ACE2 deficiency worsened epicardial adipose tissue inflammation and cardiac dysfunction in response to diet-induced obesity, which was normalized by Ang 1-7 (24 µg/kg/h).
Does ACE2 deficiency worsen epicardial adipose tissue inflammation and cardiac dysfunction in response to diet-induced obesity, and does Ang 1-7 administration reverse this?
ACE2 protects against obesity-induced epicardial adipose tissue inflammation and cardiac insulin resistance, suggesting a therapeutic role for the ACE2/Ang 1-7 axis in obesity-related heart failure.
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.
Patel et al. (2015) studied Obesity-mediated cardiac dysfunction. ACE2 deficiency and high-fat diet (with subsequent Ang 1-7 administration) vs. Wild-type mice and control diet was evaluated on Epicardial adipose tissue inflammation and cardiac dysfunction. ACE2 deficiency worsened epicardial adipose tissue inflammation and cardiac dysfunction in response to diet-induced obesity, which was normalized by Ang 1-7 (24 µg/kg/h).