Dexmedetomidine protects H9c2 cardiomyocytes against oxygen-glucose deprivation/reoxygenation-induced intracellular calcium overload and apoptosis through regulating FKBP12.6/RyR2 signaling

Abstract

Purpose

Intracellular calcium ([Ca²⁺]i) overload is a major cause of cell injury during myocardial ischemia/reperfusion (I/R). Dexmedetomidine (DEX) has been shown to exert anti-inflammatory and organ protective effects. This study aimed to investigate whether pretreatment with DEX could protect H9c2 cardiomyocytes against oxygen-glucose deprivation/reoxygenation (OGD/R) injury through regulating the Ca²⁺ signaling.

Methods

H9c2 cardiomyocytes were subjected to OGD for 12 h, followed by 3 h of reoxygenation. DEX was administered 1 h prior to OGD/R. Cell viability, lactate dehydrogenase (LDH) release, level of [Ca²⁺]i, cell apoptosis, and the expression of 12.6-kd FK506-binding protein/ryanodine receptor 2 (FKBP12.6/RyR2) and caspase-3 were assessed.

Results

Cells exposed to OGD/R had decreased cell viability, increased LDH release, elevated [Ca²⁺]i level and apoptosis rate, down-regulated expression of FKBP12.6, and up-regulated expression of phosphorylated-Ser2814-RyR2 and cleaved caspase-3. Pretreatment with DEX significantly blocked the above-mentioned changes, alleviating the OGD/R-induced injury in H9c2 cells. Moreover, knockdown of FKBP12.6 by small interfering RNA abolished the protective effects of DEX.

Conclusion

This study indicates that DEX pretreatment protects the cardiomyocytes against OGD/R-induced injury by inhibiting [Ca²⁺]i overload and cell apoptosis via regulating the FKBP12.6/RyR2 signaling. DEX may be used for preventing cardiac I/R injury in the clinical settings.

Keywords:

• dexmedetomidine
• H9c2 cardiomyocytes
• oxygen-glucose deprivation/reoxygenation
• apoptosis
• intracellular calcium overload, FKBP12.6/RyR2

Acknowledgments

This work was supported by the National Natural Science Foundation of China (81873925 and 81671880 to FHJ, 81701098 to XWM, 81601659 to KP, and 81601666 to JZ), Jiangsu Provincial Medical Youth Talents Program (QNRC2016741 to KP), Jiangsu Provincial Medical Innovation Team (CXTDA2017043 to FHJ), and Suzhou Key Disease Program (LCZX201603 to FHJ).

Disclosure

The authors report no conflicts of interest in this work.