of the population had evidence of fatty liver by ultrasound and 4.6% of the population had evidence of CAC score > 0. Among individuals with a CAC score = 0, 38% of the individuals had fatty liver compared with 58% of the individuals with a CAC score > 0. The individuals with a CAC score > 0 also had higher blood pressure and had more metabolic abnormalities. The prevalence of CAC score > 0 was increased according to baPWV quartiles and was higher in the fatty liver group in comparison with those without fatty liver. The odds ratio for CAC score > 0, after adjusting for clinical risk factors, showed a significant elevation with increasing quartiles of baPWV and the presence of fatty liver.
We showed that both fatty liver and baPWV are independently associated with the presence of CAC, a marker of preclinical atherosclerosis. These associations are independent of conventional risk factors and medical history.
PMCID: PMC3826844  PMID: 24191863
baPWV; Arterial stiffness; Coronary artery calcium (CAC) score; Atherosclerosis; Fatty liver
12.  Association between CDH13 Variants and Cardiometabolic and Vascular Phenotypes in a Korean Population 
Yonsei Medical Journal  2013;54(6):1305-1312.
Although some CDH13 single nucleotide polymorphisms (SNPs) have been shown to be determinants of blood adiponectin levels, the clinical implications of CDH13 variants are not yet completely understood. The purpose of this study was to evaluate the effects of SNPs of CDH13 on metabolic and vascular phenotypes.
Materials and Methods
We included 238 hypertensive subjects and 260 age- and sex-matched controls. Seven tagging-SNPs were identified in the CDH13 gene by whole gene sequencing. The association between these SNP variants and the risk of hypertension, metabolic traits, and carotid intima-media thickness (IMT) was examined.
Minor allele carriers of rs12444338 had a lower risk of hypertension, but the association turned out just marginal after adjusting confoudners. Blood glucose levels were higher in the minor allele carriers of c.1407C>T (p=0.01), whereas low-density lipoprotein-cholesterol levels were greater in those of rs6565105 (p=0.02). The minor allele of rs1048612 was associated with a higher body mass index (p=0.01). In addition, the mean carotid IMT was significantly associated with rs12444338 (p=0.02) and rs1048612 (p=0.02).
These results provide evidence that CDH13 variants are associated with metabolic traits and carotid atherosclerosis in Koreans. This study shows the multifaceted effects of CDH13 variants on cardiometabolic risk.
PMCID: PMC3809859  PMID: 24142632
CDH13 protein; human; hypertension; atherosclerosis; glucose; cholesterol
13.  Primary Cardiac Angiofibroma 
Korean Circulation Journal  2013;43(9):636-639.
Cardiac Angiofibroma is an uncommon intracardiac tumor. Thus far, only 4 cases of the rare intracardiac tumor have been reported. The present case-report describes an intracardiac angiofibroma in a 57-year-old healthy female. The patient was incidentally diagnosed with a left ventricle mass during echocardiography. We performed cardiac imaging, surgical excision and histological evaluation of the mass. The angiofibroma demonstrated features different from the relatively common cardiac tumors such as fibroma, myxoma and angiosarcoma. The cardiac MRI showed slightly high signal intensity on both T1 and T2, with the central core of lower signal intensity. The resected tumor was a whitish and rubbery mass. Histologically, the tumor showed the benign vascular proliferations associated with the surrounding collagen deposition.
PMCID: PMC3808861  PMID: 24174966
Cardiac tumor; Magnetic resonance imaging
14.  The Effect of Soluble RAGE on Inhibition of Angiotensin II-Mediated Atherosclerosis in Apolipoprotein E Deficient Mice 
PLoS ONE  2013;8(8):e69669.
The cross talk between RAGE and angiotensin II (AngII) activation may be important in the development of atherosclerosis. Soluble RAGE (sRAGE), a truncated soluble form of the receptor, acts as a decoy and prevents the inflammatory response mediated by RAGE activation. In this study, we sought to determine the effect of sRAGE in inhibiting AngII-induced atherosclerosis in apolipoprotein E knockout mice (Apo E KO).
