Document Detail


Aldehyde dehydrogenase activation prevents reperfusion arrhythmias by inhibiting local renin release from cardiac mast cells.
MedLine Citation:
PMID:  20697027     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
BACKGROUND: Renin released by ischemia/reperfusion from cardiac mast cells activates a local renin-angiotensin system (RAS). This exacerbates norepinephrine release and reperfusion arrhythmias (ventricular tachycardia and fibrillation), 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 ischemia/reperfusion (20 minutes of ischemia/30 minutes of reperfusion) was preceded by IPC (two 5-minute ischemia/reperfusion cycles), renin and norepinephrine release and ventricular tachycardia and fibrillation duration were markedly decreased, a cardioprotective anti-RAS effect. Activation and blockade of adenosine A(2b)/A(3) receptors and activation and inhibition of protein kinase Cepsilon (PKCepsilon) mimicked and prevented, respectively, the anti-RAS effects of IPC. Moreover, activation of A(2b)/A(3) receptors or activation of PKCepsilon 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, PKCepsilon and ALDH2 were both activated by A(2b)/A(3) receptor stimulation in HMC-1, and PKCepsilon inhibition prevented ALDH2 activation.
CONCLUSIONS: The results uncover a signaling cascade initiated by A(2b)/A(3) receptors, which triggers PKCepsilon-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 classic IPC in which cardiac myocytes are the main target, cardiac mast cells are the critical site at which the cardioprotective anti-RAS effects of IPC develop.
Authors:
Kenichiro Koda; Mariselis Salazar-Rodriguez; Federico Corti; Noel Yan-Ki Chan; Racha Estephan; Randi B Silver; Daria Mochly-Rosen; Roberto Levi
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Publication Detail:
Type:  Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't     Date:  2010-08-09
Journal Detail:
Title:  Circulation     Volume:  122     ISSN:  1524-4539     ISO Abbreviation:  Circulation     Publication Date:  2010 Aug 
Date Detail:
Created Date:  2010-08-24     Completed Date:  2010-09-15     Revised Date:  2014-09-22    
Medline Journal Info:
Nlm Unique ID:  0147763     Medline TA:  Circulation     Country:  United States    
Other Details:
Languages:  eng     Pagination:  771-81     Citation Subset:  AIM; IM    
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MeSH Terms
Descriptor/Qualifier:
Aldehyde Dehydrogenase / physiology*
Animals
Arrhythmias, Cardiac / prevention & control*
Cell Degranulation
Cell Line, Tumor
Enzyme Activation
Guinea Pigs
Humans
Ischemic Preconditioning, Myocardial
Male
Mast Cells / physiology*
Myocardial Reperfusion Injury / prevention & control*
Myocytes, Cardiac / metabolism*
Protein Kinase C-epsilon / physiology
Receptor, Adenosine A2B / physiology
Receptor, Adenosine A3 / physiology
Renin / antagonists & inhibitors*,  secretion
Renin-Angiotensin System / physiology
Grant Support
ID/Acronym/Agency:
AA11147/AA/NIAAA NIH HHS; HL34215/HL/NHLBI NIH HHS; HL46403/HL/NHLBI NIH HHS; HL47073/HL/NHLBI NIH HHS; HL73400/HL/NHLBI NIH HHS; P01 HL046403/HL/NHLBI NIH HHS; P01 HL046403-190001/HL/NHLBI NIH HHS; R01 HL034215/HL/NHLBI NIH HHS; R01 HL034215-34A1/HL/NHLBI NIH HHS; R01 HL047073/HL/NHLBI NIH HHS; R01 HL047073-13/HL/NHLBI NIH HHS; R01 HL073400/HL/NHLBI NIH HHS; R01 HL073400-05/HL/NHLBI NIH HHS; R37 AA011147/AA/NIAAA NIH HHS; UL1-RR024996/RR/NCRR NIH HHS
Chemical
Reg. No./Substance:
0/Receptor, Adenosine A2B; 0/Receptor, Adenosine A3; EC 1.2.1.3/Aldehyde Dehydrogenase; EC 2.7.11.13/Protein Kinase C-epsilon; EC 3.4.23.15/Renin
Comments/Corrections
Comment In:
Circulation. 2010 Aug 24;122(8):761-3   [PMID:  20697024 ]

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