Sirtuin 3 (SIRT3) is a deacetylase important for antioxidant protection, cell longevity, and aging. We hypothesized that SIRT3 improve oxidative resistance of aged cells and improve cell therapy in aged patients. In vitro, the proliferation and oxidative resistance of human mesenchymal stem cells (hMSCs) significantly declined with age. The expression and activity of antioxidant enzymes, including catalase (CAT) and manganese superoxide dismutase (MnSOD), increased after transfection of SIRT3 in hMSCs from older donors (O-hMSCs). The protein level of Forkhead box O3a (FOXO3a) in nucleus increased after SIRT3 overexpression. The antioxidant capacity of O-hMSCs increased after SIRT3 overexpression. 3-Amino-1,2,4-triazole (3-AT, CAT inhibitor) or diethyldithiocarbamate (DETC, SOD inhibitor) that was used to inhibit CAT or SOD activity significantly blocked the antioxidant function of SIRT3. When two inhibitors were used together, the antioxidant function of SIRT3 almost disappeared. Following myocardial infarction and intramyocardial injections of O-hMSCs in rats in vivo, the survival rate of O-hMSCs increased by SIRT3 transfection. The cardiac function of rats was improved after SIRT3-overexpressed O-hMSC transplantation. The infarct size, collagen content, and expression levels of matrix metalloproteinase 2 (MMP2) and MMP9 decreased. Besides, the protein level of vascular endothelial growth factor A and vascular density increased after cell transplantation with SIRT3-modified O-hMSCs. These results indicate that damage resistance of hMSCs decline with age and SIRT3 might protect O-hMSCs against oxidative damage by activating CAT and MnSOD through transferring FOXO3a into nucleus. Meanwhile, the therapeutic effect of aged hMSC transplantation can be improved by SIRT3 overexpression.

中文翻译：

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SIRT3 转染老龄人骨髓间充质干细胞可改善细胞治疗介导的心肌修复。

Sirtuin 3 (SIRT3) 是一种脱乙酰酶，对抗氧化保护、细胞寿命和衰老很重要。我们假设 SIRT3 可提高老年细胞的抗氧化能力并改善老年患者的细胞治疗。在体外，人类间充质干细胞（hMSCs）的增殖和抗氧化能力随着年龄的增长而显着下降。SIRT3转染后抗氧化酶的表达和活性增加，包括过氧化氢酶（CAT）和锰超氧化物歧化酶（MnSOD）在来自老年捐赠者的 hMSC (O-hMSC) 中。SIRT3过表达后细胞核中Forkhead box O3a（FOXO3a）的蛋白水平增加。SIRT3过表达后O-hMSCs的抗氧化能力增加。用于抑制 CAT 或 SOD 活性的 3-Amino-1,2,4-triazole（3-AT，CAT 抑制剂）或二乙基二硫代氨基甲酸酯（DETC，SOD 抑制剂）显着阻断了 SIRT3 的抗氧化功能。当两种抑制剂一起使用时，SIRT3的抗氧化功能几乎消失了。大鼠心肌梗塞和体内注射O-hMSCs后，SIRT3提高了O-hMSCs的存活率转染。SIRT3过表达的O-hMSC移植后大鼠心功能得到改善。梗死面积、胶原含量和基质金属蛋白酶 2 (MMP2) 和 MMP9 的表达水平降低。此外，用SIRT3修饰的O-hMSCs进行细胞移植后，血管内皮生长因子A的蛋白质水平和血管密度增加。这些结果表明，hMSCs 的抗损伤能力随着年龄的增长而下降，SIRT3 可能通过将 FOXO3a 转移到细胞核中激活 CAT 和 MnSOD 来保护 O-hMSCs 免受氧化损伤。同时，SIRT3过表达可以提高老年hMSC移植的治疗效果。