Adenylyl cyclase type V deletion increases basal left ventricular function and reduces left ventricular contractile responsiveness to β-adrenergic stimulation

Abstract

We tested the hypothesis that deletion of adenylyl cyclase type V(ACV) would be associated with decreased left ventricular (LV) contractile function and responsiveness to β-adrenergic receptor (βAR) stimulation. Absence of cardiac ACV expression was confirmed by RT-PCR and immunoblotting in ACV-deleted mice (ACV -/-). Compared to sibling mice with normal amounts of ACV (CON), basal and water-soluble forskolin derivative NKH477-stimulated cAMP production was reduced in both LV homogenates and in isolated cardiac myocytes. Basal LV +dP/dt (isolated perfused hearts) was increased (CON: 3649 ± 247 mmHg/s; ACV -/-: 4625 ± 350 mmHg/s; p = 0.035, n = 10), but the potency of dobutamine on LV +dP/dt was decreased by ACV deletion (log EC50: CON: -6.83 ± 0.14 M; ACV -/-: -5.99 ± 0.15 M; p =0.0007, n = 10). The initial rates of ATP-dependent sarcoplasmic reticulum calcium uptake, assessed in LV homogenates, showed that ACV deletion increased SERCA2a affinity for Ca2+ (log EC50: CON: -5.94 ± 0.03 M; ACV -/-:-6.09 ± 0.02 M; p = 0.001, n = 8). ACV deletion is also associated with increased phospholamban phosphorylation, decreased type 1 protein phosphatase catalytic subunit content and activity, and reduced cardiac Gαs protein content. In conclusion, ACV deletion has a favorable effect on basal LV function despite reduced cAMP levels. Increased SERCA2a affinity for Ca2+ and increased phospholamban phosphorylation are contributing factors. However, ACV deletion is associated with reduced LV contractile responsiveness to βAR stimulation, an effect that is associated with reduced Gαs protein content and reduced cAMP generating capacity in cardiac myocytes. © Steinkopff-Verlag 2006.