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1.  Aldehyde dehydrogenase activation prevents reperfusion arrhythmias by inhibiting local renin release from cardiac mast cells 
Circulation  2010;122(8):771-781.
Background
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.
Methods and Results
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.
Conclusions
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.
doi:10.1161/CIRCULATIONAHA.110.952481
PMCID: PMC2927811  PMID: 20697027
Renin; Ischemia; Reperfusion; Norepinephrine; Arrhythmia

Results 1-1 (1)