HIF1A inhibitor PX-478 reduces pathological stretch-induced calcification and collagen turnover in aortic valve.

Autor:	Salim MT; School of Chemical and Biomolecular Engineering, Georgia Institute of Technology, Atlanta, GA, United States., Villa-Roel N; The Wallace H. Coulter Department of Biomedical Engineering, Georgia Institute of Technology and Emory University, Atlanta, GA, United States., Vogel B; School of Chemistry and Biochemistry, Georgia Institute of Technology, Atlanta, GA, United States., Jo H; The Wallace H. Coulter Department of Biomedical Engineering, Georgia Institute of Technology and Emory University, Atlanta, GA, United States., Yoganathan AP; School of Chemical and Biomolecular Engineering, Georgia Institute of Technology, Atlanta, GA, United States.; The Wallace H. Coulter Department of Biomedical Engineering, Georgia Institute of Technology and Emory University, Atlanta, GA, United States.
Jazyk:	angličtina
Zdroj:	Frontiers in cardiovascular medicine [Front Cardiovasc Med] 2022 Nov 07; Vol. 9, pp. 1002067. Date of Electronic Publication: 2022 Nov 07 (Print Publication: 2022).
DOI:	10.3389/fcvm.2022.1002067
Abstrakt:	HIF1A is significantly upregulated in calcified human aortic valves (AVs). Furthermore, HIF1A inhibitor PX-478 was shown to inhibit AV calcification under static and disturbed flow conditions. Since elevated stretch is one of the major mechanical stimuli for AV calcification, we investigated the effect of PX-478 on AV calcification and collagen turnover under a pathophysiological cyclic stretch (15%) condition. Porcine aortic valve (PAV) leaflets were cyclically (1 Hz) stretched at 15% for 24 days in osteogenic medium with or without PX-478. In addition, PAV leaflets were cyclically stretched at a physiological (10%) and 15% for 3 days in regular medium to assess its effect of on HIF1A mRNA expression. It was found that 100 μM (high concentration) PX-478 could significantly inhibit PAV calcification under 15% stretch, whereas 50 μM (moderate concentration) PX-478 showed a modest inhibitory effect on PAV calcification. Nonetheless, 50 μM PX-478 significantly reduced PAV collagen turnover under 15% stretch. Surprisingly, it was observed that cyclic stretch (15% vs. 10%) did not have any significant effect on HIF1A mRNA expression in PAV leaflets. These results suggest that HIF1A inhibitor PX-478 may impart its anti-calcific and anti-matrix remodeling effect in a stretch-independent manner. Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. (Copyright © 2022 Salim, Villa-Roel, Vogel, Jo and Yoganathan.)
Databáze:	MEDLINE
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