title: Aldehyde dehydrogenase activation prevents reperfusion arrhythmias by inhibiting local renin release from cardiac mast cells.
abstract: 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.
  
  
  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.affiliation: Department of Pharmacology, Weill Cornell Medical College, New York, NY 10065, USA.
authors.forename: Kenichiro
authors.initials: K
authors.lastname: Koda
authors.forename: Mariselis
authors.initials: M
authors.lastname: Salazar-Rodriguez
authors.forename: Federico
authors.initials: F
authors.lastname: Corti
authors.forename: Noel Yan-Ki
authors.initials: NY
authors.lastname: Chan
authors.forename: Racha
authors.initials: R
authors.lastname: Estephan
authors.forename: Randi B
authors.initials: RB
authors.lastname: Silver
authors.forename: Daria
authors.initials: D
authors.lastname: Mochly-Rosen
authors.forename: Roberto
authors.initials: R
authors.lastname: Levi
mesh_terms: D000444:Aldehyde Dehydrogenase / Q000502:physiology*; D000818:Animals; D001145:Arrhythmias, Cardiac / Q000517:prevention & control*; D015550:Cell Degranulation; D045744:Cell Line, Tumor; D004789:Enzyme Activation; D006168:Guinea Pigs; D006801:Humans; D019157:Ischemic Preconditioning, Myocardial; D008297:Male; D008407:Mast Cells / Q000502:physiology*; D015428:Myocardial Reperfusion Injury / Q000517:prevention & control*; D032383:Myocytes, Cardiac / Q000378:metabolism*; D051744:Protein Kinase C-epsilon / Q000502:physiology; D043704:Receptor, Adenosine A2B / Q000502:physiology; D043684:Receptor, Adenosine A3 / Q000502:physiology; D012083:Renin / Q000378:metabolism; D012084:Renin-Angiotensin System / Q000502:physiology; D000092502:Renin Inhibitors
chemical_list: D000444:Aldehyde Dehydrogenase; D051744:Protein Kinase C-epsilon; D043704:Receptor, Adenosine A2B; D043684:Receptor, Adenosine A3; D012083:Renin; D000092502:Renin Inhibitors