Abstract
We have previously shown that distal anterior wall ischemia/reperfusion induces gene expression changes in the proximal anterior myocardial area, involving genes responsible for cardiac remodeling. Here we investigated the molecular signals of the ischemia non-affected remote lateral and posterior regions and present gene expression profiles of the entire left ventricle by using our novel and straightforward method of 2D and 3D image reconstruction. Five or 24h after repetitive 10min ischemia/reperfusion without subsequent infarction, pig hearts were explanted and myocardial samples from 52 equally distributed locations of the left ventricle were collected. Expressional changes of seven genes of interest (HIF-1α; caspase-3, transcription factor GATA4; myocyte enhancer factor 2C /MEF2c/; hexokinase 2 /HK2/; clusterin /CLU/ and excision repair cross-complementation group 4 /ERCC4/) were measured by qPCR. 2D and 3D gene expression maps were constructed by projecting the fold changes on the NOGA anatomical mapping coordinates. Caspase-3, GATA4, HK2, CLU, and ERCC4 were up-regulated region-specifically in the ischemic zone at 5 h post ischemia/reperfusion injury. Overexpression of GATA4, clusterin and ERCC4 persisted after 24 h. HK2 showed strong up-regulation in the ischemic zone and down-regulation in remote areas at 5 h, and was severely reduced in all heart regions at 24 h. These results indicate a quick onset of regulation of apoptosis-related genes, which is partially reversed in the late phase of ischemia/reperfusion cardioprotection, and highlight variations between ischemic and unaffected myocardium over time. The NOGA 2D and 3D construction system is an attractive method to visualize expressional variations in the myocardium.
Highlights
Metabolism and gene expression patterns are changing intensively in the ischemic regions of an infarcted heart, and remote heart regions respond to the injury quickly
We have previously shown that distal anterior wall ischemia/reperfusion induces gene expression changes in the proximal anterior myocardial area, involving genes responsible for cardiac remodeling
Expressional changes of seven genes of interest (HIF-1α; caspase-3, www.impactjournals.com/oncotarget transcription factor GATA4; myocyte enhancer factor 2C /MEF2c/; hexokinase 2 / HK2/; clusterin /CLU/ and excision repair cross-complementation group 4 /ERCC4/) were measured by qPCR. 2D and 3D gene expression maps were constructed by projecting the fold changes on the NOGA anatomical mapping coordinates
Summary
Metabolism and gene expression patterns are changing intensively in the ischemic regions of an infarcted heart, and remote heart regions respond to the injury quickly. Conditioning of the heart against ischemic injury is one of the most potent mechanisms to prevent the heart from ischemic damage [3,4,5,6,7]. Single or repetitive brief intervals of ischemia and reperfusion (r-I/R) induce cardioprotective effects against a subsequent ischemic insult. The second window of protection (SWOP) is mainly relying on transcriptional regulation, mediated by activation of kinases and transcription factors, and subsequent effects of proteins generated de novo. Clinical translation of ischemic preconditioning is difficult to achieve for practical reasons, elucidation of the underlying mechanisms might lead to identification of potential modulating agents and molecular targets for the development of novel therapeutic strategies [7]
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