Oxidized Low-density Lipoprotein (ox-LDL) Cholesterol Induces the Expression of miRNA-223 and L-type Calcium Channel Protein in Atrial Fibrillation

• Published in: Scientific reports 2016-08, Vol.6 (1), p.30368-30368, Article 30368
• Main Authors: He, Fengping, Xu, Xin, Yuan, Shuguo, Tan, Liangqiu, Gao, Lingjun, Ma, Shaochun, Zhang, Shebin, Ma, Zhanzhong, Jiang, Wei, Liu, Fenglian, Chen, Baofeng, Zhang, Beibei, Pang, Jungang, Huang, Xiuyan, Weng, Jiaqiang
• Format: Article
• Language: English
• Subjects: 13; 13/106; 13/51; 42; 42/109; 42/35; 692/4017; 692/4019; 692/53; Adult; Aged; Animals; Arrhythmia; Atrial Fibrillation - blood; Biomarkers - blood; Calcium channels; Calcium channels (L-type); Calcium Channels, L-Type - blood; Calcium Channels, L-Type - genetics; Calcium currents; Calcium homeostasis; Cardiac arrhythmia; Cardiovascular diseases; Cholesterol; Computer applications; Coronary artery disease; Dogs; Female; Fibrillation; Gene Expression Profiling; Heart diseases; Homeostasis; Humanities and Social Sciences; Humans; Lipoproteins, LDL - blood; Low density lipoprotein; Male; Mice; Mice, Inbred C57BL; MicroRNAs - blood; Middle Aged; miRNA; Morbidity; multidisciplinary; Protein expression; Proteins; Rheumatic heart disease; Rheumatic Heart Disease - blood; Rheumatic Heart Disease - genetics; Rodents; Science; Transcription; Transfection; Up-Regulation; Young Adult
• ISSN: 2045-2322; 2045-2322
• DOI: 10.1038/srep30368

Atrial fibrillation (AF) is the most common sustained arrhythmia causing high morbidity and mortality. While changing of the cellular calcium homeostasis plays a critical role in AF, the L-type calcium channel α1c protein has suggested as an important regulator of reentrant spiral dynamics and is a major component of AF-related electrical remodeling. Our computational modeling predicted that miRNA-223 may regulate the CACNA1C gene which encodes the cardiac L-type calcium channel α1c subunit. We found that oxidized low-density lipoprotein (ox-LDL) cholesterol significantly up-regulates both the expression of miRNA-223 and L-type calcium channel protein. In contrast, knockdown of miRNA-223 reduced L-type calcium channel protein expression, while genetic knockdown of endogenous miRNA-223 dampened AF vulnerability. Transfection of miRNA-223 by adenovirus-mediated expression enhanced L-type calcium currents and promoted AF in mice while co-injection of a CACNA1C -specific miR-mimic counteracted the effect. Taken together, ox-LDL, as a known factor in AF-associated remodeling, positively regulates miRNA-223 transcription and L-type calcium channel protein expression. Our results implicate a new molecular mechanism for AF in which miRNA-223 can be used as an biomarker of AF rheumatic heart disease.