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1.  Circulating Anti-Elastin Antibody Levels and Arterial Disease Characteristics: Associations with Arterial Stiffness and Atherosclerosis 
Yonsei Medical Journal  2015;56(6):1545-1551.
Purpose
Elastin is a major arterial structural protein, and elastin-derived peptides are related to arterial change. We previously reported on a novel assay developed using aortic elastin peptides; however, its clinical implications remain unclear. In this study, we assessed whether anti-elastin antibody titers reflect the risk of coronary artery disease (CAD) or its characteristics.
Materials and Methods
We included 174 CAD patients and 171 age- and sex-matched controls. Anti-elastin antibody titers were quantified by enzyme-linked immunosorbent assay. Parameters of arterial stiffness, including the augmentation index (AI) and heart-to-femoral pulse wave velocity (hfPWV), were measured non-invasively. The clinical and angiographic characteristics of CAD patients were also evaluated. Associations between anti-elastin levels and vascular characteristics were examined by linear regression analysis.
Results
The median blood level of anti-elastin was significantly lower in the CAD group than in the controls [197 arbitrary unit (a.u.) vs. 63 a.u., p<0.001]. Levels of anti-elastin were significantly lower in men and in subjects with hypertension, diabetes mellitus, hyperlipidemia, or high hfPWV. Nevertheless, anti-elastin levels were not dependent on atherothrombotic events or the angiographic severity of CAD. In a multivariate analysis, male sex (β=-0.38, p<0.001), diabetes mellitus (β=-0.62, p<0.001), hyperlipidemia (β=-0.29, p<0.001), and AI (β=-0.006, p=0.02) were ultimately identified as determinants of anti-elastin levels.
Conclusion
Lower levels of anti-elastin are related to CAD. The association between antibody titers and CAD is linked to arterial stiffness rather than the advancement of atherosclerosis.
doi:10.3349/ymj.2015.56.6.1545
PMCID: PMC4630041  PMID: 26446635
Elastin; antibody formation; vascular stiffness; coronary artery disease; atherosclerosis
2.  Clinical Features of Obstructive Sleep Apnea That Determine Its High Prevalence in Resistant Hypertension 
Yonsei Medical Journal  2015;56(5):1258-1265.
Purpose
Resistant hypertension (HTN) occurs in 15-20% of treated hypertensive patients, and 70-80% of resistant hypertensive patients have obstructive sleep apnea (OSA). The characteristics of resistant HTN that predispose patients to OSA have not been reported. Therefore, we aimed to determine the clinical, laboratory, and polysomnographic features of resistant HTN that are significantly associated with OSA.
Materials and Methods
Hypertensive patients (n=475) who underwent portable polysomnography were enrolled. The patients were categorized into controlled (n=410) and resistant HTN (n=65) groups. The risk factors for the occurrence of OSA in controlled and resistant hypertensive patients were compared, and independent risk factors that are associated with OSA were analyzed.
Results
Out of 475 patients, 359 (75.6%) were diagnosed with OSA. The prevalence of OSA in resistant HTN was 87.7%, which was significantly higher than that in controlled HTN (73.7%). Age, body mass index, neck circumference, waist circumference, and hip circumference were significantly higher in OSA. However, stepwise multivariate analyses revealed that resistant HTN was not an independent risk factor of OSA.
Conclusion
The higher prevalence and severity of OSA in resistant HTN may be due to the association of risk factors that are common to both conditions.
doi:10.3349/ymj.2015.56.5.1258
PMCID: PMC4541655  PMID: 26256968
Resistant hypertension; sleep apnea; polysomnography; obesity; body mass index
3.  ASSOCIATION OF CENTRAL HEMODYNAMICS WITH ESTIMATED 24-HOUR URINARY SODIUM IN PATIENTS WITH HYPERTENSION 
Journal of hypertension  2011;29(8):1502-1507.
