Heme oxygenase-1 prevents heart against myocardial infarction by attenuating ischemic injury-induced cardiomyocytes senescence
Heme oxygenase-1 prevents heart against myocardial infarction by attenuating ischemic injury-induced cardiomyocytes senescence
复制标题
血红素加氧酶-1 通过减轻缺血损伤诱导的心肌细胞衰老来预防心脏心肌梗死
DOI：
10.1016/j.ebiom.2018.11.056
复制
发表时间：
2019-01-01
期刊：
影响因子：
11.1
通讯作者：
Shan, Hongli
中科院分区：
文献类型：
--
作者：
Shan, Huitong;Li, Tianyu;Shan, Hongli
背景资料：细胞衰老是由端粒缩短和氧化应激、癌基因激活、DNA损伤等多种细胞应激引起的细胞周期稳定停滞。血红素加氧酶-1（HO-1）是一种可诱导的应激反应蛋白，具有抗氧化和抗凋亡作用。方法：采用超声心动图技术观察HO-1对心肌梗死（MI）小鼠和老年小鼠心功能的影响。Western blot检测衰老标志物p53、p16和LaminB的表达。采用免疫荧光和免疫组化方法检测p16蛋白的表达水平。SA-β-Gal染色显示心肌细胞衰老水平。结果：我们发现氯化血红素显著诱导HO-1的表达，其显著抑制含有衰老相关分泌表型的心肌细胞衰老分泌。进一步的研究表明，全身性HO-1转基因过表达通过抑制衰老诱导的细胞外基质沉积和纤维化来改善心脏功能。更重要的是，氯化血红素治疗改善了MI小鼠的心脏功能。此外，HO-1的强制表达在自然衰老小鼠和原代培养的新生小鼠cardiomyocytes.Interpretation中减弱了心肌细胞衰老：我们的研究表明，HO-1改善了心脏功能，并减弱了由缺血性损伤和衰老引发的心肌细胞衰老。此外，HO-1诱导减轻H2 O2诱导的心肌细胞衰老。最后，我们的研究提出了HO-1发挥心脏保护作用的新机制。基金：本研究得到了国家自然科学基金（81770284，单红丽）;和国家自然科学基金（81673425，81872863，周宇红）。国家自然科学基金项目（81473213徐朝乾）。国家重点研发计划项目（2017 YFC 1307403，杨宝峰），国家自然科学基金项目（81730012，杨宝峰）。(c)2018作者由Elsevier B出版。诉
Background: Cellular senescence is a stable cell-cycle arrest induced by telomere shortening and various types of cellular stress including oxidative stress, oncogene activation, DNA damage etc. Heme oxygenase-1 (HO-1) is an inducible stress-response protein that plays antioxidant and anti-apoptotic effects. However, the role and underlying mechanisms of HO-1 in cellular senescence in heart are largely unknown.Methods: Echocardiographywas employed to detect the effect of HO-1 on heart function in adult micewith myocardial infarction (MI) and aged mice. The senescence markers, p53, p16 and LaminB, were analyzed bywestern blot. The immunofluorescence and immunohistochemical staining were applied to analyze the expression level of p16. SA-beta-Gal staining showed the level of cardiomyocyte senescence.Findings: We found that hemin significantly induced the expression of HO-1, which notably suppressed cardiomyocyte senescence containing the secretion of senescence-associated secretory phenotype. Further studies showed that systemic HO-1 transgenic overexpression improved heart function by inhibiting aging-induced extracellularmatrix deposition and fibrogenesis. More importantly, treatment of hemin improved heart function in MI mice. Furthermore, forced expression of HO-1 blunted cardiomyocyte senescence in natural aged mice and in primary cultured neonatal mouse cardiomyocytes.Interpretation: Our study revealed that HO-1 improved heart function and attenuated cardiomyocyte senescence triggered by ischemic injury and aging. In addition, HO-1 induction alleviated H2O2-induced cardiomyocyte senescence. Finally, our study suggested a novel mechanism of HO-1 to play cardioprotective effect.Fund: This studywas supported by the National Natural Science Foundation of China (81770284 to Hongli Shan); and the National Natural Science Foundation of China (81673425, 81872863 to Yuhong Zhou). The National Natural Science Foundation of China (81473213 to Chaoqian Xu). National Key R&D Program of China (2017YFC1307403 to Baofeng Yang), National Natural Science Foundation of China (81730012 to Baofeng Yang). (c) 2018 The Authors. Published by Elsevier B. V.