Methods and Results
9 week old Apo E KO mice were infused subcutaneously with AngII (1 µg/min/kg) and saline for 4 weeks using osmotic mini-pumps. The mice were divided into 4 groups 1. saline infusion and saline injection; 2. saline infusion and sRAGE injection; 3. AngII infusion and saline injection; 4. AngII infusion and sRAGE injection. Saline or 0.5 µg, 1 µg, to 2 µg/day/mouse of sRAGE were injected intraperitoneally daily for 28 days. We showed that atherosclerotic plaque areas in the AngII-infused Apo E KO mice and markers of inflammation such as RAGE, ICAM-1, VCAM-1, and MCP-1 were increased in aorta compared to that of the Apo E KO mice. However, the treatment of 0.5 µg, 1 µg, and 2 µg of sRAGE in AngII group resulted in the dose-dependent decrease in atherosclerotic plaque area. We also demonstrated that sRAGE decreased RAGE expression level as well as inflammatory cytokines and cell adhesion molecules in AngII or HMGB1 treated-rat aorta vascular smooth muscle cells.
The results demonstrated that partical blockade of RAGE activation by sRAGE prevent AngII -induced atherosclerosis. Therefore these results suggested that first, RAGE activation may be important in mediating AngII-induced atherogenesis, and second, AngII activation is a major pathway in the development of atherosclerosis. Taken together, results from this study may provide the basis for future anti- atherosclerotic drug development mediated through RAGE activation.
PMCID: PMC3731311  PMID: 23936343
15.  Serum Adiponectin and Type 2 Diabetes: A 6-Year Follow-Up Cohort Study 
Diabetes & Metabolism Journal  2013;37(4):252-261.
Studies on factors which may predict the risk of diabetes are scarce. This prospective cohort study was conducted to determine the association between adiponectin and type 2 diabetes among Korean men and women.
A total of 42,845 participants who visited one of seven health examination centers located in Seoul and Gyeonggi province, Republic of Korea between 2004 and 2008 were included in this study. The incidence rates of diabetes were determined through December 2011. To evaluate the effects of adiponectin on type 2 diabetes, the Cox proportional hazard model was used.
Of the 40,005 participants, 959 developed type 2 diabetes during a 6-year follow-up. After the adjustment for age, body mass index (BMI), and waist circumference, the risks for type 2 diabetes in participants with normoglycemia had a 1.70-fold (95% confidence interval [CI], 1.21 to 2.38) increase in men and a 1.83-fold (95% CI, 1.17 to 2.86) increase in women with the lowest tertile of adiponectin when compared to the highest tertile of adiponectin. For participants with impaired fasting glucose (IFG), the risk for type 2 diabetes had a 1.46-fold (95% CI, 1.17 to 1.83) increase in men and a 2.52-fold (95% CI, 1.57 to 4.06) increase in women with the lowest tertile of adiponectin. Except for female participants with normoglycemia, all the risks remained significant after the adjustment for fasting glucose and other confounding variables. Surprisingly, BMI and waist circumference were not predictors of type 2 diabetes in men or women with IFG after adjustment for fasting glucose and other confounders.
A strong association between adiponectin and diabetes was observed. The use of adiponectin as a predictor of type 2 diabetes is considered to be useful.
PMCID: PMC3753490  PMID: 23991403
Adiponectin; Cohort studies; Diabetes mellitus; Impaired fasting glucose
16.  Protective Effect of Survivin in Doxorubicin-Induced Cell Death in H9c2 Cardiac Myocytes 
Korean Circulation Journal  2013;43(6):400-407.
Background and Objectives
Apoptosis has been known to be an important mechanism of doxorubicin-induced cardiotoxicity. Survivin, which belongs to the inhibitor of apoptosis protein family, is associated with apoptosis and alteration of the cardiac myocyte molecular pathways. Therefore, we investigated the anti-apoptotic effect and cellular mechanisms of survivin using a protein delivery system in a doxorubicin-induced cardiac myocyte injury model.
Materials and Methods
We constructed a recombinant survivin which was fused to the protein transduction domain derived from HIV-TAT protein. In cultured H9c2 cardiac myocytes, TAT-survivin (1 µM) was added for 1 hour prior to doxorubicin (1 µM) treatment for 24 hours. Cell viability and apoptosis were evaluated by 2-(4,5-dimethyltriazol-2-yl)-2,5-diphenyl tetrazolium bromide assay, caspase-3 activity, and terminal deoxynucleotidyltransferase-mediated dUTP nick end-labeling assay. We measured the expression levels of several apoptosis-related signal proteins.
