Grant: Operating Grant

Heart disease remains a significant health problem and a major cause of morbidity and mortality. The renin-angiotensin system (RAS) is a central regulator of cardiovascular function and plays a key role in the pathophysiology of hypertension, heart failure and coronary artery disease. The peptidase action of angiotensin-converting enzyme (ACE) converts Ang I to the octapeptide Ang II, which is the central mediator of the RAS. In human heart failure and diabetes, activation of the RAS has been linked to the initiation and progression of heart disease. Ang II acting via AT1 receptors impairs mechanical and electrical aspects of the heart function. Angiotensin converting enzyme 2 (ACE2) degrades Ang I and Ang II to Ang 1-7 and Ang 1-9, respectively, hence functioning effectively as a negative regulator of the RAS. In human heart failure, expression of ACE2 is upregulated thereby counterbalancing an activated RAS while several key pharmacotherapeutic agents including ACE inhibitors, angiotensin receptor and aldosterone receptor blockers, enhance ACE2 activity.Our goal is to determine the role of ACE2 in heart disease and diabetes-induced cardiovascular complications. We will be using experimental models of heart disease and diabetes similar to the disease processes affecting our patients. we will examine the effect of high blood pressure, type 2 diabetes and obesity in mice lacking ACE2 and we will used rescue strategies including recombinant ACE2 and viral-mediated overexpression of ACE2 to rescue these murine models of cardiovascular disease. Our findings will provide novel insights for therapy, in particular the possibility of using human recombinant ACE2 as potential therapy in patients with heart disease.