Cardiomyocyte-specific knockout of endothelin receptor a attenuates obesity cardiomyopathy

Biochim Biophys Acta Mol Basis Dis. 2018 Oct;1864(10):3339-3352. doi: 10.1016/j.bbadis.2018.07.020. Epub 2018 Jul 18.


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 PPARγ, insulin signaling (elevated basal/dampened insulin-stimulated phosphorylation of Akt and IRS1), phosphorylation of AMPK, ACC, upregulated GATA-4, ANP, NFATc3, PPARα, 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.

Keywords: Autophagy; Contractility; Endothelin-1; Heart; High-fat diet; Hypertrophy; Obesity.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Animals
  • Autophagy
  • Cardiomyopathies / genetics*
  • Cardiomyopathies / metabolism
  • Diet, High-Fat
  • Disease Models, Animal
  • Gene Knockout Techniques
  • Insulin Resistance
  • Male
  • Mice
  • Myocytes, Cardiac / cytology*
  • Myocytes, Cardiac / drug effects
  • Myocytes, Cardiac / metabolism
  • Obesity / complications*
  • Obesity / genetics
  • Obesity / metabolism
  • PPAR gamma / metabolism
  • Palmitic Acid / pharmacology
  • Receptor, Endothelin A / genetics*
  • Receptor, Endothelin A / metabolism
  • Receptors, Leptin / metabolism
  • Signal Transduction


  • PPAR gamma
  • Receptor, Endothelin A
  • Receptors, Leptin
  • leptin receptor, mouse
  • Palmitic Acid