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Adiponectin Determines Farnesoid X Receptor Agonism-Mediated Cardioprotection Against Post-Infarction Remodelling and Dysfunction

Adiponectin Determines Farnesoid X Receptor Agonism-Mediated Cardioprotection Against Post-Infarction Remodelling and Dysfunction

Yunlong Xia, Fuyang Zhang, Shihao Zhao, Yueyang Li, Xiyao Chen, Erhe Gao, Xinyue Xu, Zhenyu Xiong, Xiaomeng Zhang, Jinglong Zhang, Huishou Zhao, Wei Wang, Helin Wang, Yanjie Guo, Yi Liu, Congye Li, Shan Wang, etc.

Cardiovasc Res. 2018 Aug 1;114(10):1335-1349.

PMID: 29668847

Abstract:

Aims:
The farnesoid X receptor (FXR) is a member of the metabolic nuclear receptor superfamily that plays a critical regulatory role in cardiovascular physiology/pathology. However, the role of systemic FXR activation in the chronic phase in myocardial infarction (MI)-induced cardiac remodelling and dysfunction remains unclear. In this study, we aimed to elucidate the role of long-term FXR activation on post-MI cardiac remodelling and dysfunction.
Methods and results:
Mice underwent either MI surgery or sham operation. At 1 week after MI, both sham and MI mice were gavaged with 25 mg/kg/d of a synthetic FXR agonist (GW4064) or a vehicle control for 7 weeks, and cardiac performance was assessed by consecutive echocardiography studies. Administration of GW4064 significantly increased left ventricular ejection fraction at 4 weeks and 8 weeks after MI (both P < 0.01). Moreover, GW4064 treatment increased angiogenesis and mitochondrial biogenesis, reduced cardiomyocyte loss and inflammation, and ameliorated cardiac remodelling as evidenced by heart weight, lung weight, atrial natriuretic peptide/brain natriuretic peptide levels, and myocardial fibrosis at 8 weeks post-MI. At the molecular level, GW4064 significantly increased FXR mRNA expression and transcriptional activity in heart tissue. Moreover, over-expression of myocardial FXR failed to exert significant cardioprotection in vivo, indicating that GW4064 improved post-MI heart remodelling and function independent of myocardial FXR expression/activity. Among the four down-stream soluble molecules of FXR, plasma adiponectin was most significantly increased by GW4064. In cultured adipocytes, GW4064 increased mRNA levels and protein expression of adiponectin. Conditioned medium of GW4064-treated adipocytes activated AMPK-PGC-1α signalling and reduced hypoxia-induced cardiomyocyte apoptosis, all of which were attenuated by an adiponectin neutralizing anti-body. More importantly, when knocking-out adiponectin in mice, the cardioprotective effects of GW4064 were attenuated.
Conclusions:
We are the first to show that FXR agonism ameliorated post-MI cardiac dysfunction and remodelling by stimulating adiponectin secretion. Thus, we demonstrated that FXR agonism is a potential therapeutic strategy in post-MI heart failure.

Chemicals Related in the Paper:

Catalog Number	Product Name	Structure	CAS Number	Price
AP278779309	GW4064		278779-30-9	Price

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