The survivin level was significantly reduced in a dose dependent manner up to 1 µM of doxorubicin in concentration. Purified recombinant TAT-survivin protein was efficiently delivered to H9c2 cardiac myocytes, and its transduction showed an anti-apoptotic effect, demonstrated by reduced caspase-3 activity and the apoptotic index, concomitantly with increased cell viability against doxorubicin injury. The phosphorylation of p38 mitogen-activated protein (MAP) kinase and the release of Smac from mitochondria were suppressed and the expression levels of Bcl-2 and cAMP response element-binding protein (CREB), the transcription factor of Bcl-2, were recovered following TAT-survivin transduction, indicating that survivin had an anti-apoptotic effect against doxorubicin injury.
Our results suggest that survivin has a potentially cytoprotective effect against doxorubicin-induced cardiac myocyte apoptosis through mechanisms that involve a decrease in the phosphorylation of p38 MAP kinase, mitochondrial Smac release, and increased expression of Bcl-2 and CREB.
PMCID: PMC3717423  PMID: 23882289
Apoptosis; Doxorubicin; Myocytes, cardiac
17.  Association between Serine/Threonine Kinase 39 Gene Polymorphism, Hypertension, and Other Cardiovascular Risk Factors in Koreans 
Korean Circulation Journal  2013;43(1):13-22.
Background and Objectives
Although the association between single nucleotide polymorphisms (SNPs) of Serine/Threonine Kinase 39 (STK39) and hypertension has been reported, the prior studies have been inconsistent. The aim of this study is to evaluate the association between rs3754777 and rs6749447, the two SNPs of STK39, and hypertension and other cardiovascular risk factors in Koreans, residing in the Republic of Korea.
Subjects and Methods
We included 238 hypertensive patients and 260 controls. The associations between genotype and haplotype combination and hypertension were examined. In addition, possible SNP-related differences in the adjusted blood pressure and other cardiovascular risk factors were analyzed.
There was no significant association between the two SNPs and hypertension. However, the carriers of AA genotype of rs3754777 showed lower blood glucose and cholesterol levels, particularly in females. Genotype of rs6749447 was associated with the waist circumference, triglyceride, and high density lipoprotein-cholesterol levels, only in gender-stratified analysis. The effects of haplotype combinations on risk factors were compatible with genotype effects of each SNP.
Associations between the two SNPs of STK39, rs3754777 and rs6749447, and hypertension were not significant. However, the two SNPs showed genotype-related differences in blood glucose, lipids, and waist circumference, especially in women. Further studies are needed to clarify the effect of STK39 variants in these cardiovascular risk factors.
PMCID: PMC3569562  PMID: 23408757
STK39 protein, human; Hypertension; Cholesterol; Waist circumference; Glucose
18.  Disulfide Bonds within the C2 Domain of RAGE Play Key Roles in Its Dimerization and Biogenesis 
PLoS ONE  2012;7(12):e50736.
The receptor for advanced glycation end products (RAGE) on the cell surface transmits inflammatory signals. A member of the immunoglobulin superfamily, RAGE possesses the V, C1, and C2 ectodomains that collectively constitute the receptor's extracellular structure. However, the molecular mechanism of RAGE biogenesis remains unclear, impeding efforts to control RAGE signaling through cellular regulation.
Methodology and Result
We used co-immunoprecipitation and crossing-linking to study RAGE oligomerization and found that RAGE forms dimer-based oligomers. Via non-reducing SDS-polyacrylamide gel electrophoresis and mutagenesis, we found that cysteines 259 and 301 within the C2 domain form intermolecular disulfide bonds. Using a modified tripartite split GFP complementation strategy and confocal microscopy, we also found that RAGE dimerization occurs in the endoplasmic reticulum (ER), and that RAGE mutant molecules without the double disulfide bridges are unstable, and are subjected to the ER-associated degradation.
Disulfide bond-mediated RAGE dimerization in the ER is the critical step of RAGE biogenesis. Without formation of intermolecular disulfide bonds in the C2 region, RAGE fails to reach cell surface.
This is the first report of RAGE intermolecular disulfide bond.
PMCID: PMC3524233  PMID: 23284645
19.  Association of CYP2C19*2 and *3 Genetic Variants with Essential Hypertension in Koreans 
Yonsei Medical Journal  2012;53(6):1113-1119.
