Gul Rukhsana, Park Dae-Ryoung, Shawl Asif Iqbal, Im Soo-Yeul, Nam Tae-Sik, Lee Sun-Hwa, Ko Jae-Ki, Jang Kyu Yoon, Kim Donghee, Kim Uh-Hyun
Department of Biochemistry, Chonbuk National University Medical School, Jeonju, Korea.
National Creative Research Laboratory for Ca2+ signaling Network, Chonbuk National University Medical School, Jeonju, Korea.
PLoS One. 2016 Mar 9;11(3):e0149125. doi: 10.1371/journal.pone.0149125. eCollection 2016.
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.
Ca2+信号在心脏肥厚性重塑中起重要作用，但其潜在机制仍知之甚少。我们研究了Ca2+动员第二信使NAADP和环ADP核糖（cADPR）在异丙肾上腺素β-肾上腺素能刺激诱导的心脏肥大中的作用。异丙肾上腺素诱导了最初的Ca2+瞬变，随后是持续的Ca2+升高。用8-溴-cADPR抑制cADPR途径仅消除了持续的Ca2+增加，而用巴弗洛霉素A1抑制NAADP途径则消除了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。NAADP和cADPR的顺序产生得到了生化证实。在从CD38基因敲除小鼠获得的心肌细胞中，异丙肾上腺素介导的Ca2+增加和cADPR产生，但不是NAADP产生，明显减少。CD38基因敲除小鼠从慢性异丙肾上腺素输注诱导的心肌肥大、间质纤维化以及缩短分数和射血分数降低中得到挽救。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+信号促进适应性不良的心脏肥大的发展。
