Abstract 1549: Adenylyl Cyclase Type VI Deletion Reduces Left Ventricular Function in Response to β-Adrenergic Receptor Stimulation
Background: Adenylyl cyclase type VI (ACVI) is an effector for β-adrenergic receptor (βAR) signaling. Cardiac expression of ACVI increases Ca2+ handling, LV function and survival in heart failure. To understand the role of endogenous ACVI on LV function, we made, for the first time, ACVI knockout mice (AC-KO).
Methods & Results: ACVI expression was absent; other AC isoforms were unchanged (QRT-PCR). Body and LV weights and LV sizes (echo) were normal. βAR stimulation yielded reduction in LV cAMP in AC-KO mice, and studies of isolated hearts showed reduced LV +dP/dt and -dP/dt responses (Figures⇓). LV samples of AC-KO mice had reductions in: PKA activity (CON: 471±54; AC-KO: 313±16 pmol/mg/min; P=0.015, n=8); phospholamban phosphorylation (CON: 648±96; AC-KO: 299±81 du; P=0.015, n=8); and SERCA2a affinity for Ca2+ (EC50: CON: 0.76±0.03; AC-KO: 2.68±0.08 μM; P<0.0001, n=8). These striking biochemical abnormalities provide a likely mechanism for reduced βAR responsiveness.
Conclusion: ACVI deletion impairs Ca2+ handling and cAMP generation and adversely affects LV responsiveness to βAR stimulation.