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Survivin Gene Therapy using Ultrasound-targeted Microbubble Destruction in a Rat Model of Doxorubicin-induced Cardiomyopathy

With the recent advent of gene therapy, anti-apoptotic therapy has been receiving spotlight as a potential modality to inhibit the deterioration of pump function in the failing heart. We hypothesized that anti-apoptotic therapy using survivin gene delivery will 1) salvage H9c2 cells exposed to doxorubicin toxicity, and 2) ameliorate the progressive decline in left ventricular function in a rat model of doxorubicin-induced cardiomyopathy. The in vitro data suggested that survivin successfully prevented cell death under doxorubicin stress by both direct and indirect/paracrine mechanisms. Doxorubicin-treated animals developed progressive left ventricular dysfunction as evident by echocardiography and invasive pressure-volume loop analysis, which was prevented by ultrasound-mediated survivin plasmid delivery, but not empty plasmid delivery. Post-mortem analysis of myocardial tissue indicated a lowered apoptotic index in survivin-treated hearts, with evidence of decrease in interstitial fibrosis. In conclusion, survivin gene therapy was shown to ameliorate doxorubicin-induced cardiomyopathy, by decreasing apoptosis and preventing adverse remodeling.

Identiferoai:union.ndltd.org:TORONTO/oai:tspace.library.utoronto.ca:1807/33283
Date20 November 2012
CreatorsLee, Paul Jae-Hyuk
ContributorsLeong-Poi, Howard
Source SetsUniversity of Toronto
Languageen_ca
Detected LanguageEnglish
TypeThesis

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