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学科主题: 基础医学
题名:
Cardioprotection by CaMKII-delta B Is Mediated by Phosphorylation of Heat Shock Factor 1 and Subsequent Expression of Inducible Heat Shock Protein 70
作者: Peng, Wei2; Zhang, Yan2,3; Zheng, Ming2; Cheng, Heping2; Zhu, Weizhong; Cao, Chun-Mei2; Xiao, Rui-Ping1
关键词: CaMKII isoforms ; CaMKII-delta B ; oxidative stress ; hypoxia ; cardiomyocyte apoptosis ; iHSP70 ; HSF1
刊名: CIRCULATION RESEARCH
发表日期: 2010-01-08
DOI: 10.1161/CIRCRESAHA.109.210914
卷: 106, 期:1, 页:102-110
收录类别: SCI
文章类型: Article
WOS标题词: Science & Technology
类目[WOS]: Cardiac & Cardiovascular Systems ; Hematology ; Peripheral Vascular Disease
研究领域[WOS]: Cardiovascular System & Cardiology ; Hematology
关键词[WOS]: CA2+/CALMODULIN-DEPENDENT PROTEIN-KINASE ; MUSCLE CELL APOPTOSIS ; TRANSCRIPTION FACTOR ; CARDIAC-HYPERTROPHY ; IN-VIVO ; BETA(1)-ADRENERGIC STIMULATION ; DILATED CARDIOMYOPATHY ; INDEPENDENT ACTIVATION ; VENTRICULAR MYOCYTES ; INHIBITION PROTECTS
英文摘要:

Rationale: Ca(2+)/calmodulin-dependent protein kinase (CaMK)II is a multifunctional kinase involved in vital cellular processes such as Ca(2+) handling and cell fate regulation. In mammalian heart, 2 primary CaMKII isoforms, delta B and delta C, localize in nuclear and cytosolic compartments, respectively. Although previous studies have established an essential role of CaMKII-delta C in cardiomyocyte apoptosis, the functional role of the more abundant isoform, CaMKII-delta B, remains elusive.

Objective: Here, we determined the potential role of CaMKII-delta B in regulating cardiomyocyte viability and explored the underlying mechanism.

Methods and Results: In cultured neonatal rat cardiomyocytes, the expression of CaMKII-delta B and CaMKII-delta C was inversely regulated in response to H(2)O(2)-induced oxidative stress with a profound reduction of the former and an increase of the later. Similarly, in vivo ischemia/reperfusion (IR) led to an opposite regulation of these CaMKII isoforms in a rat myocardial IR model. Notably, overexpression of CaMKII-delta B protected cardiomyocytes against oxidative stress-, hypoxia-, and angiotensin II-induced apoptosis, whereas overexpression of its cytosolic counterpart promoted apoptosis. Using cDNA microarray, real-time PCR and Western blotting, we demonstrated that overexpression of CaMKII-delta B but not CaMKII-delta C elevated expression of heat shock protein (HSP)70 family members, including inducible (i)HSP70 and its homolog (Hst70). Moreover, overexpression of CaMKII-delta B led to phosphorylation and activation of heat shock factor (HSF)1, the primary transcription factor responsible for HSP70 gene regulation. Importantly, gene silencing of iHSP70, but not Hst70, abolished CaMKII-delta B-mediated protective effect, indicating that only iHSP70 was required for CaMKII-delta B elicited antiapoptotic signaling.

Conclusions: We conclude that cardiac CaMKII-delta B and CaMKII-delta C were inversely regulated in response to oxidative stress and IR injury, and that in contrast to CaMKII-delta C, CaMKII-delta B serves as a potent suppressor of cardiomyocyte apoptosis triggered by multiple death-inducing stimuli via phosphorylation of HSF1 and subsequent induction of iHSP70, marking both CaMKII-delta isoforms as promising therapeutic targets for the treatment of ischemic heart disease. (Circ Res. 2010;106:102-110.)

语种: 英语
所属项目编号: 2007CB512100
项目资助者: Peking University ; 973 Program ; NIH ; National Institute on Aging
WOS记录号: WOS:000273403600018
Citation statistics:
内容类型: 期刊论文
URI标识: http://ir.bjmu.edu.cn/handle/400002259/67215
Appears in Collections:基础医学院_心血管所_期刊论文

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作者单位: 1.NIA, Cardiovasc Sci Lab, Ctr Gerontol Res, NIH, Baltimore, MD 21224 USA
2.Peking Univ, Inst Mol Med, Beijing 100871, Peoples R China
3.Peking Univ, Inst Cardiovasc Sci, Beijing 100871, Peoples R China

Recommended Citation:
Peng, Wei,Zhang, Yan,Zheng, Ming,et al. Cardioprotection by CaMKII-delta B Is Mediated by Phosphorylation of Heat Shock Factor 1 and Subsequent Expression of Inducible Heat Shock Protein 70[J]. CIRCULATION RESEARCH,2010,106(1):102-110.
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