Objective
High salt intake is known to be the most pivotal environmental factor in the pathogenesis of hypertension. However, the association of high sodium intake with central hemodynamics in hypertensive subjects has not been well defined. Here, we determined the association of estimated 24-hour urine sodium and potassium excretion estimated from a spot urine analysis with parameters of central pulse wave analysis in 515 hypertensive subjects.
Methods
Fasting spot urine samples were obtained in the early morning after the first void, and estimated 24-hour urine sodium and potassium excretion were estimated from measurement of urine sodium, potassium, and creatinine. Central hemodynamics and arterial stiffness parameters were assessed via pulse wave analysis of the radial artery.
Results
The estimated 24-hour sodium and potassium excretion values were 150 ± 40 and 49 ± 10 mEq, respectively. There was a step-wise decrease in pulse pressure amplification with increasing estimated 24-hour urine sodium excretion. Multiple linear regression analyses revealed that both estimated 24-hour urine sodium excretion and sodium/potassium ratio were independently associated with increases in central pulse pressure, augmented aortic pressure, augmentation index and were inversely associated with pulse pressure amplification.
Conclusion
The estimated 24-hour urinary sodium excretion is independently associated with central hemodynamics. This may provide the basis for prospective interventional studies of epidemiologic scale to determine the potential beneficial effects of reduced salt consumption on central hemodynamics.
doi:10.1097/HJH.0b013e3283486311
PMCID: PMC4535170  PMID: 21666493
Hypertension; sodium; pulse pressure amplification; central pulse pressure
4.  Insulin Protects Cardiac Myocytes from Doxorubicin Toxicity by Sp1-Mediated Transactivation of Survivin 
PLoS ONE  2015;10(8):e0135438.
Insulin inhibits ischemia/reperfusion-induced myocardial apoptosis through the PI3K/Akt/mTOR pathway. Survivin is a key regulator of anti-apoptosis against doxorubicin-induced cardiotoxicity. Insulin increases survivin expression in cardiac myocytes to mediate cytoprotection. However, the mechanism by which survivin mediates the protective effect of insulin against doxorubicin-associated injury remains to be determined. In this study, we demonstrated that pretreatment of H9c2 cardiac myocytes with insulin resulted in a significant decrease in doxorubicin-induced apoptotic cell death by reducing cytochrome c release and caspase-3 activation. Doxorubicin-induced reduction of survivin mRNA and protein levels was also significantly perturbed by insulin pretreatment. Reducing survivin expression with survivin siRNA abrogated insulin-mediated inhibition of caspase-3 activation, suggesting that insulin signals to survivin inhibited caspase-3 activation. Interestingly, pretreatment of H9c2 cells with insulin or MG132, a proteasome inhibitor, inhibited doxorubicin-induced degradation of the transcription factor Sp1. ChIP assay showed that pretreatment with insulin inhibited doxorubicin-stimulated Sp1 dissociation from the survivin promoter. Finally using pharmacological inhibitors of the PI3K pathway, we showed that insulin-mediated activation of the PI3K/Akt/mTORC1 pathway prevented doxorubicin-induced proteasome-mediated degradation of Sp1. Taken together, insulin pretreatment confers a protective effect against doxorubicin-induced cardiotoxicity by promoting Sp1-mediated transactivation of survivin to inhibit apoptosis. Our study is the first to define a role for survivin in cellular protection by insulin against doxorubicin-associated injury and show that Sp1 is a critical factor in the transcriptional regulation of survivin.
doi:10.1371/journal.pone.0135438
PMCID: PMC4535909  PMID: 26271039
5.  Characterization of CD8+CD57+ T cells in patients with acute myocardial infarction 
Cellular and Molecular Immunology  2014;12(4):466-473.
