SIRT1 in the cardiomyocyte protects mitochondria and the heart against doxorubicin treatment in mice

Identification: Hosoda, Ryusuke


Description

SIRT1 in the cardiomyocyte protects mitochondria and the heart against doxorubicin treatment in mice
 
Ryusuke Hosoda, Atsushi Kuno, Yoshiyuki Horio
Department of Pharmacology, Sapporo Medical University School of Medicine, Japan
 
Background: Mitochondrial damage plays a key role in pathogenesis of doxorubicin (DOX)-induced cardiotoxicity. SIRT1 is an NAD+-dependent deacetylase that promotes cellular adaptation in response to various stresses, in part, by maintaining mitochondrial function. Here, we examined whether SIRT1 in the cardiomyocyte affords protection against DOX-induced cardiotoxicity by using cardiomyocyte-specific SIRT1 knockout mice, and, if any, whether SIRT1 attenuates mitochondrial damage.
Methods and Results: DOX (4 IP injections of 5 mg/kg/week) was administered to mice with cardiomyocyte-specific deletion of SIRT1 by tamoxifen (SIRT1 cKO) and mice without Cre recombinase served as wild type (WT). In Experiment 1, cardiac tissues sampled at 1 week after final DOX injection were examined. Echocardiography at baseline showed that left ventricular (LV) dimension and LV fractional shortening (%FS, 32.7 vs. 33.8%), an index of LV systolic function, were comparable in WT and SIRT1 cKO. Dox treatment significantly reduced %FS in both mice.  However, %FS after DOX was lower in SIRT1 cKO than in WT (24.6 vs. 27.3%, P<0.05). Cardiac mRNA levels of ANP and BNP, markers of cardiac dysfunction, were significantly higher in SIRT1 cKO than those in WT (2.4-fold and 2.4-fold, respectively, P<0.05). Transcript levels of nuclear-encoded mitochondrial genes (Tfam, Cox5b, Atp5a1, and citrate synthase) were unchanged in the SIRT1 cKO heart. In Experiment 2, both genotypes of mice received vehicle (PBS) or DOX at the same dose as in Experiment 1, and cardiac tissues were sampled. In DOX-treated mice, myocardial level of an oxidative stress marker nitrotyrosine was significantly higher (+68%) in SIRT1 cKO than that in WT. The myocardial mitochondrial DNA (mtDNA) copy number determined by qPCR was not changed in SIRT1 cKO compared with WT after DOX. However, level of mtDNA deletion analyzed by a long-range PCR method was significantly increased by DOX in SIRT1 cKO, but such a change was not observed in WT.  
Conclusion: The findings suggest that SIRT1 in the cardiomyocyte protects against doxorubicin-induced cardiac dysfunction in mice, probably by reducing damaged mitochondria and oxidative stress.  

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