Abstract
After severe myocardial infarction (MI), heart failure results from ischemia, fibrosis, and remodeling. A promising therapy to enhance cardiac function and induce therapeutic angiogenesis via a paracrine mechanism in MI is myoblast sheet transplantation. We hypothesized that in a rat model of MI-induced chronic heart failure, this therapy could be further improved by overexpression of the antiapoptotic, antifibrotic, and proangiogenic hepatocyte growth factor (HGF) in the myoblast sheets. We studied the ability of wild type (L6-WT) and human HGF-expressing (L6-HGF) L6 myoblast sheet-derived paracrine factors to stimulate cardiomyocyte, endothelial cell, or smooth muscle cell migration in culture. Further, we studied the autocrine effect of hHGF-expression on myoblast gene expression profiles by use of microarray analysis. We induced MI in Wistar rats by left anterior descending coronary artery (LAD) ligation and allowed heart failure to develop for 4 weeks. Thereafter, we administered L6-WT (n = 15) or L6-HGF (n = 16) myoblast sheet therapy. Control rats (n = 13) underwent LAD ligation and rethoracotomy without therapy, and five rats underwent a sham operation in both surgeries. We evaluated cardiac function with echocardiography at 2 and 4 weeks after therapy, and analyzed cardiac angiogenesis and left ventricular architecture from histological sections at 4 weeks. Paracrine mediators from L6-HGF myoblast sheets effectively induced migration of cardiac endothelial and smooth muscle cells but not cardiomyocytes. Microarray data revealed that hHGF-expression modulated myoblast gene expression. In vivo, L6-HGF sheet therapy effectively stimulated angiogenesis in the infarcted and non-infarcted areas. Both L6-WT and L6-HGF therapies enhanced cardiac function and inhibited remodeling in a similar fashion. In conclusion, L6-HGF therapy effectively induced angiogenesis in the chronically failing heart. Cardiac function, however, was not further enhanced by hHGF expression.
Highlights
The quiescent post-inflammatory scar tissue after myocardial infarction (MI) impairs cardiac function and restricts ventricular dilatation
We evaluated the amount of hHGF protein secreted into the culture medium from the L6-Hepatocyte growth factor (HGF) myoblast sheets
To ascertain that the hHGF produced by the myoblast sheets was active on primary cells isolated from rat myocardium, we determined by a scratch-wound assay the ability and selectivity of myoblast-secreted hHGF to induce cell migration in these cultures containing cardiomyocytes, endothelial cells, smooth muscle cells, and fibroblasts
Summary
The quiescent post-inflammatory scar tissue after myocardial infarction (MI) impairs cardiac function and restricts ventricular dilatation. The active processes such as inflammation, cell death and necrosis, proteolytic activity, and overall tissue response to ischemia have gradually ended, and the tissue has become fibrotic, quiescent, and dysfunctional. In chronic heart failure (HF), regeneration of such fibroblast- and collagenrich scar tissue depleted of myocytes has proved to be an extensive task for pharmacological or cellular therapy. Acute myocardial infarction [2], ischemia reperfusion injury [3], and congestive heart failure [4] induce expression of HGF. HGF has been suggested to counteract damage and to mediate a regenerative response [5]. Extensive research has focused on the beneficial effect of HGF in the acute early stages of MI; little is known, about the role HGF plays in the chronic stage of HF
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