Abstract 18910: Angiotensin Converting Enzyme 2 Deficiency Results in Cardiac Insulin Resistance in Response to High-Fat Diet

Abstract

Background: Activation of the renin-angiotensin system (RAS) can alter the cardiac energy substrate preference, thereby contributing to the progression of heart failure. Angiotensin converting enzyme (ACE) 2 is a key negative regulator of the RAS where it metabolizes angiotensin (Ang) II into Ang (1-7). Hypothesis: Myocardial ACE2 was upregulated in response to high-fat diet in wildtype (WT) mice. We hypothesize that ACE2 upregulation is a compensatory response and loss of ACE2 will worsened obesity and its associated cardiomyopathy. Methods and Results: ACE2-null (ACE2-/y; ACE2KO) and WT litter-mate control mice were fed with high-fat diet (HFD; 45 kcal%) or control diet (10 kcal%) and studied at 6-months of age. In contrast to our hypothesis, loss of ACE2 resulted in decreased obesity in response to HFD compared to WT mice (body weight at 6-months: 45.9±4.3 in ACE2KO-HFD vs 51.4±1.55 in WT-HFD; p<0.05). Conversely, ACE2KO-HFD mice showed increased fasting plasma glucose levels (6.76±0.7 in ACE2KO-HFD vs 5.11±0.6 in WT-HFD; p<0.05) with worsened whole-body insulin resistance. We subjected hearts to ex vivo aerobic perfusions to measure cardiac energy metabolism. ACE2KO-HFD hearts showed markedly decreased cardiac work along with reduced insulin response suggesting increased myocardial insulin resistance. ACE2KO-HFD hearts relied predominantly on fat metabolism as the energy source, a feature observed in cardiomyopathy. Pressure-volume analysis showed worsened diastolic dysfunction in the ACE2KO hearts compared to WT hearts in response to HFD, which was primarily due to impaired active relaxation (Tau(Weiss): 7.41±0.4 in ACE2KO-HFD vs 6.26±0.52 in WT-HFD; p<0.05). Metabolic and functional changes in the ACE2KO-HFD were associated with impaired insulin signaling (decreased p-Akt) and decreased phosphorylation of AMPK. ACE2KO-HFD hearts also showed increased pyruvate dehydrogenase kinase 4 expression and phosphorylation of pyruvate dehydrogenase. Conclusions: Renin-angiotensin system plays an important role in cardiac metabolism. We found a novel role of ACE2 in cardiac insulin signaling, where ACE2 negatively regulates obesity and hyperglycemia induced cardiac insulin-resistance and alterations in cardiac metabolism.