Nicotinic acid adenine dinucleotide phosphate (NAADP) and cyclic ADP-Ribose (cADPR) mediate Ca²⁺signaling in cardiac hypertrophy induced by β-Adrenergic Stimulation

Ca²⁺ signaling plays a fundamental role in cardiac hypertrophic remodeling, but the underlying mechanisms remain poorly understood. We investigated the role of Ca²⁺mobilizing second messengers, NAADP and cADPR, in the cardiac hypertrophy induced by βadrenergic stimulation by isoproterenol. Isoproterenol induced an initial Ca²⁺ transients followed by sustained Ca²⁺rises. Inhibition of the cADPR pathway with 8BrcADPR abolished only the sustained Ca²⁺ increase, whereas inhibition of the NAADP pathway with bafilomycinA1 abolished both rapid and sustained phases of the isoproterenolmediated signal, indicating that the Ca²⁺ signal is mediated by a sequential action of NAADP and cADPR. The sequential production of NAADP and cADPR was confirmed biochemically. The isoproterenolmediated Ca²⁺ increase and cADPR production, but not NAADP production, were markedly reduced in cardiomyocytes obtained from CD38 knockout mice. CD38 knockout mice were rescued from chronic isoproterenol infusioninduced myocardial hypertrophy, interstitial fibrosis, and decrease in fractional shortening and ejection fraction. Thus, our findings indicate that βadrenergic stimulation contributes to the development of maladaptive cardiac hypertrophy via Ca²⁺ signaling mediated by NAADPsynthesizing enzyme and CD38 that produce NAADP and cADPR, respectively.