osteoprotegerin and Cardiomegaly

The mortality of end-stage renal disease (ESRD) patients, including those receiving long-term peritoneal dialysis (PD), has remained unacceptably high owing to the prevalence of cardiovascular disease. It is well recognized that both traditional Framingham risk factors and kidney disease-related risk factors may contribute to the high prevalence of cardiovascular disease in these patients. Of the different risk factors, chronic inflammation frequently is observed in long-term PD patients. The causes of inflammation are usually complex and multifactorial, involving both dialysis-related and dialysis-unrelated factors. Inflammation is strongly associated with cardiovascular disease and malnutrition, and has been shown consistently to be a powerful predictor of mortality and adverse cardiovascular outcomes in PD patients. In this article we review the prevalence and potential causes of chronic inflammation in PD patients. More importantly, we provide emerging evidence that shows the serious consequences of chronic systemic inflammation in PD patients and the important contribution of inflammation to adverse clinical outcomes.

Topics: C-Reactive Protein; Cachexia; Calcinosis; Cardiomegaly; Chronic Disease; Heart Failure; Humans; Inflammation; Insulin Resistance; Kidney Failure, Chronic; Osteoprotegerin; Peritoneal Dialysis; Prevalence

Osteoprotegerin (OPG) may play a role in the progression of cardiac hypertrophy and heart failure. However, its pathophysiological role in changes in cardiac structure and function with ageing remains to be elucidated.. We conducted experiments using 2.5- and 12-month-old OPG(-/-) mice and age-matched wild-type (WT) mice and compared the morphology and function of the left ventricle (LV). Both 2.5- and 12-month-old OPG(-/-) mice showed a higher systolic blood pressure and a greater heart weight/body weight ratio than age-matched WT mice. Twelve-month-old OPG(-/-) mice had a significantly larger LV chamber and reduced wall thickness compared with age-matched WT mice, and contractile function was decreased. The morphological differences were accompanied by an increase in the number of apoptotic cells and activation of tumour necrosis factor-related apoptosis-inducing ligand (TRAIL) in the LV of 12-month-old OPG(-/-) mice. Correspondingly, OPG small interfering RNA induced the expressions of TRAIL and cleaved caspase-3 in cultured cardiac myocytes. In addition, these mice revealed a decrease in interstitial fibrosis, activation of matrix metalloproteinase (MMP)-2 and tissue inhibitors of MMP-1 and -2, and inactivation of procollagen α1 synthesis. Moreover, intraperitoneal administration of recombinant OPG to either 2.5- or 12-month-old OPG(-/-) mice for 28 days led to partial improvement of LV structure and function without affecting systolic blood pressure.. These results suggest that OPG plays a role in preserving myocardial structure and function with ageing through a reduction in apoptosis and preservation of the matrix structure. In addition, this appears to be independent of effects on the vasculature.

Topics: Aging; Animals; Blood Pressure; Cardiomegaly; Fibrosis; Heart Ventricles; Mice; Mice, Transgenic; Osteoprotegerin; Ventricular Remodeling

The present study aims to study the role of receptor activator of nuclear factor kappa B ligand/receptor activator of nuclear factor kappa B/osteoprotegerin (RANKL/RANK/OPG) system in cardiac hypertrophy in a spontaneous hypertension rat (SHR) model and the effects of amlodipine and atorvastatin intervention. Thirty-six-week-old male SHRs were randomly divided into four groups: 1) SHR control group; 2) amlodipine alone (10 mg/kg/d) group, 3) atorvastatin alone (10 mg/kg/d) group, 4) combination of amlodinpine and atorvastatin (10 mg/kg/d for each) group. Same gender, weight, and age of Wistar-Kyoto (WKY) rats with normal blood pressure were used as normal control. Drugs were administered by oral gavage over 12 weeks. The thicknesses of left ventricle walls, left ventricle weight, and cardiac function were measured by transthoracic echocardiography. Left ventricular pressure and function were assessed by hemodynamic examination. Cardiomyocyte hypertrophy and collagen accumulation in cardiac tissue were measured by hematoxylin and eosin (HE) and Masson staining, respectively. The hydroxyproline content of cardiac tissue was examined by biochemistry technique. RANKL, RANK and OPG mRNA, protein expression and tissue localization were studied by RT-PCR, Immunohistochemistry and Western blot. Treatment with amlodipine or atorvastatin alone significantly decreased left ventricular mass index, cardiomyocyte cross-sectional area and interstitial fibrosis in SHR (each P < 0.05). Moreover, combined amlodipine and atorvastatin treatment induced significant reversal of left ventricular hypertrophy and decreased cardiomyocyte cross-sectional area and interstitial fibrosis in SHR to a greater extent than each agent alone (P < 0.05). Compared with WKY rats, the myocardial expression of RANKL, RANK, and OPG was increased. Both amlodipine and atorvastatin reduced RANKL, RANK, and OPG expression, with the best effects seen with the combination. Based on our results, activation of the RANKL/RANK/OPG system may be an important factor leading to ventricular remodeling in SHR rats. Amlodipine and atorvastatin could improve ventricular remodeling in SHR rats through intervention with the RANKL/RANK/OPG system.

