Cardiomyocyte-specific knockout of endothelin receptor a attenuates obesity cardiomyopathy

BIOCHIMICA ET BIOPHYSICA ACTA-MOLECULAR BASIS OF DISEASE

卷:1864

Article

Ceylan, Asli F.^1,2  Wang, Shuyi¹  Kandadi, Machender R.¹  Chen, Jie³  Hua, Yinan¹  Pei, Zhaohui³  Nair, Sreejayan¹  Ren, Jun¹ 

[1] Univ Wyoming, Coll Hlth Sci, Ctr Cardiovasc Res & Alternat Med, Laramie, WY 82071 USA

[2] Ankara Yildirim Beyazit Univ, Fac Med, Ankara, Turkey

[3] Third Hosp Nanchang, Dept Cardiol 2, Nanchang 330009, Jiangxi, Peoples R China

关键词: Endothelin-1;    Obesity;    Heart;    High-fat diet;    Hypertrophy;    Contractility;    Autophagy;   

DOI  :  10.1016/j.bbadis.2018.07.020

来源: Elsevier

【 摘 要 】

Endothelin (ET)-1 is implicated in the pathophysiology of cardiovascular diseases although its role in obesity anomalies has not been fully elucidated. This study was designed to examine the impact of ET-1 receptor A (ETA) ablation on obesity-induced changes in cardiac geometry and contractile function, as well as the mechanisms involved with a focus on autophagy. Cardiomyocyte-specific ETA receptor knockout (ETAKO) and WT mice were fed either low-fat (10% calorie from fat) or high-fat (45% calorie from fat) diet for 24 weeks. Glucose tolerance test was examined to confirm insulin resistance. High-fat diet intake compromised myocardial geometry (enlarged left ventricular diameters in systole and diastole), morphology (cardiac hypertrophy, increased wall thickness and interstitial fibrosis), contractile function (reduced fractional shortening, ejection fraction and cardiomyocyte shortening) and intracellular Ca2+ handling, the effect of which was significantly attenuated by ETAKO. TUNEL staining revealed overt apoptosis in high-fat-fed group, the effect was reverted by ETAKO. Western blot analysis noted that high-fat intake downregulated leptin receptor and PPAR gamma, insulin signaling (elevated basal/dampened insulin-stimulated phosphorylation of Akt and IRS1), phosphorylation of AMPK, ACC, upregulated GATA-4, ANP, NFATc3, PPAR alpha, m-TOR/p70s6k signaling, which were attenuated by ETAKO with the exception of AMPK/ACC. Furthermore, high-fat intake suppressed cardiac autophagy, which was abrogated by ETAKO. In cultured murine cardiomyocytes, palmitic acid challenged mimicked high-fat diet-induced hypertrophic and autophagic responses, the effect of which were abolished by the ETA receptor antagonist BQ123 or mTOR inhibitor rapamycin. These results suggest that inhibition of ETA rescues high-fat intake-induced cardiac anomalies possibly through autophagy regulation.

【 授权许可】

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