Adriamycin (ADM) is one of the most effective chemotherapeutic agents used against verity of cancers. Despite its clinical efficacy, the drug is therapeutically associated wih selective toxicity to the heart. Patients with ADM therapy often develop delayed cardiomyopathy and overt congestive heart failure. In the past decade, considerable efforts have been made to develop a therapy which could block ADM cardio-toxicity, but still no effective therapy is available to combat an establish ADM cardiomyopathy. Cardiac transplantation remains the only definitive solution to improve survival of patients with irreversible ADM cardiomyopathy. The underlying mechanism of this drug toxicity is not yet fully understood, but it is generally believe that increased production of reactive oxygen species (ROS) from mitochondria is involved. Because discontinuation of ADM therapy for a cancer patient is difficult, new understanding is needed to define the underlying mechanism causing this drug toxicity, and to identify new therapeutic targets which could be used to protect the heart from ADM cardiomyopathy. My laboratory has specific interest in sirtuins, which are capable of protecting the heart from variou pathological stimuli. Recently, we identified a sirtuin isoform, SIRT3 which protects cardiomyocytes from oxidative stress-mediated cell death. SIRT3-deficent mice develop cardiomyopathy associated with interstitial fibrosis, and transgenic mice with cardiac-specific over expression of SIRT3 are protected from developing catecholamine-induced cardiomyopathy and heart failure. We also found that SIRT3 levels are significantly reduced during ADM cardio-toxicity, and over expression of SIRT3 protects hearts from ADM-mediated loss of cardiac function. Furthermore, our preliminary data show that ADM-cardio-toxicity is associated with massive acetylation of mitochondrial proteins, and that this effect can be blocked by over expression of SIRT3. These observations led us to hypothesize that SIRT3 has the potential to protect the heart from ADM mediated cardiac injury. Therefore, by maintaining or elevating intracellular levels of SIRT3 cardiomyopathy resulting from ADM therapy can be prevented. We will test this hypothesis in the following three aims. (1) Study whether SIRT3 activation can block ADM-mediated death of cardiomyocytes and differentiation of cardiac fibroblasts to myofibroblasts and the development of cardiomyopathy in mice. (2) Determine the underlying mechanisms through which SIRT3 protects the heart from ADM-mediated cardiomyopathy. (3) Study whether pharmacological candidates capable of activating endogenous SIRT3 levels hold the potential to block ADM cardiomyopathy without compromising anti-cancer activity of the drug. A successful outcome of these three aims will advance our understanding of the basic mechanism causing ADM cardiomyopathy, and that this may guide us to develop new therapeutic strategies to combating selective toxicity of anti- cancer drugs to the heart.
Anticancer drugs often exert serious side effects to the heart. Patients receiving adriamycin (ADM) anti-cancer therapy develop delayed cardiomyopathy, which is a precursor to congestive heart failure. Besides cardiac transplantation, no effective therapy is presently available to reverse an established ADM cardiomyopathy. My laboratory has identified a molecule called SIRT3, which protects the heart from various oxidative stresses. This project is designed to test the hypothesis whether SIRT3 activation can block development of ADM cardiomyopathy without compromising anti-cancer activity of the drug.
|Pillai, Vinodkumar B; Bindu, Samik; Sharp, Will et al. (2016) Sirt3 protects mitochondrial DNA damage and blocks the development of doxorubicin-induced cardiomyopathy in mice. Am J Physiol Heart Circ Physiol 310:H962-72|
|Samant, Sadhana A; Pillai, Vinodkumar B; Sundaresan, Nagalingam R et al. (2015) Histone Deacetylase 3 (HDAC3)-dependent Reversible Lysine Acetylation of Cardiac Myosin Heavy Chain Isoforms Modulates Their Enzymatic and Motor Activity. J Biol Chem 290:15559-69|
|Sundaresan, Nagalingam R; Bindu, Samik; Pillai, Vinodkumar B et al. (2015) SIRT3 Blocks Aging-Associated Tissue Fibrosis in Mice by Deacetylating and Activating Glycogen Synthase Kinase 3Î². Mol Cell Biol 36:678-92|
|Pillai, Vinodkumar B; Samant, Sadhana; Sundaresan, Nagalingam R et al. (2015) Honokiol blocks and reverses cardiac hypertrophy in mice by activating mitochondrial Sirt3. Nat Commun 6:6656|
|Samant, Sadhana A; Zhang, Hannah J; Hong, Zhigang et al. (2014) SIRT3 deacetylates and activates OPA1 to regulate mitochondrial dynamics during stress. Mol Cell Biol 34:807-19|
|Ming, Mei; Han, Weinong; Zhao, Baozhong et al. (2014) SIRT6 promotes COX-2 expression and acts as an oncogene in skin cancer. Cancer Res 74:5925-33|
|Nagalingam, Raghu S; Sundaresan, Nagalingam R; Noor, Mariam et al. (2014) Deficiency of cardiomyocyte-specific microRNA-378 contributes to the development of cardiac fibrosis involving a transforming growth factor Î² (TGFÎ²1)-dependent paracrine mechanism. J Biol Chem 289:27199-214|
|Pillai, Vinodkumar B; Sundaresan, Nagalingam R; Gupta, Mahesh P (2014) Regulation of Akt signaling by sirtuins: its implication in cardiac hypertrophy and aging. Circ Res 114:368-78|
|Pillai, Vinodkumar B; Sundaresan, Nagalingam R; Kim, Gene et al. (2013) Nampt secreted from cardiomyocytes promotes development of cardiac hypertrophy and adverse ventricular remodeling. Am J Physiol Heart Circ Physiol 304:H415-26|
|Sundaresan, Nagalingam R; Vasudevan, Prabhakaran; Zhong, Lei et al. (2012) The sirtuin SIRT6 blocks IGF-Akt signaling and development of cardiac hypertrophy by targeting c-Jun. Nat Med 18:1643-50|