Abstract 91: Cardiac-directed Expression of Adenylyl Cyclase Catalytic Domain Reduces Left Ventricular Systolic and Diastolic Dysfunction in Pressure-overload

Abstract

Background and Objective: A fusion protein (C1C2) constructed by fusing the intracellular C1 and C2 segments of adenylyl cyclase type 6 (AC6), retains beneficial effects of AC6 expression, without increasing cAMP generation. For example, transgenic mice with cardiac-directed C1C2 expression have normal left ventricular (LV) function despite reduced cAMP generation. Furthermore, sustained isoproterenol (Iso) infusion reduces LV function in normal mice, but, in contrast, C1C2 mice show increased LV function with sustained Iso infusion. The effects of C1C2 expression in pressure-overload is unknown. Methods: LV pressure overload was induced by transaortic constriction (TAC) in C1C2 mice and in transgene negative mice. Three weeks after TAC, LV systolic and diastolic function were measured, and Ca2+ handling was assessed in isolated cardiac myocytes. Results: C1C2 expression reduced LV hypertrophy (p=0.017), increased LV peak pressure development (+dP/dt, p=0.018), and improved LV peak pressure decay (-dP/dt, p=0.038) in the pressure-overload ( Table ). Cytosolic peak Ca2+ concentration was increased (p=0.047), and time to peak Ca2+ transient and Tau were decreased (p=0.002 and p=0.003, respectively) in cardiac myocytes isolated from pressure-overloaded hearts ( Table ). Conclusions: Cardiac-directed C1C2 expression reduces LV hypertrophy, improves Ca2+ handling, and increases LV systolic and diastolic function in pressure-overload. These data provide a rationale for further exploration of C1C2 gene transfer as a potential treatment for heart failure.