Although T cells are known to be involved in the pathogenesis of coronary artery disease, it is unclear which subpopulation of T cells contributes to pathogenesis in acute myocardial infarction (MI). We studied the immunological characteristics and clinical impact of CD8+CD57+ T cells in acute MI patients. The frequency of CD57+ cells among CD8+ T cells was examined in peripheral blood sampled the morning after acute MI events. Interestingly, the frequency of CD57+ cells in the CD8+ T-cell population correlated with cardiovascular mortality 6 months after acute MI. The immunological characteristics of CD8+CD57+ T cells were elucidated by surface immunophenotyping, intracellular cytokine staining and flow cytometry. Immunophenotyping revealed that the CD8+CD57+ T cells were activated, senescent T cells with pro-inflammatory and tissue homing properties. Because a high frequency of CD8+CD57+ T cells is associated with short-term cardiovascular mortality in acute MI patients, this specific subset of CD8+ T cells might contribute to acute coronary events via their pro-inflammatory and high cytotoxic capacities. Identification of a pathogenic CD8+ T-cell subset expressing CD57 may offer opportunities for the evaluation and management of acute MI.
doi:10.1038/cmi.2014.74
PMCID: PMC4496543  PMID: 25152079
acute myocardial infarction; CD8+CD57+ T cells; immunosenescence
6.  Genetic Testing of Korean Familial Hypercholesterolemia Using Whole-Exome Sequencing 
PLoS ONE  2015;10(5):e0126706.
Familial hypercholesterolemia (FH) is a genetic disorder with an increased risk of early-onset coronary artery disease. Although some clinically diagnosed FH cases are caused by mutations in LDLR, APOB, or PCSK9, mutation detection rates and profiles can vary across ethnic groups. In this study, we aimed to provide insight into the spectrum of FH-causing mutations in Koreans. Among 136 patients referred for FH, 69 who met Simon Broome criteria with definite family history were enrolled. By whole-exome sequencing (WES) analysis, we confirmed that the 3 known FH-related genes accounted for genetic causes in 23 patients (33.3%). A substantial portion of the mutations (19 of 23 patients, 82.6%) resulted from 17 mutations and 2 copy number deletions in LDLR gene. Two mutations each in the APOB and PCSK9 genes were verified. Of these anomalies, two frameshift deletions in LDLR and one mutation in PCSK9 were identified as novel causative mutations. In particular, one novel mutation and copy number deletion were validated by co-segregation in their relatives. This study confirmed the utility of genetic diagnosis of FH through WES.
doi:10.1371/journal.pone.0126706
PMCID: PMC4427254  PMID: 25962062
7.  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.
doi:10.1007/s00109-013-1091-4
PMCID: PMC3846495  PMID: 24132651
sRAGE; N-glycoform; arterial injury; arterial inflammation; neointimal hyperplasia; therapeutic window
8.  Vessel Ultrasound Sonographic Assessment of Soluble Receptor for Advanced Glycation End Products Efficacy in a Rat Balloon Injury Model 
Objective
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.
Methods
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.
Results
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.
Conclusions
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.
doi:10.1016/j.curtheres.2014.08.001
PMCID: PMC4229510  PMID: 25408789
neointima; N-glycosylationl; soluble receptor for advanced glycation end products; vascular injury; vessel sonography
9.  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
doi:10.3346/jkms.2014.29.10.1379
PMCID: PMC4214938  PMID: 25368491
Blood Pressure; γ-Glutamyltransferase; Gender
11.  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.
Purpose
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.
Results
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).
Conclusion
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.
doi:10.3349/ymj.2014.55.5.1310
PMCID: PMC4108817  PMID: 25048490
Sleep apnea; hypertension; polysomnography; neck circumference; lowest oxygen saturation level
12.  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 
Abstract
Aims/Introduction
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.
Results
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.
Conclusions
A combination of rosiglitazone and losartan attenuates myocardial fibrosis and dysfunction in type 2 diabetic rats.
doi:10.1111/jdi.12153
PMCID: PMC4210065  PMID: 25411595
Angiotensin II receptor blocker; Diabetic cardiomyopathy; Peroxisome proliferator‐activated receptor‐gamma agonist
13.  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.
doi:10.1371/journal.pone.0098113
PMCID: PMC4035334  PMID: 24866016
14.  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.
