β-adrenergic Receptor in Cardiac Injury and Atherosclerotic Plaque Stability: Role of NADPH Oxidase 4 (NOX4)

JI Program: Cardiovascular

Cardiovascular disease (CVD) is the leading cause of death worldwide, representing 31% of all deaths. Emerging evidence suggests that stress in adulthood acts as a disease trigger in individuals with high atherosclerotic burden and is a determinant of prognosis and clinical outcomes. Increases in cardiovascular events were reported immediately after traumatic events such as natural disasters, war, and terrorist attacks of 9-11. Although the link between various stressors and disease end points is obvious, much less is known about the pathophysiological mechanisms through which stress responses transform into changes that initiate the development and progression of CVD. Another challenge is addressing the stressors by intervention, because such events are stochastic and therefore difficult to predict. We propose to elucidate the molecular signaling pathways which regulate the transformation of stress responses into cardiovascular events in people with atherosclerotic burden using mouse models of oxidative stress available in the Runge laboratory. Our proposal has three innovative aspects. First, our team has complementary strengths required for investigating the effect of sympathetic adrenergic activation on the onset of cardiovascular events in the backdrop of high atherosclerotic burden. Second, we generated atherosclerosis data using novel Apoe-/-/mNox4TG (mitochondria-targeted NADPH oxidase 4 transgenic) mice and Apoe-/-/Nox4-/- mice. Third, we plan to evaluate the effect of metformin and GKT137831 on β-AR activation associated cardiac dysfunction in mNox4TG mice and atherosclerotic burden and plaque stability in Apoe-/-/mNox4TG mice. Our research strategy includes the following two specific aims: (1) determine the molecular mechanism of sympathetic activation induced cardiac inflammatory injuries in mice deficient in and with mitochondrial-targeted overexpression of Nox4; (2) investigate the mechanisms of β-AR induced atherosclerotic burden/ plaque instability in Apoe-/- mice deficient in and with mitochondrial-targeted overexpression of Nox4. Together, these studies will establish the role of NOX4 NADPH oxidase in cardiovascular events in the backdrop of high atherosclerotic burden and potentially identify strategies that work in concert with standard of care treatment for the prevention of cardiovascular events under stress conditions.