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Sunitinib malate is a multi-targeted tyrosine kinase inhibitor used extensively for treatment of human tumors. However, cardiovascular adverse effects of sunitinib limit its clinical use. It is pivotal to elucidate molecular targets that mediate sunitinib-induced cardiotoxicity. Sirtuin 3 (Sirt3) is an effective mitochondrial deacetylase that has been reported to regulate sensitivity of different types of cells to chemotherapies, but roles of Sirt3 in sunitinib-induced cardiotoxicity have not been investigated. In the present study, we established wild type, Sirt3-knockout, and Sirt3-overexpressing mouse models of sunitinib (40 mg kg−1 day−1 for 28 days)-induced cardiotoxicity and examined cardiovascular functions and pathological changes. We further cultured wild type, Sirt3-knockout, and Sirt3-overexpressing primary mouse cardiac pericytes and analyzed sunitinib (10 μMol for 48 h)-induced alterations in cellular viability, cell death processes, and molecular pathways. Our results show that sunitinib predominantly induced hypertension, left ventricular systolic dysfunction, and cardiac pericyte death accompanied with upregulation of Sirt3 in cardiac pericytes, and these cardiotoxicities were significantly attenuated in Sirt3-knockout mice, but aggravated in Sirt3-overexpressing mice. Mechanistically, sunitinib induced cardiac pericyte death through inhibition of GSTP1/JNK/autophagy pathway and Sirt3 interacted with and inhibited GSTP1, further inhibiting the pathway and aggravating sunitinib-induced pericyte death. Conclusively, we demonstrate that Sirt3 promotes sensitivity to sunitinib-induced cardiotoxicity via GSTP1/JNK/autophagy pathway. Our results suggest Sirt3 might be a potential target for developing cardioprotective therapies for sunitinib-receiving patients. [ABSTRACT FROM AUTHOR]

Background and Objective: MicroRNA (miR)-499 rs3746444 polymorphisms may participate in the pathogenesis of autoimmune diseases, but the results remain conflicting. We further investigated this association using a meta-analysis. Methods: We conducted a retrieval of studies and obtained the eligible studies if they met inclusion criteria. Two researchers independently extracted the data from original articles. The genotype frequencies were analysed using Stata software. Results: We finally archived six eligible studies that included 1,118 cases and 1,673 controls. After pooling the data, the results indicated that homozygote TT had an overall association with autoimmune diseases (TC + CC vs. TT: odds ratio [OR] 1.31, 95 % CI 1.11-1.55, p = 0.001). The allele C, genotype TC and CC, may be associated with rheumatoid arthritis (RA) risks in Mediterranean populations (C vs. T: OR 2. 00, 95 % CI 1.37-2.91, p < 0.001; TC vs. CC + TT: OR 1.76, 95 % CI 1.27-2.44; p = 0.001; CC vs. TC + TT: OR 2.31, 95 % CI 1.24-4.27, p = 0.008; CC vs. TT: OR 2.92, 95 % CI 1.59-5.37 , p = 0.001; TC vs. TT: OR 1.98, 95 % CI 1.42-2.77). The genotype TT may decrease the risk of RA in Mediterranean populations (TC + CC vs. TT: OR 2.15, 95 % CI 1.57-2.94, p < 0.001) rather than in East Asians. Conclusions: This study suggested that miR-499 polymorphisms were associated with a significantly increased risk of RA in Mediterranean populations. [ABSTRACT FROM AUTHOR]