ACE2 deficiency worsens epicardial adipose tissue inflammation and cardiac dysfunction in response to diet-induced obesity

Vaibhav B. Patel, Jun Mori, Brent A. McLean, Ratnadeep Basu, Subhash K. Das, Tharmarajan Ramprasath, Nirmal Parajuli, Josef M. Penninger, Maria B. Grant, Gary D. Lopaschuk, Gavin Y. Oudit

Research output: Contribution to journalArticle

60 Scopus citations

Abstract

Obesity is increasing in prevalence and is strongly associated with metabolic and cardiovascular disorders. The renin-angiotensin system (RAS) has emerged as a key pathogenic mechanism for these disorders; angiotensin (Ang)-converting enzyme 2 (ACE2) negatively regulates RAS by metabolizing Ang II into Ang 1-7. We studied the role of ACE2 in obesity-mediated cardiac dysfunction. ACE2 null (ACE2KO) and wild-type (WT) mice were fed a high-fat diet (HFD) or a control diet and studied at 6 months of age. Loss of ACE2 resulted in decreased weight gain but increased glucose intolerance, epicardial adipose tissue (EAT) inflammation, and polarization of macrophages into a proinflammatory phenotype in response to HFD. Similarly, human EAT in patients with obesity and heart failure displayed a proinflammatory macrophage phenotype. Exacerbated EAT inflammation in ACE2KO-HFD mice was associated with decreased myocardial adiponectin, decreased phosphorylation of AMPK, increased cardiac steatosis and lipotoxicity, and myocardial insulin resistance, which worsened heart function. Ang 1-7 (24 μg/kg/h) administered to ACE2KO-HFD mice resulted in ameliorated EAT inflammation and reduced cardiac steatosis and lipotoxicity, resulting in normalization of heart failure. In conclusion, ACE2 plays a novel role in heart disease associated with obesity wherein ACE2 negatively regulates obesity-induced EAT inflammation and cardiac insulin resistance.

Original languageEnglish (US)
Pages (from-to)85-95
Number of pages11
JournalDiabetes
Volume65
Issue number1
DOIs
StatePublished - Jan 1 2016

ASJC Scopus subject areas

  • Internal Medicine
  • Endocrinology, Diabetes and Metabolism

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    Patel, V. B., Mori, J., McLean, B. A., Basu, R., Das, S. K., Ramprasath, T., Parajuli, N., Penninger, J. M., Grant, M. B., Lopaschuk, G. D., & Oudit, G. Y. (2016). ACE2 deficiency worsens epicardial adipose tissue inflammation and cardiac dysfunction in response to diet-induced obesity. Diabetes, 65(1), 85-95. https://doi.org/10.2337/db15-0399