Cardiac steatosis potentiates angiotensin II effects in the heart

Denis J. Glenn, Michelle C. Cardema, Wei Ni, Yan Zhang, Yerem Yeghiazarians, Dmitry Grapov, Oliver Fiehn, David G. Gardner

Research output: Contribution to journalArticle

16 Scopus citations

Abstract

Lipid accumulation in the heart is associated with obesity and diabetes and may play an important role in the pathogenesis of heart failure. The renin-angiotensin system is also thought to contribute to cardiovascular morbidity in obese and diabetic patients. We hypothesized that the presence of lipid within the myocyte might potentiate the cardiomyopathic effects of ANG II in the cardiac diacylglycerol acyl transferase 1 (DGAT1) transgenic mouse model of myocyte steatosis. Treatment with ANG II resulted in a similar increase in blood pressure in both nontransgenic and DGAT1 transgenic mice. However, ANG II in DGAT1 transgenic mice resulted in a marked increase in interstitial fibrosis and a reduction in systolic function compared with nontransgenic littermates. Lipidomic analysis revealed that >20% of lipid species were significantly altered between nontransgenic and DGAT1 transgenic animals, whereas 3% were responsive to ANG II administration. ROS were also increased by ANG II in DGAT1 transgenic hearts. ANG II treatment resulted in increased expression of transforming growth factor (TGF)-β2 and the type I TGF-β receptor as well as increased phosphorylation of Smad2 in DGAT1 transgenic hearts. Injection of neutralizing antibodies to TGF-β resulted in a reduction in fibrosis in DGAT1 transgenic hearts treated with ANG II. These results suggest that myocyte steatosis amplifies the fibrotic effects of ANG II through mechanisms that involve activation of TGF-β signaling and increased production of ROS.

Original languageEnglish (US)
Pages (from-to)H339-H350
JournalAmerican Journal of Physiology - Heart and Circulatory Physiology
Volume308
Issue number4
DOIs
StatePublished - Feb 15 2015

Keywords

  • Angiotensin
  • Diacylglycerol acyl transferase 1
  • Fibrosis
  • Lipotoxixity
  • Transforming growth factor-β

ASJC Scopus subject areas

  • Physiology
  • Cardiology and Cardiovascular Medicine
  • Physiology (medical)

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  • Cite this

    Glenn, D. J., Cardema, M. C., Ni, W., Zhang, Y., Yeghiazarians, Y., Grapov, D., Fiehn, O., & Gardner, D. G. (2015). Cardiac steatosis potentiates angiotensin II effects in the heart. American Journal of Physiology - Heart and Circulatory Physiology, 308(4), H339-H350. https://doi.org/10.1152/ajpheart.00742.2014