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C1q/tumor necrosis factor-related protein-3, a newly identified adipokine, is a novel antiapoptotic, proangiogenic, and cardioprotective molecule in the ischemic mouse heart.

ABSTRACT: Obesity and diabetes mellitus adversely affect postischemic heart remodeling via incompletely understood mechanisms. C1q/tumor necrosis factor-related protein-3 (CTRP3) is a newly identified adipokine exerting beneficial metabolic regulation, similar to adiponectin. The aim of the present study was to determine whether CTRP3 may regulate postischemic cardiac remodeling and cardiac dysfunction, and, if so, to elucidate the underlying mechanisms.Male adult mice were subjected to myocardial infarction (MI) via left anterior descending coronary artery occlusion. Both the effect of MI on endogenous CTRP3 expression/production and the effect of exogenous CTRP3 (adenovirus or recombinant CTRP3) replenishment on MI injury were investigated. MI significantly inhibited adipocyte CTRP3 expression and reduced the plasma CTRP3 level, reaching a nadir 3 days after MI. CTRP3 replenishment improved survival rate (P<0.05), restored cardiac function, attenuated cardiomyocyte apoptosis, increased revascularization, and dramatically reduced interstitial fibrosis (all P<0.01). CTRP3 replenishment had no significant effect on cardiac AMP-activated protein kinase phosphorylation but significantly increased Akt phosphorylation and expression of hypoxia inducing factor-1? and vascular endothelial growth factor. Surprisingly, treatment of human umbilical vascular endothelial cells with CTRP3 did not directly affect nitric oxide production or tube formation. However, preconditioned medium from CTRP3-treated cardiomyocytes significantly enhanced human umbilical vascular endothelial cell tube formation, an effect blocked by either pretreatment of cardiomyocytes with a PI3K inhibitor or pretreatment of human umbilical vascular endothelial cells with a vascular endothelial growth factor inhibitor. Finally, the protective effect of adipocyte-conditioned medium against hypoxia-induced cardiomyocyte injury is significantly blunted when CTRP3 is knocked down.CTRP3 is a novel antiapoptotic, proangiogenic, and cardioprotective adipokine, the expression of which is significantly inhibited after MI.

SUBMITTER: Yi W

PROVIDER: S-EPMC3391311 | biostudies-literature | 2012 Jun

REPOSITORIES: biostudies-literature

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C1q/tumor necrosis factor-related protein-3, a newly identified adipokine, is a novel antiapoptotic, proangiogenic, and cardioprotective molecule in the ischemic mouse heart.

Yi Wei W Sun Yang Y Yuan Yuexing Y Lau Wayne Bond WB Zheng Qijun Q Wang Xiaoliang X Wang Yajing Y Shang Xiying X Gao Erhe E Koch Walter J WJ Ma Xin-Liang XL

Circulation 20120531 25

<h4>Background</h4>Obesity and diabetes mellitus adversely affect postischemic heart remodeling via incompletely understood mechanisms. C1q/tumor necrosis factor-related protein-3 (CTRP3) is a newly identified adipokine exerting beneficial metabolic regulation, similar to adiponectin. The aim of the present study was to determine whether CTRP3 may regulate postischemic cardiac remodeling and cardiac dysfunction, and, if so, to elucidate the underlying mechanisms.<h4>Methods and results</h4>Male ...[more]

