Up-regulation of heme oxygenase-1 after infarct initiation reduces mortality, infarct size and left ventricular remodeling: experimental evidence and proof of concept

Journal of Translational Medicine

Antonio L’Abbate³  Nader G Abraham¹  Gualtiero Pelosi²  Nicoletta Vesentini²  Marco Matteucci³  Cristina Barsanti³  Claudia Kusmic² 

[1] Marshall University School of Medicine, Huntington, WV, USA;CNR Institute of Clinical Physiology, Via G Moruzzi 1, 56124 Pisa, Italy;Institute of Life Sciences, Scuola Superiore Sant’Anna, Pisa, Italy

关键词: Tin mesoporphyrin;    Cobalt protoporphyrin IX;    Connexin-43;    Ventricular remodeling;    Left ventricular vascularity;    Coronary microvascular reactivity;    Myocardial infarction;   

Others  :  815137
DOI  :  10.1186/1479-5876-12-89

 received in 2013-05-24, accepted in 2014-03-27,  发布年份 2014

【 摘 要 】

Background

Up-regulation of HO-1 by genetic manipulation or pharmacological pre-treatment has been reported to provide benefits in several animal models of myocardial infarction (MI). However, its efficacy following MI initiation (as in clinical reality) remains to be tested. Therefore, this study investigated whether HO-1 over-expression, by cobalt protoporphyrin (CoPP) administered after LAD ligation, is still able to improve functional and structural changes in left ventricle (LV) in a rat model of 4-week MI.

Methods

A total of 144 adult male Wistar rats were subjected to either left anterior coronary artery ligation or sham-operation. The effect of CoPP treatment (5 mg/kg i.p. at the end of the surgical session and, then, once a week for 4 weeks) was evaluated on the basis of survival, electro- and echocardiography, plasma levels of B-type natriuretic peptide (BNP), endothelin-1 and prostaglandin E2, coronary microvascular reactivity, MI size, LV wall thickness and vascularity. Besides, the expression of HO-1 and connexin-43 in different LV territories was assessed by western blot analysis and immunohistochemistry, respectively.

Results

CoPP induced an increased expression of HO-1 protein with >16 h delay. CoPP treatment significantly reduced mortality, MI size, BNP concentration, ECG alterations, LV dysfunction, microvascular constriction, capillary rarefaction and restored connexin-43 expression as compared to untreated MI. These functional and structural changes were paralleled by increased HO-1 expression in all LV territories. HO activity inhibition by tin-mesoporphyrin abolished the differences between CoPP-treated and untreated MI animals.

Conclusions

This is the first report demonstrating the putative role of pharmacological induction of HO-1 following coronary occlusion to benefit infarcted and remote territories, leading to better cardiac function in a 4-week MI outcome.

【 授权许可】

   
2014 Kusmic et al.; licensee BioMed Central Ltd.

【 图 表 】

Figure 1.

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