SIRT1 activation attenuates diastolic dysfunction by reducing cardiac fibrosis in a model of anthracycline cardiomyopathy

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• 作者：Donato Cappetta¹ ; ² ; Grazia Esposito¹ ; ² ; Elena Piegari¹ ; Rosa Russo¹ ; Loreta Pia Ciuffreda¹ ; Alessia Rivellino¹ ; Liberato Berrino¹ ; Francesco Rossi¹ ; Antonella De Angelis ; ¹ ; ³ ; ^{antonella.deangelis@unina2.it" class="auth_mail" title="E-mail the corresponding author} ; Konrad Urbanek¹ ; ³
• 关键词：Diastolic dysfunction ; Cardiac fibroblasts ; Doxorubicin-induced cardiomyopathy ; SIRT1 ; Resveratrol
• 刊名：International Journal of Cardiology
• 出版年：2016
• 出版时间：15 February 2016
• 年：2016
• 卷：205
• 期：Complete
• 页码：99-110
• 全文大小：2652 K

文摘

Doxorubicin (DOXO) is an effective anti-neoplastic drug but its clinical benefits are hampered by cardiotoxicity. Oxidative stress, apoptosis and myocardial fibrosis mediate the anthracycline cardiomyopathy. ROS trigger TGF-β pathway that activates cardiac fibroblasts promoting fibrosis. Myocardial stiffness contributes to diastolic dysfunction, less studied aspect of anthracycline cardiomyopathy. Considering the role of SIRT1 in the inhibition of the TGF-β/SMAD3 pathway, resveratrol (RES), a SIRT1 activator, might improve cardiac function by interfering with the development of cardiac fibrosis in a model of DOXO-induced cardiomyopathy.

Methods

F344 rats received a cumulative dose of 15 mg/kg of DOXO in 2 weeks or DOXO + RES (DOXO and RES, 2.5 mg/kg/day, concomitantly for 2 weeks and then RES alone for 1 more week). The effects of RES on cardiac fibroblasts were also tested in vitro.

Results

Along with systolic dysfunction, DOXO was also responsible of diastolic abnormalities. Myocardial stiffness correlated with fibroblast activation and collagen deposition. DOXO + RES co-treatment significantly improved ± dP/dt and, more interestingly, ameliorated end-diastolic pressure/volume relationship. Treatment with RES resulted in reduced fibrosis and fibroblast activation and, most importantly, the mortality rate was significantly reduced in DOXO + RES group. Fibroblasts isolated from DOXO + RES-treated rats, in which SIRT1 was upregulated, showed decreased levels of TGF-β and pSMAD3/SMAD3 when compared to cells isolated from DOXO-exposed hearts.

Conclusions

Our findings reveal a key role of SIRT1 in supporting animal survival and functional parameters of the heart. SIRT1 activation by interfering with fibrogenesis can improve relaxation properties of myocardium and attenuate myocardial remodeling related to chemotherapy.