权益分类	功能权益	普通用户	{{item.name}}会员
{{category.name}}	{{benefitItem.name}}

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

细胞衰老是细胞功能下降的重要现象。最近，研究表明，细胞衰老是由氧化应激在短时间内在增殖细胞中诱导的。这种现象被称为过早衰老。然而，它仍然是未知的，是否过早衰老也可以诱导心肌细胞。本研究的目的是探讨是否可以诱导衰老样表型的心肌细胞通过模拟氧化应激与阿霉素（DOX）。在从老年大鼠（24月龄）获得的心肌细胞中，与年轻大鼠相比，衰老相关的b-半乳糖苷酶（SA b-gal）染色显著增加，细胞周期蛋白依赖性激酶抑制剂（cdk-1）p21^<cip 1/waf 1>、p27^和p16 ^的蛋白或RNA水平<kip1><INK4a>增加。在老年心肌细胞中也观察到心肌肌钙蛋白I磷酸化和端粒酶活性降低。新生大鼠培养卡的处理 ...更多信息低浓度DOX（10 μ <-7>mol/L）不诱导细胞凋亡，但诱导氧化应激，这一点通过2 '，7'-二氯荧光素二乙酸酯染色证实。在DOX处理的新生心肌细胞中，观察到SA b-gal阳性染色增加，cdk-I表达，心肌肌钙蛋白I磷酸化降低，端粒酶活性降低，与老年心肌细胞相同。在DOX处理的新生心肌细胞中观察到在衰老细胞中通常观察到的mRNA表达的改变（下调：α-MHC、GATA 4、Nkx 2.5，上调：ANP、血管紧张素II受体）。我们还发现，PML蛋白和乙酰化p53，参与应激诱导的增殖细胞早衰的关键蛋白，与DOX处理的心肌细胞衰老的细胞改变有关。总之，DOX处理的心肌细胞表现出与老年大鼠心肌细胞相似的特征性变化。PML相关的p53乙酰化可能是心肌细胞衰老样改变的潜在机制。这些发现表明氧化应激诱导心肌功能障碍的一种新机制。少