The cytochrome P450 2C19 (CYP2C19) metabolizes arachidonic acid to produce epoxyicosanoid acids, which are involved in vascular tone and regulation of blood pressure. Recent findings suggest that CYP2C19 gene might be considered as a novel candidate gene for treatment of cardiovascular disease. The aim of the present study was to evaluate the association between two variants, CYP2C19*2 (681G>A) and CYP2C19*3 (636G>A) and the development of essential hypertension (EH) in Koreans.
Materials and Methods
We carried out an association study in a total of 1190 individuals (527 hypertensive subjects and 663 unrelated healthy controls). The CYP2C19 polymorphisms were genotyped using the SNaPShot™ assay.
The distribution of alleles and genotypes of CYP2C19*3 showed significant difference between hypertensive patients and normal controls (p=0.011 and p=0.013, respectively). Logistic regression analysis indicated that the CYP2C19*3 (636A) allele carriers were significantly associated with EH [odds ratio, 0.691; 95% confidence interval (CI), 0.512-0.932, p=0.016], in comparison to wild type homozygotes (CYP2C19*1/*1). Neither genotype nor allele distribution of CYP2C19*2 polymorphism showed significant differences between hypertensive and control groups (p>0.05).
Our present findings strengthen the evidence of an association between CYP2C19 gene polymorphism and EH prevalence. In particular, the CYP2C19*3 defective allele may contribute to reduced risk for the development of EH.
PMCID: PMC3481368  PMID: 23074110
Essential hypertension; CYP2C19; polymorphism; association study; Koreans
20.  Role of Inflammation in the Pathogenesis of Arterial Stiffness 
Yonsei Medical Journal  2012;53(2):258-261.
Increased arterial stiffness is an independent predictor of cardiovascular disease independent from blood pressure. Recent studies have shed new light on the importance of inflammation on the pathogenesis of arterial stiffness. Arterial stiffness is associated with the increased activity of angiotensin II, which results in increased NADPH oxidase activity, reduced NO bioavailability and increased production of reactive oxygen species. Angiotensin II signaling activates matrix metalloproteinases (MMPs) which degrade TGFβ precursors to produce active TGFβ, which then results in increased arterial fibrosis. Angiotensin II signaling also activates cytokines, including monocyte chemoattractant protein-1, TNF-α, interleukin-1, interleukin-17 and interleukin-6. There is also ample clinical evidence that demonstrates the association of inflammation with increased arterial stiffness. Recent studies have shown that reductions in inflammation can reduce arterial stiffness. In patients with rheumatoid arthritis, increased aortic pulse wave velocity in patients was significantly reduced by anti tumor necrosis factor-α therapy. Among the major classes of anti hypertensive drugs, drugs that block the activation of the RAS system may be more effective in reducing the progression of arterial stiffness. Thus, there is rationale for targeting specific inflammatory pathways involved in arterial stiffness in the development of future drugs. Understanding the role of inflammation in the pathogenesis of arterial stiffness is important to understanding the complex puzzle that is the pathophysiology of arterial stiffening and may be important for future development of novel treatments.
PMCID: PMC3282971  PMID: 22318811
Arterial stiffness; inflammation; angiotensin II
21.  Plasma Adiponectin Concentration and Its Association with Metabolic Syndrome in Patients with Heart Failure 
Yonsei Medical Journal  2011;53(1):91-98.
Plasma adiponectin concentrations are inversely related with metabolic syndrome (MetS), and MetS is associated with increased risk for heart failure (HF). However, the relationship between adiponectin and MetS in HF remains undetermined. Therefore, we tested whether MetS was associated with the degree of plasma adiponectin concentrations in HF patients.
Materials and Methods
One hundred twenty eight ambulatory HF patients with left ventricular ejection fraction of <50% (80 males, 61.8±11.9 years old) were enrolled for this cross-sectional study. Echocardiographic measurements were performed, and plasma concentrations of adiponectin, lipoproteins, apolipoproteins (apoB, apoA1) and high sensitive C-reactive protein (hsCRP) were measured.
