Heat Shock Protein 47 (HSP47) Antisense Oligonucleotides Reduce Cardiac Remodeling and Improve Cardiac Function in a Rat Model of Myocardial Infarction

Abstract

Background: Cardiac remodeling after acute myocardial infarction is regulated by components of the extracellular matrix. The 47 kD heat shock protein 47 (HSP47) is a collagen-specific molecular chaperone that plays a major role during procollagen processing and/or secretion. Objective: The purpose of the study was to determine whether HSP47 inhibition can mitigate ligated left anterior descending (LAD) coronary artery-induced myocardial infarction in rats. Methods: Rats were randomly divided into four experimental groups and subjected to the following treatments: 1) intravenous (IV) administration of saline; 2) ligation of the LAD coronary artery; 3) ligation of the LAD coronary artery + IV administration of HSP47 antisense oligonucleotides; or 4) IV administration of HSP47 antisense oligonucleotides. We investigated cardiac histopathology, performed immunoblot and immunohistochemical analyses, and examined cardiac function. Results: Rats with ligated LAD coronary artery experienced upregulation of HSP47 expression, remodeling of the left ventricle, and cardiac dysfunction. In contrast, rats with ligated LAD coronary artery treated with HSP47 antisense oligonucleotides had significantly reduced HSP47 expression, cardiac remodeling, and improved cardiac function. Intravenous (IV) administration of HSP47 antisense oligonucleotides alone had no effect on cardiac morphology. Conclusion: The data strongly support the idea that changes in the extracellular matrix and its components are important determinants of cardiac remodeling after myocardial infarction.

Key words

myocardial infarction - heart disease - myocardial protection - remodeling - gene therapy - HSP47 - antisense - rat model

References

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