Gul R1,2, Park DR1,2, Shawl AI1,2, Im SY1,2, Nam TS1,2, Lee SH3, Ko JK3,4, Jang KY5, Kim D6, Kim UH1,2,4.
Abstract
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 β-adrenergic stimulation by isoproterenol. Isoproterenol induced an initial Ca2+ transients followed by sustained Ca2+ rises. Inhibition of the cADPR pathway with 8-Br-cADPR abolished only the sustained Ca2+ increase, whereas inhibition of the NAADP pathway with bafilomycin-A1 abolished both rapid and sustained phases of the isoproterenol-mediated 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 isoproterenol-mediated 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 infusion-induced myocardial hypertrophy, interstitial fibrosis, and decrease in fractional shortening and ejection fraction. Thus, our findings indicate that β-adrenergic stimulation contributes to the development of maladaptive cardiac hypertrophy via Ca2+ signaling mediated by NAADP-synthesizing enzyme and CD38 that produce NAADP and cADPR, respectively.
A schematic model showing signaling pathways underlying β-AR-mediated NAADP-synthesizing enzyme and CD38 activation.
Binding of ISO to β-AR stimulates AC, thus activating PKA. PKA induces Ca2+ influx that leads to activation of an NAADP-synthesizing enzyme (NSE) to produce NAADP. NAADP-mediated Ca2+ mobilization from the acidic Ca2+ stores results in activation of CD38. cADPR produced by CD38 in the endocytic vesicles induces Ca2+ release from SR Ca2+ stores. cADPR-mediated Ca2+ release induces SOCE, resulting in a sustained Ca2+ signal. NE: norepinephrine; SR: sarcoplasmic reticulum; NSE: NAADP-synthesizing enzyme; AC, adenylyl cyclase; PKA, protein kinase A; SOCE, store-operated Ca2+ entry.
Date from PubMed(http://www.ncbi.nlm.nih.gov/pubmed/26959359)