The Anatolian Journal of Cardiology
Original Investigation

Hypoxia-Induced Sarcoplasmic Reticulum Ca2+ Leak Is Reversed by Ryanodine Receptor Stabilizer JTV-519 in HL-1 Cardiomyocytes


Department of Pathophysiology, Third Faculty of Medicine, Charles University, Prague, Czech Republic


Department of Cardiology, University Hospital Královské Vinohrady, Prague, Czech Republic


Department of Internal Medicine, University Hospital Královské Vinohrady, Prague, Czech Republic

Anatol J Cardiol 2022; 26: 476-484
DOI: 10.5152/AnatolJCardiol.2022.1223
Read: 57 Downloads: 19 Published: 01 June 2022

Background: To assess whether hypoxia, as can be found in obstructive sleep apnea syndrome, is causally associated with the development of heart failure through a direct effect on calcium leakage from the sarcoplasmic reticulum.

Methods: The impact of hypoxia on sarcoplasmic reticulum calcium leakage and expres- sion of RyR2 (ryanodine receptor2) and SERC2a (sarcoplasmic reticulum Ca2+ATPase 2a) was investigated together with the outcomes of JTV-519 and S107 treatment. HL-1 car- diomyocytes were cultured for 7 days on gas-permeable cultureware under control (12% O2) or hypoxic (1% O2) conditions with or without JTV-519 or S107. SRCL was assessed using a Fluo-5N probe. Gene and protein expression was analyzed using qPCR and western blotting.

Results: Hypoxic exposure increased sarcoplasmic reticulum calcium leakage by 39% and reduced RyR2 gene expression by 52%. No effect on RyR2 protein expression was observed. Treatment with 1μM JTV-519 reduced sarcoplasmic reticulum calcium leakage by 52% and 35% under control and hypoxic conditions, respectively. Administration of 1 μM JTV-519 increased RyR2 gene expression by 89% in control conditions. No effect on SRCL, RyR2, or SERC2a gene, or protein expression was observed with S107 treatment.

Conclusion: Hypoxia increased sarcoplasmic reticulum calcium leakage which was ame- liorated by JTV-519 treatment independently of gene or protein expression. JTV-519 rep- resents a possible treatment for obstructive sleep apnea-associated HF.

Cite this article as: Trinh MD, Fiserova I, Vacek L, et al. Hypoxia- induced sarcoplasmic reticulum Ca2+ leak is reversed by ryanodine receptor stabilizer JTV-519 in HL-1 cardiomyocytes. Anatol J Cardiol. 2022;26(6):476-484.

ISSN 2149-2263 EISSN 2149-2271