Activated expression of cardiac adenylyl cyclase 6 reduces dilation and dysfunction of the pressure-overloaded heart

Background and objectiveCardiac-directed adenylyl cyclase 6 (AC6) expression attenuates left ventricular (LV) hypertrophy and dysfunction in cardiomyopathy, but its effects in the pressure-overloaded heart are unknown.MethodsMice with cardiac-directed and regulated expression of AC6 underwent transaortic constriction (TAC) to induce LV pressure overload. Ten days prior to TAC, and for the duration of the 4 week study, cardiac myocyte AC6 expression was activated in one group (AC-On) but not the other (AC-Off). Multiple measures of LV systolic and diastolic function were obtained 4 week after TAC, and LV samples assessed for alterations in Ca2+ signaling.ResultsLV contractility, as reflected in the end-systolic pressure–volume relationship (Emax), was increased (p = 0.01) by activation of AC6 expression. In addition, diastolic function was improved (p < 0.05) and LV dilation was reduced (p < 0.05). LV samples from AC-On mice showed reduced protein expression of sodium/calcium exchanger (NCX1) (p < 0.05), protein phosphatase 1 (PP1) (p < 0.01), and increased phosphorylation of phospholamban (PLN) at Ser16 (p < 0.05). Finally, sarcoplasmic reticulum (SR) Ca2+ content was increased in cardiac myocytes isolated from AC-On mice (p < 0.05).ConclusionsActivation of cardiac AC6 expression improves function of the pressure-overloaded and failing heart. The predominant mechanism for this favorable adaptation is improved Ca2+ handling, a consequence of increased PLN phosphorylation, reduced NCX1, reduced PP1 expression, and increased SR Ca2+ content.

Research highlights
► Activation of cardiac adenylyl cyclase expression attenuates the deleterious effects on heart function associated with pressure overload.
► Both systolic and diastolic heart function were increased by activation of cardiac adenylyl cyclase expression.
► The predominant mechanism for these favorable effects is improved Ca2+ handling, a consequence of increased phospholamban phosphorylation, reduced expression of NCX1 and protein phosphatase-1, and increased SR Ca2+ content.