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- Title
ACE2 Deficiency Worsens Epicardial Adipose Tissue Inflammation and Cardiac Dysfunction in Response to Diet-Induced Obesity.
- Authors
Patel, Vaibhav B.; Mori, Jun; McLean, Brent A.; Basu, Ratnadeep; Das, Subhash K.; Ramprasath, Tharmarajan; Parajuli, Nirmal; Penninger, Josef M.; Grant, Maria B.; Lopaschuk, Gary D.; Oudit, Gavin Y.
- 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.
- Subjects
ADIPOSE tissues; INFLAMMATION; OBESITY; DISEASE prevalence; ANGIOTENSIN converting enzyme; FATTY degeneration; HEART failure; MACROPHAGES; HEART metabolism; ANIMAL experimentation; BLOOD sugar; DIET; ENZYME-linked immunosorbent assay; HEART; INSULIN resistance; MICE; PEPTIDES; PERICARDIUM; PHOSPHORYLATION; PHOSPHOTRANSFERASES; POLYMERASE chain reaction; RESEARCH funding; TUMOR necrosis factors; VASODILATORS; WESTERN immunoblotting; WEIGHT gain; OXIDATIVE stress; ANGIOTENSIN I; GLUCOSE intolerance; ADIPONECTIN; STROKE volume (Cardiac output); PHARMACODYNAMICS
- Publication
Diabetes, 2016, Vol 65, Issue 1, p85
- ISSN
0012-1797
- Publication type
journal article
- DOI
10.2337/db15-0399