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Effects of substitution of Cx43 by Cx32 on myocardial energy metabolism, tolerance to ischaemia and preconditioning protection
Author(s) -
RodríguezSinovas Antonio,
Sánchez Jose A.,
GonzálezLoyola Alejandra,
Barba Ignasi,
Morente Miriam,
Aguilar Rio,
Agulló Esperanza,
MiróCasas Elisatet,
Esquerda Neus,
RuizMeana Marisol,
GarcíaDorado David
Publication year - 2010
Publication title -
the journal of physiology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.802
H-Index - 240
eISSN - 1469-7793
pISSN - 0022-3751
DOI - 10.1113/jphysiol.2009.186577
Subject(s) - substitution (logic) , energy metabolism , cardiology , ischemia , myocardial ischaemia , medicine , pharmacology , chemistry , computer science , programming language
Connexin 43 (Cx43) plays an important role in cardioprotective signalling by mechanisms at least in part independent of gap junctional communication. To investigate whether this role is related to specific properties of this connexin isoform, we used a knock‐in mouse model in which the coding region of Cx43 is replaced by that of Cx32. Homozygous Cx43KI32 mice showed reduced cell‐to‐cell Lucifer Yellow transfer ( P < 0.01), but QRS duration and left ventricular fractional shortening (echocardiography) were similar to those in wild‐type animals. NMR spectroscopy detected reduced ATP and increased lactate content in myocardium from homozygous Cx43KI32 animals ( P < 0.05). Despite this, isolated homozygous Cx43KI32 hearts showed smaller infarcts after ischaemia–reperfusion (40 min/60 min) as compared to hearts from heterozygous and wild‐type animals (13 and 31% reduction, respectively, P < 0.05). Cardiac myocytes isolated from Cx43KI32 mouse hearts also showed a reduced rate of cell death after simulated ischaemia–reperfusion. In a separate series of experiments, both ischaemic (4 cycles of 3.5 min of ischaemia and 5 min of reperfusion) and pharmacological (50 μmol l −1 diazoxide, 10 min) preconditioning reduced infarct size in hearts from wild‐type mice (by 24.84 and 26.63%, respectively, P < 0.05), but only ischaemic preconditioning was effective in hearts from heterozygous animals and both preconditioning strategies failed to protect Cx43KI32 homozygous hearts. These results demonstrate that Cx43 has an important and previously unknown modulatory effect in myocardial energy metabolism and tolerance to ischaemia, and plays a critical role in preconditioning protection, by mechanisms that are specific for this connexin isoform.