Nicotinic Acid Adenine Dinucleotide Phosphate (NAADP) and Cyclic ADP-Ribose (cADPR) Mediate Ca2+ Signaling in Cardiac Hypertrophy Induced by β-Adrenergic Stimulation.
Nicotinic Acid Adenine Dinucleotide Phosphate (NAADP) and Cyclic ADP-Ribose (cADPR) Mediate Ca2+ Signaling in Cardiac Hypertrophy Induced by β-Adrenergic Stimulation.
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DOI：
10.1371/journal.pone.0149125
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发表时间：
2016
期刊：
影响因子：
3.7
通讯作者：
Kim UH
中科院分区：
文献类型：
--
作者：
Gul R;Park DR;Shawl AI;Im SY;Nam TS;Lee SH;Ko JK;Jang KY;Kim D;Kim UH
Ca2+信号在心脏肥厚重塑中起着重要作用，但其潜在机制尚不清楚。我们研究了Ca2+动员第二信使NAADP和cADPR在异丙肾上腺素刺激β-肾上腺素能引起的心肌肥厚中的作用。异丙肾上腺素诱导最初的Ca2+瞬态，随后持续的Ca2+升高。用8-Br-cADPR抑制cADPR通路仅能消除持续的Ca2+增加，而用巴非霉素- a1抑制NAADP通路可同时消除异丙肾上腺素介导信号的快速和持续阶段，表明Ca2+信号是由NAADP和cADPR的顺序作用介导的。生物化学证实了NAADP和cADPR的顺序产生。在CD38敲除小鼠的心肌细胞中，异丙肾上腺素介导的Ca2+增加和cADPR的产生，而不是NAADP的产生，明显减少。CD38基因敲除小鼠从慢性异丙肾上腺素输注引起的心肌肥大、间质纤维化、缩短分数和射血分数降低中获救。因此，我们的研究结果表明，β-肾上腺素能刺激通过分别产生NAADP和cADPR的NAADP合成酶和CD38介导的Ca2+信号传导促进了适应性不良心脏肥厚的发展。
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.