Cardiac Overexpression of S100A6 Attenuates Cardiomyocyte Apoptosis and Reduces Infarct Size After Myocardial Ischemia‐Reperfusion

Background Cardiomyocyte‐specific transgenic mice overexpressing S100A6, a member of the family of EF‐hand calcium‐binding proteins, develop less cardiac hypertrophy, interstitial fibrosis, and myocyte apoptosis after permanent coronary ligation, findings that support S100A6 as a potential therapeut...

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Published in:	Journal of the American Heart Association Vol. 6; no. 2
Main Authors:	Mofid, Azadeh, Newman, Nadav S., Lee, Paul J. H., Abbasi, Cynthia, Matkar, Pratiek N., Rudenko, Dmitriy, Kuliszewski, Michael A., Chen, Hao H., Afrasiabi, Kolsoom, Tsoporis, James N., Gramolini, Anthony O., Connelly, Kim A., Parker, Thomas G., Leong‐Poi, Howard
Format:	Journal Article
Language:	English
Published:	England John Wiley and Sons Inc 01-02-2017 Wiley
Subjects:	Animals Animals, Newborn Apoptosis Blotting, Western Cell Cycle Proteins - biosynthesis Cell Cycle Proteins - genetics Disease Models, Animal Gene Expression Regulation, Developmental gene therapy hypertrophy Immunohistochemistry In Situ Nick-End Labeling ischemia‐reperfusion Myocardial Infarction - etiology Myocardial Infarction - genetics Myocardial Infarction - metabolism Myocardial Reperfusion Injury - complications Myocardial Reperfusion Injury - metabolism Myocytes, Cardiac - metabolism Myocytes, Cardiac - pathology Original Research Rats Rats, Inbred F344 Real-Time Polymerase Chain Reaction RNA - genetics S100 Calcium Binding Protein A6 - biosynthesis S100 Calcium Binding Protein A6 - genetics S100A6 Signal Transduction ultrasound‐targeted microbubble destruction S100A6 apoptosis gene therapy ultrasound‐targeted microbubble destruction ischemia‐reperfusion hypertrophy
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Summary:	Background Cardiomyocyte‐specific transgenic mice overexpressing S100A6, a member of the family of EF‐hand calcium‐binding proteins, develop less cardiac hypertrophy, interstitial fibrosis, and myocyte apoptosis after permanent coronary ligation, findings that support S100A6 as a potential therapeutic target after acute myocardial infarction. Our purpose was to investigate S100A6 gene therapy for acute myocardial ischemia‐reperfusion. Methods and Results We first performed in vitro studies to examine the effects of S100A6 overexpression and knockdown in rat neonatal cardiomyocytes. S100A6 overexpression improved calcium transients and protected against apoptosis induced by hypoxia‐reoxygenation via enhanced calcineurin activity, whereas knockdown of S100A6 had detrimental effects. For in vivo studies, human S100A6 plasmid or empty plasmid was delivered to the left ventricular myocardium by ultrasound‐targeted microbubble destruction in Fischer‐344 rats 2 days prior to a 30‐minute ligation of the left anterior descending coronary artery followed by reperfusion. Control animals received no therapy. Pretreatment with S100A6 gene therapy yielded a survival advantage compared to empty‐plasmid and nontreated controls. S100A6‐pretreated animals had reduced infarct size and improved left ventricular systolic function, with less myocyte apoptosis, attenuated cardiac hypertrophy, and less cardiac fibrosis. Conclusions S100A6 overexpression by ultrasound‐targeted microbubble destruction helps ameliorate myocardial ischemia‐reperfusion, resulting in lower mortality and improved left ventricular systolic function post–ischemia‐reperfusion via attenuation of apoptosis, reduction in cardiac hypertrophy, and reduced infarct size. Our results indicate that S100A6 is a potential therapeutic target for acute myocardial infarction.
Bibliography:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23
ISSN:	2047-9980 2047-9980
DOI:	10.1161/JAHA.116.004738