Adiponectin concentrations in HF patients with MetS (n=43) were significantly lower than those without MetS (n=85) (9.7±7.0 vs. 15.8±10.9 µg/mL, p=0.001). Higher concentrations of apoB (p=0.017), apoB/A1 ratio (p<0.001), blood urea nitrogen (p=0.034), creatinine (p=0.003), and fasting insulin (p=0.004) were observed in HF patients with MetS compared with those without MetS. In HF patients with MetS, adiponectin concentrations were negatively correlated with hsCRP (r=-0.388, p=0.015) and positively correlated with the ratio of early mitral inflow velocity to early diastolic mitral annular velocity, E/E' (r=0.399, p=0.015). There was a significant trend towards decreased adiponectin concentrations with an increasing number of components of MetS (p for trend=0.012).
Our study demonstrated that adiponectin concentrations decreased in HF patients with MetS, and that relationship between adiponectin, inflammation and abnormal diastolic function, possibly leading to the progression of HF.
PMCID: PMC3250329  PMID: 22187237
Adiponectin; metabolic syndrome; heart failure
22.  Non-Dipper Status and Left Ventricular Hypertrophy as Predictors of Incident Chronic Kidney Disease 
Journal of Korean Medical Science  2011;26(9):1185-1190.
We have hypothesized that non-dipper status and left ventricular hypertrophy (LVH) are associated with the development of chronic kidney disease (CKD) in non-diabetic hypertensive patients. This study included 102 patients with an estimated glomerular filtration rate (eGFR) ≥ 60 mL/min/1.73 m2. Ambulatory blood pressure monitoring and echocardiography were performed at the beginning of the study, and the serum creatinine levels were followed. During the average follow-up period of 51 months, CKD developed in 11 patients. There was a significant difference in the incidence of CKD between dippers and non-dippers (5.0% vs 19.0%, P < 0.05). Compared to patients without CKD, patients with incident CKD had a higher urine albumin/creatinine ratio (52.3 ± 58.6 mg/g vs 17.8 ± 29.3 mg/g, P < 0.01), non-dipper status (72.7% vs 37.4%, P < 0.05), the presence of LVH (27.3% vs 5.5%, P < 0.05), and a lower serum HDL-cholesterol level (41.7 ± 8.3 mg/dL vs 50.4 ± 12.4 mg/dL, P < 0.05). Based on multivariate Cox regression analysis, non-dipper status and the presence of LVH were independent predictors of incident CKD. These findings suggest that non-dipper status and LVH may be the therapeutic targets for preventing the development of CKD in non-diabetic hypertensive patients.
PMCID: PMC3172656  PMID: 21935274
Blood Pressure Monitoring, Ambulatory; Hypertrophy, Left Ventricular; Renal Insufficiency, Chronic
23.  Serum cytokine profiles in healthy young and elderly population assessed using multiplexed bead-based immunoassays 
Lipid metabolites and cytokines, including chemokines and growth factors, are the key regulators of immune cell function and differentiation, and thus, dysregulation of these regulators is associated with various human diseases. However, previous studies demonstrating a positive correlation of cytokine levels with aging may have been influenced by various environmental factors and underlying diseases. Also, data regarding cytokine profiling in the elderly are limited to a small subset of cytokines.
We compared the profiles of 22 cytokines, including chemokines and growth factors, in a case-controlled study group of a gender-matched, healthy cohort of 55 patients over the age of 65 and 55 patients under the age of 45. Assessment of serum cytokine concentrations was performed using commercially-available multiplex bead-based sandwich immunoassays.
Soluble CD40 ligand (sCD40L) and transforming growth factor alpha (TGF-α) levels were significantly higher in the elderly patients, whereas granulocyte colony-stimulating factor (G-CSF), granulocyte-monocyte colony-stimulating factor (GM-CSF), and monocyte chemoattractant protein-1 (MCP-1) levels were significantly lower in the elderly patients. The partial correlation analysis demonstrating the correlation between cytokine levels when controlled for gender, systolic blood pressure, total cholesterol, HDL cholesterol, triglyceride, and serum creatinine levels further demonstrated that G-CSF, GM-CSF, and MCP-1 had significant negative correlations with age, whereas sCD40L and TGF-α had significant positive correlations.
Future studies will focus on examining the significance of these age-related changes in circulating cytokines and other biological markers and their potential contribution to the development of different age-associated diseases.
