Aldehyde dehydrogenase activation prevents reperfusion arrhythmias by inhibiting local renin release from cardiac mast cells.
Aldehyde dehydrogenase activation prevents reperfusion arrhythmias by inhibiting local renin release from cardiac mast cells.
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DOI：
10.1161/circulationaha.110.952481
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发表时间：
2010-08-24
期刊：
影响因子：
37.8
通讯作者：
Levi R
中科院分区：
文献类型：
--
作者：
Koda K;Salazar-Rodriguez M;Corti F;Chan NY;Estephan R;Silver RB;Mochly-Rosen D;Levi R
心肌肥大细胞缺血再灌注(I/R)释放的肾素可激活局部肾素-血管紧张素系统(RAS)。这加剧了去甲肾上腺素释放和再灌注性心律失常(VT/VF)，使RAS成为治疗心肌缺血的新靶点。我们研究了缺血预适应(IPC)是否能在体外阻止豚鼠心脏RAS的激活。I/R(20min缺血/30min再灌流)先于IPC(2×5min I/R循环)，肾素和去甲肾上腺素释放明显减少，VT/VF持续时间明显缩短，具有抗RAS的心肌保护作用。激活和阻断腺苷A2B/A3受体和激活和抑制PKCε分别模拟和阻止IPC的抗RAS作用。此外，激活A2B/A3受体或激活PKCε可阻止过氧化氢引起的肥大细胞脱颗粒和肾素释放。激活和抑制线粒体乙醛脱氢酶-2(ALDH2)也分别模拟和阻止IPC的心脏保护抗RAS效应。此外，ALDH2的激活抑制了HMC-1中反应性醛的脱颗粒和肾素的释放。值得注意的是，A2B/A3受体刺激均可激活PKCε和ALDH2，抑制PKCε可阻止ALDH2的激活。这些结果揭示了由A2B/A3受体启动的信号级联反应，它触发了PKCε介导的心肌肥大细胞ALDH2的激活，通过阻止肥大细胞肾素的释放和局部RAS激活的功能障碍而有助于IPC诱导的心脏保护。因此，与心肌细胞是主要靶点的经典IPC不同，心肌肥大细胞是IPC发挥心脏保护抗RAS效应的关键部位。
Renin released by ischemia/reperfusion (I/R) from cardiac mast cells activates a local renin-angiotensin system (RAS). This exacerbates norepinephrine release and reperfusion arrhythmias (VT/VF), making RAS a new therapeutic target in myocardial ischemia. We investigated whether ischemic preconditioning (IPC) prevents cardiac RAS activation in guinea-pig hearts ex-vivo. When I/R (20-min ischemia/30-min reperfusion) was preceded by IPC (2×5-min I/R cycles), renin and norepinephrine release and VT/VF duration were markedly decreased, a cardioprotective anti-RAS effect. Activation and blockade of adenosine A2b/A3-receptors, and activation and inhibition of PKCε, mimicked and prevented, respectively, the anti-RAS effects of IPC. Moreover, activation of A2b/A3-receptors, or activation of PKCε, prevented degranulation and renin release elicited by peroxide in cultured mast cells (HMC-1). Activation and inhibition of mitochondrial aldehyde dehydrogenase type-2 (ALDH2) also mimicked and prevented, respectively, the cardioprotective anti-RAS effects of IPC. Furthermore, ALDH2 activation inhibited degranulation and renin release by reactive aldehydes in HMC-1. Notably, PKCε and ALDH2 were both activated by A2b/A3-receptor stimulation in HMC-1, and PKCε inhibition prevented ALDH2 activation. The results uncover a signaling cascade initiated by A2b/A3-receptors, which triggers PKCε-mediated ALDH2 activation in cardiac mast cells, contributing to IPC-induced cardioprotection by preventing mast-cell renin release and the dysfunctional consequences of local RAS activation. Thus, unlike classical IPC where cardiac myocytes are the main target, cardiac mast cells are the critical site at which the cardioprotective anti-RAS effects of IPC develop.