Department of Cardiovascular Diseases, Mayo Clinic , Rochester, Minnesota.
Shanghai Institute of Cardiovascular disease, Zhongshan Hospital, Fudan University , Shanghai , China.
Am J Physiol Heart Circ Physiol. 2018 Nov 1;315(5):H1127-H1136. doi: 10.1152/ajpheart.00685.2017. Epub 2018 Jul 13.
Cardiac fibrosis is a biological process that increases with age and contributes to myocardial dysfunction. Humanin (HN) is an endogenous mitochondria-derived peptide that has cytoprotective effects and reduces oxidative stress. The present study aimed to test the hypothesis that chronic supplementation of exogenous HN in middle-aged mice could prevent and reverse cardiac fibrosis and apoptosis in the aging heart. Female C57BL/6N mice at 18 mo of age received 14-mo intraperitoneal injections of vehicle (old group; n = 6) or HN analog (HNG; 4 mg/kg 2 times/wk, old + HNG group, n = 8) and were euthanized at 32 mo of age. C57BL/6N female mice (young group, n = 5) at 5 mo of age were used as young controls. HNG treatment significantly increased the ratio of cardiomyocytes to fibroblasts in aging hearts, as shown by the percentage of each cell type in randomly chosen fields after immunofluorescence staining. Furthermore, the increased collagen deposition in aged hearts was significantly reduced after HNG treatment, as indicated by picrosirius red staining. HNG treatment also reduced in aging mice cardiac fibroblast proliferation (5'-bromo-2-deoxyuridine staining) and attenuated transforming growth factor-β, fibroblast growth factor-2, and matrix metalloproteinase-2 expression (immunohistochemistry or real-time PCR). Myocardial apoptosis was inhibited in HNG-treated aged mice (TUNEL staining). To decipher the pathway involved in the attenuation of the myocardial fibrosis by HNG, Western blot analysis was done and showed that HNG upregulated the Akt/glycogen synthase kinase -3β pathway in aged mice. Exogenous HNG treatment attenuated myocardial fibrosis and apoptosis in aged mice. The results of the present study suggest a role for the mitochondria-derived peptide HN in the cardioprotection associated with aging. NEW & NOTEWORTHY Cardiac fibrosis is a biological process that increases with age and contributes to myocardial dysfunction. Humanin is an endogenous mitochondria-derived peptide that has cytoprotective effects and reduces oxidative stress. Here, we demonstrate, for the first time, that exogenous humanin treatment attenuated myocardial fibrosis and apoptosis in aging mice. We also detected upregulated Akt/glycogen synthase kinase-3β pathway in humanin analog-treated mice, which might be the mechanism involved in the cardioprotective effect of humanin analog in aging mice.
心肌纤维化是一种随年龄增长而增加的生物学过程，可导致心肌功能障碍。人源素（HN）是一种内源性线粒体衍生肽，具有细胞保护作用并减少氧化应激。本研究旨在验证以下假设：在中年小鼠中慢性补充外源性 HN 可预防和逆转衰老心脏中的心肌纤维化和细胞凋亡。18 月龄的雌性 C57BL/6N 小鼠接受了 14 个月的腹腔内注射载体（老年组；n = 6）或 HN 类似物（HNG；4mg/kg，每周 2 次，老年+HNG 组，n = 8），并在 32 月龄时安乐死。5 月龄的 C57BL/6N 雌性小鼠（年轻组，n = 5）用作年轻对照。HNG 处理显著增加了衰老心脏中心肌细胞与成纤维细胞的比例，这通过免疫荧光染色后随机选择的视野中每种细胞类型的百分比来显示。此外，在用 HNG 处理后，衰老心脏中胶原沉积的增加显著减少，如天狼猩红染色所示。HNG 处理还降低了衰老小鼠心脏成纤维细胞的增殖（5'-溴-2-脱氧尿苷染色），并减弱了转化生长因子-β、成纤维细胞生长因子-2 和基质金属蛋白酶-2 的表达（免疫组织化学或实时 PCR）。HNG 处理的衰老小鼠心肌细胞凋亡受到抑制（TUNEL 染色）。为了解 HNG 减轻心肌纤维化的途径，进行了 Western blot 分析，结果表明 HNG 上调了衰老小鼠中的 Akt/糖原合酶激酶-3β途径。外源性 HNG 处理可减轻衰老小鼠的心肌纤维化和细胞凋亡。本研究的结果表明，线粒体衍生肽 HN 在与衰老相关的心脏保护中起作用。