PMCID: PMC3146842  PMID: 21774806
24.  Alagebrium Chloride, a Novel Advanced Glycation End-Product Cross Linkage Breaker, Inhibits Neointimal Proliferation in a Diabetic Rat Carotid Balloon Injury Model 
Korean Circulation Journal  2010;40(10):520-526.
Background and Objectives
Vascular perturbation induced by advanced glycation end-products (AGEs) leads to progression of atherosclerosis, plaque instability, and vascular inflammation, which results in a higher risk of neointimal proliferation. Here we investigated the inhibitory effect of alagebrium chloride (ALT-711), a breaker of AGE-based cross links, on neointimal proliferation in a carotid artery balloon injury model in diabetic rats induced by streptozotocin (STZ).
Materials and Methods
Rat aortic vascular smooth muscle cells (RASMCs) were treated with 1-100 µM of alagebrium added 24 hours before the addition of AGEs. This in vivo study was done using 8-week-old male rats that were injected intraperitoneally with 80 mg/kg STZ. Sixteen weeks later, the diabetic rats were treated with 10 mg/kg alagebrium for 4 weeks, after which carotid artery balloon injury was induced. After 4 weeks, the animals were sacrificed for histological analysis.
Proliferation of RASMCs was significantly inhibited in alagebrium-treated cells. Alagebrium dose-dependently inhibited AGE-mediated formation of reactive oxygen species (ROS), extracellular signal-regulated kinase phosphorylation, and cyclooxygenase-2 expression. The cellular mechanisms of AGE-induced connective tissue and extracellular matrix expression were decreased in the alagebrium-treated group. This in vivo study shows that expression of AGE receptors and neointima hyperplasia are significantly suppressed in balloon-injured rats treated with alagebrium.
Alagebrium treatment in diabetic rats significantly inhibits neointimal hyperplasia after carotid balloon injury due to its inhibition of intracellular ROS synthesis, which results in inhibition of RASMCs proliferation.
PMCID: PMC2978295  PMID: 21088756
Alagebrium; Advanced glycation end-products; Neointimal hyperplasia
25.  Association of Plasma Retinol-Binding Protein 4, Adiponectin, and High Molecular Weight Adiponectin with Insulin Resistance in Non-Diabetic Hypertensive Patients 
Yonsei Medical Journal  2010;51(3):375-384.
The aim of this study was to determine whether retinol-binding protein 4 (RBP4), adiponectin and high molecular weight (HMW) adiponectin are associated with insulin resistance (IR) and metabolic parameters in non-diabetic hypertensive patients. Also, we sought to compare the predictive values of these adipocytokines for IR in non-diabetic hypertensive patients.
Materials and Methods
Analyses of RBP4, adiponectin, and HMW adiponectin were performed on 308 non-diabetic hypertensives (148 males, age 58 ± 10 years, 189 non-metabolic syndrome and 119 metabolic syndrome). The homeostasis model assessment (HOMA) index for IR, lipid profiles, and anthropometric measure-ments were assessed.
There was no significant difference in RBP4 levels according to the presence of metabolic syndrome, although adiponectin and HMW adiponectin were significantly lower in metabolic syndrome. Correlation analysis of log RBP4 with IR and metabolic indices revealed that there was no significant correlation of RBP4 with waist circumference (r = 0.056, p = 0.324), HDL cholesterol (r = 0.005, p = 0.934), ApoB/ApoAI ratio (r = 0.066, p = 0.270), and the HOMA index (r = 0.017, p = 0.756). However, adiponectin and HMW adiponectin showed significant correlations with the HOMA index (r = - 0.247, p < 0.001; r = - 0.296, p < 0.001) and metabolic parameters. With IR defined as HOMA index ≥ 2.5, HMW adiponectin did not demonstrate a superior predictive value for IR compared to adiponectin (AUC = 0.680 vs. 0.648, p = 0.083). The predictive value of RBP4 for IR was minimal (AUC = 0.534).
RBP4 was not associated with IR or metabolic indices and the predictive value for IR was minimal in hypertensives. HMW adiponectin didn't have a superior predictive value for IR compared to adiponectin. Therefore, we can suggest that RBP4 and HMW adiponectin don't have more additive information than adiponectin in non-diabetic hypertensives.
PMCID: PMC2852793  PMID: 20376890
Retinol-binding proteins; adiponectin; hypertension; insulin resistance

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