cMyBP-C was decreased via KLHL3-mediated proteasomal degradation in congenital heart diseases
cMyBP-C was decreased via KLHL3-mediated proteasomal degradation in congenital heart diseases
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先天性心脏病中 cMyBP-C 通过 KLHL3 介导的蛋白酶体降解而减少
DOI：
10.1016/j.yexcr.2017.03.025
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发表时间：
2017
影响因子：
3.7
通讯作者：
Zhao Yanyan
中科院分区：
文献类型：
--
作者：
Wang Leitong;Lai Guangrui;Chu Guoming;Liang Xiaoyan;Zhao Yanyan
心肌肌球蛋白结合蛋白C（cMyBP-C）是一种心脏结构和调节蛋白; cMyBP-C的突变经常与肥厚型心肌病（HCM）和扩张型心肌病（DCM）相关。心脏特异性转录因子可能调控cMyBP-C的表达。然而，cMyBP-C在先天性心脏病（CHD）中的作用仍然知之甚少。在目前的研究中，蛋白质印迹和MRM方法显示，与没有CHD的胎儿相比，CHD胎儿的cMyBP-C表达显著降低。进一步通过免疫沉淀和免疫荧光实验发现cMyBP-C与KLHL 3相互作用，cMyBP-C的降解是由KLHL 3介导的泛素化引起的。此外，同型半胱氨酸（Hcy，CHD的危险因素）治疗引起cMyBP-C的减少和KLHL 3的表达增加，和蛋白酶体抑制剂MG 132逆转Hcy诱导的cMyBP-C表达减少。最后，我们证实了同型半胱氨酸减少cMyBP-C促进心肌细胞凋亡。这些结果表明，Hcy通过KLHL 3介导的泛素-蛋白酶体途径降低cMyBP-C的表达，从而影响心脏发育。
Cardiac myosin binding protein C (cMyBP-C) is a cardiac structural and regulatory protein; mutations of cMyBP-C are frequently associated with hypertrophic cardiomyopathy (HCM) and dilated cardiomyopathy (DCM). Cardiac special transcription factors may regulate the expression of cMyBP-C. However, the role of cMyBP-C in congenital heart diseases (CHD) remains poorly understood. In the current study, western blotting and the MRM approach showed that cMyBP-C expression was significantly reduced in fetuses with CHD compared to those without. Furthermore, we found that cMyBP-C interacted with KLHL3 by immunoprecipitation and immunofluorescence, and the degradation of cMyBP-C was caused by KLHL3-mediated ubiquitination. In addition, homocysteine (Hcy, a risk factor of CHD) treatment caused a decrease in cMyBP-C and an increase in KLHL3 expression, and the proteasome inhibitor MG132 reversed the Hcy-induced reduction of cMyBP-C expression. Finally, we verified that reduced cMyBP-C by Hcy promoted apoptosis in cardiomyocytes. These results demonstrate that Hcy decreases the expression of cMyBP-C through a KLHL3-mediated ubiquitin–proteasome pathway, and thereby influences heart development.