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SIRT3 Blocks Doxorubicin Induced Cardiac Hypertrophic Response by Suppressing ROS Synthesis from Mitochondria
Author(s) -
Pillai Vinodkumar,
Samant Sadhana,
Kim Gene,
Gupta Mahesh
Publication year - 2015
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.29.1_supplement.977.11
Subject(s) - sirt3 , doxorubicin , pharmacology , medicine , endogeny , mitochondrion , endocrinology , cancer research , chemistry , sirtuin , chemotherapy , biochemistry , enzyme , nad+ kinase
Background and Objective Doxorubicin is widely used to treat different types of cancers. Most serious adverse effect of doxorubicin is cardiomyopathy. Here we investigated whether the mitochondrial deacetylase SIRT3 can attenuate doxorubicin induced cardiac hypertrophy in mice. Methods and Results Doxorubicin treatment induced increased ROS levels in cardiomyocytes, which was significantly reduced by the overexpression of SIRT3. Further, SIRT3 overexpression significantly decreased doxorubicin induced cardiomyocyte death. Doxorubicin also induced exacerbated mitochondrial DNA damage in SIRT3 knockout cardiac fibroblasts (CF) as well as in mouse embryonic fibroblasts (MEFs). These results suggest that SIRT3 is capable of reducing doxorubicin induced ROS synthesis from mitochondria, thereby blocking its deleterious effects. To examine the cardioprotective effects of SIRT3 from doxorubicin induced damage in vivo, we treated wild type and cardiac‐specific SIRT3 over‐expressing transgenic mice with a cumulative dose of 15mg/kg of doxorubicin. Mice expressing cardiac‐specific SIRT3 (Sirt3‐Tg) showed 33% reduced HW/BW ratio compared to control mice. Echocardiographic evaluation of hearts showed significantly reduced fractional shortening in control mice compared to Sirt3‐Tg mice (24.6 vs 34.7 %, P<0.05)). Further, Masson's trichrome staining showed significantly reduced fibrosis in doxorubicin treated Sirt3‐Tg mice, compared to controls, thus suggesting that SIRT3 is capable of blocking doxorubicin‐induced cardiac hypertrophic response. Conclusion Our study suggests that SIRT3 is an endogenous negative regulator of doxorubicin induced cardiac hypertrophic response.