Dantrolene inhibits lysophosphatidylcholine-induced valve interstitial cell calcific nodule formation via blockade of the ryanodine receptor

Frontiers in Cardiovascular Medicine

Cardiovascular Medicine

Jennifer P. Connell¹  K. Jane Grande-Allen¹  Farshad Amirkhosravi²  Christopher B. Sylvester³  William J. West⁴  Angelina S. Bortoletto⁵ 

[1] Department of Bioengineering, Rice University, Houston, TX, United States;Department of Bioengineering, Rice University, Houston, TX, United States;Department of Surgery, Houston Methodist Hospital, Houston, TX, United States;Department of Bioengineering, Rice University, Houston, TX, United States;Medical Scientist Training Program, Baylor College of Medicine, Houston, TX, United States;Department of Bioengineering, Rice University, Houston, TX, United States;Morsani College of Medicine, University of South Florida, Tampa, FL, United States;Medical Scientist Training Program, Baylor College of Medicine, Houston, TX, United States;Center for Cell and Gene, Stem Cells, and Regenerative Medicine Center, Translational and Molecular Medicine Program, Baylor College of Medicine, Houston, TX, United States;

关键词: aortic valve;    calcification;    lysophosphatidylcholine;    dantrolene;    apoptosis;    ryanodine receptor;    valve interstitial cell;    calcific aortic valve disease;   

DOI  :  10.3389/fcvm.2023.1112965

 received in 2022-11-30, accepted in 2023-03-09,  发布年份 2023

来源: Frontiers

【 摘 要 】

Calcific aortic valve disease (CAVD), a fibrocalcific thickening of the aortic valve leaflets causing obstruction of the left ventricular outflow tract, affects nearly 10 million people worldwide. For those who reach end-stage CAVD, the only treatment is highly invasive valve replacement. The development of pharmaceutical treatments that can slow or reverse the progression in those affected by CAVD would greatly advance the treatment of this disease. The principal cell type responsible for the fibrocalcific thickening of the valve leaflets in CAVD is valvular interstitial cells (VICs). The cellular processes mediating this calcification are complex, but calcium second messenger signaling, regulated in part by the ryanodine receptor (RyR), has been shown to play a role in a number of other fibrocalcific diseases. We sought to determine if the blockade of calcium signaling in VICs could ameliorate calcification in an in vitro model. We previously found that VICs express RyR isotype 3 and that its modulation could prevent VIC calcific nodule formation in vitro. We sought to expand upon these results by further investigating the effects of calcium signaling blockade on VIC gene expression and behavior using dantrolene, an FDA-approved pan-RyR inhibitor. We found that dantrolene also prevented calcific nodule formation in VICs due to cholesterol-derived lysophosphatidylcholine (LPC). This protective effect corresponded with decreases in intracellular calcium flux, apoptosis, and ACTA2 expression but not reactive oxygen species formation caused by LPC. Interestingly, dantrolene increased the expression of the regulator genes RUNX2 and SOX9, indicating complex gene regulation changes. Further investigation via RNA sequencing revealed that dantrolene induced several cytoprotective genes that are likely also responsible for its attenuation of LPC-induced calcification. These results suggest that RyR3 is a viable therapeutic target for the treatment of CAVD. Further studies of the effects of RyR3 inhibition on CAVD are warranted.

【 授权许可】

Unknown   
© 2023 Sylvester, Amirkhosravi, Bortoletto, West, Connell and Grande-Allen.