Statins improve cardiac endothelial function to prevent heart failure with preserved ejection fraction through upregulating circRNA-RBCK1

• Published in: Nature communications Vol. 15; no. 1; p. 2953
• Main Authors: Li, Bin, Bai, Wen-Wu, Guo, Tao, Tang, Zhen-Yu, Jing, Xue-Jiao, Shan, Ti-Chao, Yin, Sen, Li, Ying, Wang, Fu, Zhu, Mo-Li, Lu, Jun-Xiu, Bai, Yong-Ping, Dong, Bo, Li, Peng, Wang, Shuang-Xi
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 05.04.2024; Nature Publishing Group; Nature Portfolio
• Subjects: 13/95; 14/32; 38/15; 631/337/384; 631/80/304; 692/4019/592/75/230; Animals; Circular RNA; Congestive heart failure; Ejection fraction; Endothelial cells; Endothelial Cells - metabolism; Gene expression; Heart failure; Heart Failure - drug therapy; Heart Failure - genetics; Heart Failure - metabolism; Humanities and Social Sciences; Hydroxymethylglutaryl-CoA Reductase Inhibitors - pharmacology; Kinases; Lovastatin; Male; Mice; MicroRNAs - metabolism; miRNA; multidisciplinary; Protein kinase C; Proteins; Ribonucleic acid; RNA; RNA, Circular - genetics; Science; Science (multidisciplinary); Statins; Stroke Volume - physiology; Ubiquitin-Protein Ligases
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/s41467-024-47327-z

Heart failure with preserved ejection fraction (HFpEF) is associated with endothelial dysfunction. We have previously reported that statins prevent endothelial dysfunction through inhibition of microRNA-133a (miR-133a). This study is to investigate the effects and the underlying mechanisms of statins on HFpEF. Here, we show that statins upregulate the expression of a circular RNA (circRNA-RBCK1) which is co-transcripted with the ring-B-box-coiled-coil protein interacting with protein kinase C-1 (RBCK1) gene. Simultaneously, statins increase activator protein 2 alpha (AP-2α) transcriptional activity and the interaction between circRNA-RBCK1 and miR-133a. Furthermore, AP-2α directly interacts with RBCK1 gene promoter in endothelial cells. In vivo, lovastatin improves diastolic function in male mice under HFpEF, which is abolished by loss function of endothelial AP-2α or circRNA-RBCK1. This study suggests that statins upregulate the AP-2α/circRNA-RBCK1 signaling to suppress miR-133a in cardiac endothelial cells and prevent diastolic dysfunction in HFpEF. Endothelial dysfunction has been shown to occur in HFpEF and we know that statins can target endothelial dysfunction by inhibiting miR-133a. Here the authors show that statins improve diastolic dysfunction in HFpEF by increasing the levels of a circRNA which, in turns, binds to miR-133a modulating its downstream targets.