PMID: 22653084

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Project description:Heme oxygenase-1 (HO-1) is an inducible stress-response protein that imparts antioxidant and antiapoptotic effects. However, its pathophysiological role in cardiac remodeling and chronic heart failure (HF) is unknown. We hypothesized that induction of HO-1 in HF alleviates pathological remodeling.Adult male nontransgenic and myocyte-restricted HO-1 transgenic mice underwent either sham operation or coronary ligation to induce HF. Four weeks after ligation, nontransgenic HF mice exhibited postinfarction left ventricular (LV) remodeling and dysfunction, hypertrophy, fibrosis, oxidative stress, apoptosis, and reduced capillary density, associated with a 2-fold increase in HO-1 expression in noninfarcted myocardium. Compared with nontransgenic mice, HO-1 transgenic HF mice exhibited significantly (P<0.05) improved postinfarction survival (94% versus 57%) and less LV dilatation (end-diastolic volume, 46+/-8 versus 85+/-32 microL), mechanical dysfunction (ejection fraction, 65+/-9% versus 49+/-16%), hypertrophy (LV/tibia length 4.4+/-0.4 versus 5.2+/-0.6 mg/mm), interstitial fibrosis (11.2+/-3.1% versus 18.5+/-3.5%), and oxidative stress (3-fold reduction in tissue malondialdehyde). Moreover, myocyte-specific HO-1 overexpression in HF promoted tissue neovascularization and ameliorated myocardial p53 expression (2-fold reduction) and apoptosis. In isolated mitochondria, mitochondrial permeability transition was inhibited by HO-1 in a carbon monoxide (CO)-dependent manner and was recapitulated by the CO donor tricarbonylchloro(glycinato)ruthenium(II) (CORM-3). HO-1-derived CO also prevented H2O2-induced cardiomyocyte apoptosis and cell death. Finally, in vivo treatment with CORM-3 alleviated postinfarction LV remodeling, p53 expression, and apoptosis.HO-1 induction in the failing heart is an important cardioprotective adaptation that opposes pathological LV remodeling, and this effect is mediated, at least in part, by CO-dependent inhibition of mitochondrial permeability transition and apoptosis. Augmentation of HO-1 or its product, CO, may represent a novel therapeutic strategy for ameliorating HF.

Project description:Background:C1q TNF related protein 3 (CTRP3) is a relatively novel hormonal factor primarily derived from adipose tissue and has anti-diabetic properties. To determine if CTRP3 could play a role in early childhood development, the purpose of this study was to establish the presence of CTRP3 in breast milk (BM) and to determine whether CTRP3 levels were correlated with pregravid obesity status of the mother. Methods:Breast milk was collected from breast-feeding mothers who had a pregravid body mass index (BMI) classification of normal weight (BMI 18-25 kg/m2, n = 23) or obese (BMI > 30 kg/m2, n = 14). Immunoprecipitation followed by immunoblot analysis confirmed the presence of CTRP3 in BM. The concentration of CTRP3 in BM samples was determined by ELISA. Additional bioactive components were also measured by commercially available assays: ghrelin, insulin, leptin, adiponectin, interleukin-6 (IL-6), tumor necrosis factor-alpha (TNF-?), and glucose. Bioactive components in normal weight and obese mothers were compared using unpaired t-test (parametric) and Mann-Whitney U-test (non-parametric), as appropriate. Results:The primary findings of this study are that the adipokine CTRP3 is present in BM and CTRP3 levels are increased with pregravid obesity. Additionally, this study independently confirmed previous work that BM from obese mothers has a higher concentration of insulin and leptin. Further, no differences were observed in BM between obese and normal weight mothers in ghrelin, adiponectin, IL-6, TNF-?, or glucose levels. Conclusion:This study identified a novel factor in BM, CTRP3, and showed that BM CTRP3 levels higher in obese mothers. Because of the purported insulin sensitizing effect of CTRP3, it is possible that the elevated levels of CTRP3 in the BM of obese mothers may offset negative effects of elevated leptin and insulin levels in the BM of obese mothers. Future studies will need to be conducted to determine the relevance of CTRP3 in BM and to examine the presence of other adipose tissue-derived hormonal factors.

Dataset Information

C1q/tumor necrosis factor-related protein-3, a newly identified adipokine, is a novel antiapoptotic, proangiogenic, and cardioprotective molecule in the ischemic mouse heart.

Publications

C1q/tumor necrosis factor-related protein-3, a newly identified adipokine, is a novel antiapoptotic, proangiogenic, and cardioprotective molecule in the ischemic mouse heart.

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