Deletion of the inducible 70-kDa heat shock protein genes in mice impairs cardiac contractile function and calcium handling associated with hypertrophy
Deletion of the inducible 70-kDa heat shock protein genes in mice impairs cardiac contractile function and calcium handling associated with hypertrophy
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DOI：
10.1161/circulationaha.105.598409
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发表时间：
2006-06-06
期刊：
影响因子：
37.8
通讯作者：
Dillmann, Wolfgang H.
中科院分区：
文献类型：
--
作者：
Kim, Yun-Kyung;Suarez, Jorge;Dillmann, Wolfgang H.
背景-Hspa 1a和Hspa 1b基因编码应激诱导的70-kDa热休克蛋白（Hsp 70），保护细胞免受损伤，如缺血。产生了两个基因（KO）无效突变的小鼠，并探讨了它们的心脏表型。方法和结果-KO小鼠的心率和血压正常。来自KO小鼠的心脏更容易受到缺血/再灌注引起的功能和细胞损伤。在Hsp 70-KO小鼠中出现心脏肥大。KO小鼠心肌细胞中的Ca 2+瞬变表现出延迟的（120%）钙下降和肌浆网钙含量降低。细胞缩短减少了35%，收缩和舒张速率减慢了40%。这些改变可归因于Hsp 70的缺乏，因为KO培养的心肌细胞中Hsp 70的病毒表达恢复了这些参数。肌细胞功能障碍的一个潜在机制可能是SERCA 2a表达降低。这一假设得到了长期钙下降和SERCA 2a蛋白减少的支持。病毒SERCA 2a表达恢复收缩性和Ca 2+瞬变。我们检测了Jun N-末端激酶（JNK）、p38-丝裂原活化蛋白激酶（p38-MAPK）、Raf-1和细胞外信号调节激酶（ERK）在SERCA 2a下调和KO小鼠心脏表型中的参与。磷酸化JNK、p38-MAPK、Raf-1和ERK的水平在KO心脏中升高。在正常心肌细胞中Raf-1 - ERK通路的激活导致SERCA 2a降低。结论-Hsp 70的缺失导致心肌细胞功能障碍和Hsp 70-KO心脏对缺血/再灌注的应激反应受损。此外，Hsp 70基因的缺失可能通过激活JNK、p38-MAPK、Raf-1和ERK而诱导心功能障碍和心肌肥大的发展。
Background - Hspa1a and Hspa1b genes encode stress-inducible 70-kDa heat shock proteins (Hsp70) that protect cells from insults such as ischemia. Mice with null mutations of both genes (KO) were generated, and their cardiac phenotype was explored.Methods and Results - Heart rate and blood pressures were normal in the KO mice. Hearts from KO mice were more susceptible to both functional and cellular damage by ischemia/reperfusion. Cardiac hypertrophy developed in Hsp70-KO mice. Ca2+ transients in cardiomyocytes of KO mice showed a delayed (120%) calcium decline and decreased sarcoplasmic reticulum calcium content. Cell shortening was decreased by 35%, and rates of contraction and relaxation were slower by 40%. These alterations can be attributed to the absence of Hsp70 because viral expression of Hsp70 in KO cultured cardiomyocytes restored these parameters. One mechanism underlying myocyte dysfunction could be decreased SERCA2a expression. This hypothesis was supported by a prolonged calcium decline and decreased SERCA2a protein. Viral SERCA2a expression restored contractility and Ca2+ transients. We examined the involvement of Jun N-terminal kinase (JNK), p38-mitogen-activated protein kinase (p38-MAPK), Raf-1, and extracellular signal - regulated kinase (ERK) in SERCA2a downregulation and the cardiac phenotype of KO mice. Levels of phosphorylated JNK, p38-MAPK, Raf-1, and ERK were elevated in KO hearts. Activation of the Raf-1 - ERK pathway in normal cardiomyocytes resulted in decreased SERCA2a.Conclusions - Absence of Hsp70 leads to dysfunctional cardiomyocytes and impaired stress response of Hsp70-KO hearts against ischemia/reperfusion. In addition, deletion of Hsp70 genes might induce cardiac dysfunction and development of cardiac hypertrophy through the activation of JNK, p38-MAPK, Raf-1, and ERK.