Cardiac ankyrin repeat protein contributes to dilated cardiomyopathy and heart failure
Cardiac ankyrin repeat protein contributes to dilated cardiomyopathy and heart failure
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DOI：
10.1096/fj.201902802rr
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发表时间：
2021-04
期刊：
影响因子：
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通讯作者：
Na Zhang;Feiming Ye;Yu Zhou;Wei Zhu;Cuiping Xie;Haiqiong Zheng;Han Chen;Jinghai Chen;Xiaojie Xie
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文献类型：
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作者：
Na Zhang;Feiming Ye;Yu Zhou;Wei Zhu;Cuiping Xie;Haiqiong Zheng;Han Chen;Jinghai Chen;Xiaojie Xie
心脏锚蛋白重复序列蛋白（CARP）是一种心脏特异性应激反应蛋白，在病理刺激下发挥多种作用调节心脏重塑。我们研究了基础条件下CARP在小鼠出生后心脏发育和功能中的作用。通过超声心动图和组织学染色评估，在心脏中选择性过表达CARP的转基因小鼠（CARP Tg）表现出扩张的心腔、受损的心脏功能和心脏纤维化。此外，这些小鼠的寿命较短，对缺血性急性心肌梗死的存活率也较低。免疫荧光显示CARP蛋白主要聚集在心肌细胞核中。微阵列分析显示，CARP的核定位与钙处理蛋白的抑制有关。体外实验表明，CARP过表达导致细胞收缩和钙瞬变减少。在扩张型心肌病和终末期心力衰竭患者的尸检心脏标本中，CARP显著增加。总之，我们的数据确定CARP是扩张型心肌病和心力衰竭的关键因素，这与其对钙处理蛋白的调节有关。
Cardiac ankyrin repeat protein (CARP) is a cardiac‐specific stress‐response protein which exerts diverse effects to modulate cardiac remodeling in response to pathological stimuli. We examined the role of CARP in postnatal cardiac development and function under basal conditions in mice. Transgenic mice that selectively overexpressed CARP in heart (CARP Tg) exhibited dilated cardiac chambers, impaired heart function, and cardiac fibrosis as assessed by echocardiography and histological staining. Furthermore, the mice had a shorter lifespan and reduced survival rate in response to ischemic acute myocardial infarction. Immunofluorescence demonstrated the overexpressed CARP protein was predominantly accumulated in the nuclei of cardiomyocytes. Microarray analysis revealed that the nuclear localization of CARP was associated with the suppression of calcium‐handling proteins. In vitro experiments revealed that CARP overexpression resulted in decreased cell contraction and calcium transient. In post‐mortem cardiac specimens from patients with dilated cardiomyopathy and end‐stage heart failure, CARP was significantly increased. Taken together, our data identified CARP as a crucial contributor in dilated cardiomyopathy and heart failure which was associated with its regulation of calcium‐handling proteins.