Topics: Administration, Oral; Amlodipine; Animals; Antihypertensive Agents; Atorvastatin; Cardiomegaly; Cross-Sectional Studies; Disease Models, Animal; Gene Expression Profiling; Hydroxyproline; Hypertension; Immunohistochemistry; Male; Myocardium; NF-kappa B; Osteoprotegerin; RANK Ligand; Rats, Inbred SHR; Real-Time Polymerase Chain Reaction; Reverse Transcriptase Polymerase Chain Reaction; Treatment Outcome; Ventricular Function, Left

The circulating osteoprotegerin (OPG) level reflects a series of cardiovascular diseases; however, the source(s) of circulating OPG remain(s) to be determined. This study explored whether OPG is released in the coronary circulation and whether it is associated with cardiac structure and function. Fifty-six patients (67±10 years old, male 57%, hypertension 73%, coronary artery disease 50%) were enrolled, and blood samples were collected simultaneously from the orifice of the left coronary artery (CA) and the coronary sinus (CS) after angiography. The concentration of OPG was higher in the CS than in the CA (7.7±4.1 vs. 6.7±3.6 pmol/l, p<0.001). The trans-cardiac OPG concentration was significantly (p=0.019) decreased in patients who have been prescribed either an angiotensin converting enzyme inhibitor or an angiotensin II type 1 receptor blocker (ACEI/ARB). In patients subgroup who did not take an ACEI/ARB (n=27), the trans-cardiac OPG level was positively correlated with age (r=0.396, p=0.041) and relative wall thickness of left ventricle (r=0.534, p=0.004). In multivariate linear regression analysis, relative wall thickness remained to be the independent variable for the trans-cardiac OPG level (p=0.004). Moreover, trans-cardiac OPG was significantly (p=0.021) increased in patients with relative wall thickness greater than 0.45 but it did not differ if the left ventricular mass index was increased (≥116 for males, or ≥ 104 for females, g/m(2)) or not (p=0.627). This study suggests that OPG is secreted into the coronary circulation and is associated with concentric remodeling/hypertrophy of LV, possibly in interactions with the renin-angiotensin system.

Topics: Adult; Aged; Aged, 80 and over; Cardiomegaly; Coronary Circulation; Coronary Sinus; Coronary Vessels; Female; Heart Ventricles; Humans; Male; Middle Aged; Myocardium; Osteoprotegerin; Renin-Angiotensin System

Cardiac hypertrophy is a risk factor independent of blood pressure; however, the mechanisms that distinguish pathological remodelling due to local cues from pressure overload are unresolved. This study was aimed at discovering a novel gene expression mechanism in heart failure.. In angiotensin II type 1 receptor (AT1R) transgenic mice (TG), we found a significant increase of mRNA and total STAT3 (T-STAT3) protein, but not STAT3 phosphorylated at residues Y705 and S727. A net increase in nuclear accumulation of this unphosphorylated form of STAT3 (U-STAT3) correlated with the development of cardiac hypertrophy and dysfunction, which are associated with abnormal expression of osteopontin and regulator of G protein signalling 2 genes. Nuclear accumulation of U-STAT3 is induced by angiotensin II treatment in neonatal cardiac myocytes, fibroblasts, and AT1R-expressing human embryonic kidney 293 (HEK-AT1R) cells. Chromatin immunoprecipitation demonstrated that U-STAT3 binds to the target gene promoter, and siRNA-mediated knockdown of STAT3 expression significantly altered the expression of target genes in HEK-AT1R cells. T-STAT3 in TG mouse hearts and the phosphorylation-deficient Y705F mutant STAT3 in HEK-AT1R cells physically interacted with transcription co-activator p300.. Chronic activation of AT1R induces unregulated expression of the Stat3 gene, leading to nuclear accumulation of U-STAT3, which significantly correlated with progression of cardiac hypertrophy.

Topics: Animals; Cardiomegaly; Cell Nucleus; Cells, Cultured; Gene Expression Regulation; Mice; Mice, Inbred C57BL; Myocytes, Cardiac; Osteoprotegerin; p300-CBP Transcription Factors; Phosphorylation; Receptor, Angiotensin, Type 1; RGS Proteins; STAT3 Transcription Factor