Epicardial adipose tissie-derived leptin induce MMPs/TIMPs imbalance and promotes myocardial remodeling in high fat diet-induced obese rats

Autor: Lei Liu, Chaodi Luo, Meng Li, Gang Tian, Lifei Cao, Danjun Zhu
Rok vydání: 2021
Předmět:
Zdroj: European Heart Journal. 42
ISSN: 1522-9645
0195-668X
DOI: 10.1093/eurheartj/ehab724.3342
Popis: Background and aims Epicardial adipose tissue (EAT)-derived leptin contributes to myocardial remodeling in metabolic syndrome. However, the precise mechanisms remain to be determined. The present study was designed to elucidate the adverse effects of EAT-derived leptin on obesity-related myocardial remodeling. Methods and results Eight-week-old male Wistar rats were divided into two groups that received either a normal diet (control, n=10) or a high-fat diet (obese, n=10) for 12 weeks. Obese rats exhibited abnormal myocardial structure, diastolic dysfunction and abundant collagen deposition. Local leptin expression in obese rats EAT upregulated along with adipocyte hypertrophy, accompanied by renin-angiotensin-aldosterone system (RAAS) activation and increased oxidative stress level. Leptin receptor (ObR) and angiotensin II type 1 receptor (AT1R) expression in obese EAT were significantly higher than that in control. In vitro, mature adipocytes treated with angiotensin II (Ang II) exhibited pronounced leptin synthesis and secretion by promoting AP-1 nuclear translocation via the AT1R-ROS-ERK1/2 pathway. Moreover, cardiac fibroblasts were incubated with obese rat EAT-conditioned medium (EAT-CM), plus various inhibitors. EAT-derived leptin promoted proliferation of cardiac fibroblasts associated with increased ERK1/2 phosphorylation and induced MMPs/TIMPs imbalance, stimulating upregulation of type I collagen via the JAK2/STAT3-TGF-β1/Smad3 pathway in cardiac fibroblasts of obese rats. Conclusions The paracrine effect of EAT-derived leptin on myocardial remodeling, inducing MMPs/TIMPs imbalance and promoting the proliferation of cardiac fibroblasts via activating ERK1/2 and JAK2/STAT3-TGF-β1/Smad3 pathway in obesity. Funding Acknowledgement Type of funding sources: Foundation. Main funding source(s): the Nature Science Foundation of China (grant no. 81873513, 81600574, and 30871042)
Databáze: OpenAIRE
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