Purpose
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.
Results
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.
Conclusion
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.
doi:10.3349/ymj.2014.55.3.635
PMCID: PMC3990060  PMID: 24719129
Cardiopulmonary exercise test; heart failure; red cell distribution width
15.  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.
doi:10.3349/ymj.2014.55.3.551
PMCID: PMC3990091  PMID: 24719118
Carotid intima-media thickness; carotid plaque; cardiovascular diseases; primary prevention; atherosclerosis
16.  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]
doi:10.5483/BMBRep.2014.47.1.285
PMCID: PMC4163848  PMID: 24388105
Atherosclerosis; Membrane receptor; Smooth muscle cell; Vascular inflammation
17.  Arterial stiffness, fatty liver and the presence of coronary artery calcium in a large population cohort 
Background
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.
Method
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.
Results
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.
Conclusion
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.
doi:10.1186/1475-2840-12-162
PMCID: PMC3826844  PMID: 24191863
baPWV; Arterial stiffness; Coronary artery calcium (CAC) score; Atherosclerosis; Fatty liver
18.  Association between CDH13 Variants and Cardiometabolic and Vascular Phenotypes in a Korean Population 
Yonsei Medical Journal  2013;54(6):1305-1312.
Purpose
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.
Results
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).
Conclusion
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.
doi:10.3349/ymj.2013.54.6.1305
PMCID: PMC3809859  PMID: 24142632
CDH13 protein; human; hypertension; atherosclerosis; glucose; cholesterol
19.  The Reality of Aging Viewed from the Arterial Wall 
Pulse  2013;1(2):77-88.
An exclusive interview conducted by Professors Jeong Bae Park and Sungha Park with Dr. Edward Lakatta in Seoul while he was visiting for the Pulse of Asia 2013 in Seoul. In this interview, Dr. Lakatta explains and describes vascular aging and aging.
doi:10.1159/000354100
PMCID: PMC4315346  PMID: 26587427
20.  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.
doi:10.4070/kcj.2013.43.9.636
PMCID: PMC3808861  PMID: 24174966
Cardiac tumor; Magnetic resonance imaging
21.  The Effect of Soluble RAGE on Inhibition of Angiotensin II-Mediated Atherosclerosis in Apolipoprotein E Deficient Mice 
PLoS ONE  2013;8(8):e69669.
Background
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.
Conclusion
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.
doi:10.1371/journal.pone.0069669
PMCID: PMC3731311  PMID: 23936343
22.  Serum Adiponectin and Type 2 Diabetes: A 6-Year Follow-Up Cohort Study 
Diabetes & Metabolism Journal  2013;37(4):252-261.
Background
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.
Methods
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.
Results
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.
Conclusion
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.
doi:10.4093/dmj.2013.37.4.252
PMCID: PMC3753490  PMID: 23991403
Adiponectin; Cohort studies; Diabetes mellitus; Impaired fasting glucose
23.  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.
Results
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.
Conclusion
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.
doi:10.4070/kcj.2013.43.6.400
PMCID: PMC3717423  PMID: 23882289
Apoptosis; Doxorubicin; Myocytes, cardiac
24.  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.
Results
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.
Conclusion
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.
doi:10.4070/kcj.2013.43.1.13
PMCID: PMC3569562  PMID: 23408757
STK39 protein, human; Hypertension; Cholesterol; Waist circumference; Glucose
25.  Disulfide Bonds within the C2 Domain of RAGE Play Key Roles in Its Dimerization and Biogenesis 
PLoS ONE  2012;7(12):e50736.
Background
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.
Conclusion
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.
Significance
This is the first report of RAGE intermolecular disulfide bond.
doi:10.1371/journal.pone.0050736
PMCID: PMC3524233  PMID: 23284645

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