cMyBP-C was decreased via KLHL3-mediated proteasomal degradation in congenital heart diseases.
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.
Department of Clinical Genetics, Shengjing Hospital of China Medical University, Shenyang, Liaoning, 110000, China; Department of Medical Genetics, China Medical University, Shenyang 110000, Liaoning, China.
Leitong
L
Wang
Department of Clinical Genetics, Shengjing Hospital of China Medical University, Shenyang, Liaoning, 110000, China.
Guangrui
G
Lai
Department of Clinical Genetics, Shengjing Hospital of China Medical University, Shenyang, Liaoning, 110000, China.
Guoming
G
Chu
Department of Clinical Genetics, Shengjing Hospital of China Medical University, Shenyang, Liaoning, 110000, China.
Xiaoyan
X
Liang
Department of Clinical Genetics, Shengjing Hospital of China Medical University, Shenyang, Liaoning, 110000, China; Department of Medical Genetics, China Medical University, Shenyang 110000, Liaoning, China. Electronic address: yyzhao@sj-hospital.org.
Yanyan
Y
Zhao
D048868:Adaptor Proteins, Signal Transducing; D000818:Animals; D002352:Carrier Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D002478:Cells, Cultured; D005260:Female; D006330:Heart Defects, Congenital / Q000378:metabolism*; D006710:Homocysteine / Q000494:pharmacology; D006801:Humans; D008840:Microfilament Proteins; D011247:Pregnancy; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism*; D051381:Rats; D000099163:Myosin Binding Protein C
D048868:Adaptor Proteins, Signal Transducing; D002352:Carrier Proteins; D006710:Homocysteine; D008840:Microfilament Proteins; D046988:Proteasome Endopeptidase Complex; D000099163:Myosin Binding Protein C; C489837:KLHL3 protein, human
Cardiac myosin binding protein C (cMyBP-C); Congenital heart diseases (CHD); Homocysteine (Hcy); Kelch like protein 3 (KLHL3); Ubiquitin–proteasome pathway