The mechanism of senescence in cardiomyocytes and application of a therapeutic approach for heart failure

心肌细胞衰老机制及其在心力衰竭治疗中的应用

基本信息

批准号：
17590711
负责人：
ADACHI Susumu
金额：
$ 1.79万
依托单位：
TOKYO MEDICAL AND DENTAL UNIVERSITY
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (C)
财政年份：
2005
资助国家：
日本
起止时间：
2005 至 2006
项目状态：
已结题

来源：
https://kaken.nii.ac.jp/en/grant/KAKENHI-PROJECT-17590711/
关键词：
cardiomyocytes premature senescence cell cycle cardiac fibroblast doxorubicin 老化心不全 SA-β-gal

项目摘要

Cellular senescence is an important phenomenon in decreased cellular function. Recently, it was shown that cellular senescence is induced in proliferating cells within a short period of time by oxidative stresses. This phenomenon is known as premature senescence. However, it is still unknown whether premature senescence can be also induced in cardiomyocytes. The aim of the present study was to investigate whether a senescence-like phenotype can be induced in cardiomyocytes by simulating oxidative stress with doxorubicin (DOX). In cardiomyocytes obtained from aged rats (24 months of age), the staining for senescence-associated b-galactosidase (SA b-gal) increased significantly and the protein or RNA lelvels of cyclin-dependent kinase inhibitors (cdk-Is) p21^<cip1/waf1>, p27^<kip1> andp16^<INK4a> increased compared to those of young rats. Decreased cardiac troponin I phosphorylation and telomerase activity were also observed in aged cardiomyocytes. Treatment of cultured neonatal rat card … More iomyocytes with a low concentration of DOX (10^<-7>mol/L) did not induce apoptosis but did induce oxidative stress, which was confirmed by 2', 7'-dichlorofluorescin diacetate staining. In DOX-treated neonatal cardiomyocytes, increased positive staining for SA b-gal, cdk-I expression, decreased cardiac troponin I phosphorylation, and decreased telomerase activity were observed, as aged cardiomyocytes. Alterations in mRNA expression typically seen in aged cells were observed in DOX-treated neonatal cardiomyocytes (downregulation : a-MHC, GATA4, Nkx2.5, upregulation : ANP, angiotensin II receptor). We also found that PML protein and acetylated p53, key proteins involved in stress-induced premature senescence in proliferating cells, were associated with cellular alterations of senescence in DOX-treated cardiomyocytes. In conclusion, cardiomyocytes treated with DOX showed characteristic changes similar to cardiomyocytes of aged rats. PML-related p53 acetylation may be an underlying mechanism of senescence-like alterations in cardiomyocytes. These findings indicate a novel mechanism of myocardial dysfunction induced by oxidative stress. Less

细胞衰老在短时间内通过氧化应力降低了细胞。通过用阿霉素（Dox）模拟氧化应激（DOX）。（CDK-IS）与年轻大鼠相比，P21^<CIP1/WAF1>，P27^<kip1>和P16^<ink4a>增加了。使用L）TAL心肌细胞，SA B-GAL的正态增加，CDK-I表达，心脏肌钙蛋白iPhosphoration降低，端粒酶降低，在DOX治疗的Neonatal cardionyocycytes（A-Mhc，a-mhc，a-mhc，a-mhc，a-neonatal cartymerocyts）中观察到了老化的心肌细胞。 GATA4，NKX2.5，上调：ANP，血管紧张素II受体。大鼠。与PML相关的P53乙酰化可能表明氧化应激诱导的心肌功能障碍的新机制。