Working Paper Article Version 1 This version is not peer-reviewed

Calcineurin Suppresses Cardiomyocyte-protective Autophagy Under Chronic Intermittent Hypoxia by Downregulating the AMPK Pathway

Version 1 : Received: 22 June 2021 / Approved: 24 June 2021 / Online: 24 June 2021 (14:58:22 CEST)

How to cite: Xie, S.; Liu, W.; Jin, M.; Li, X.; Wang, T.; Zeng, S.; Nie, H.; Dong, Z.; Ke, Z.; Hu, K. Calcineurin Suppresses Cardiomyocyte-protective Autophagy Under Chronic Intermittent Hypoxia by Downregulating the AMPK Pathway. Preprints 2021, 2021060605 Xie, S.; Liu, W.; Jin, M.; Li, X.; Wang, T.; Zeng, S.; Nie, H.; Dong, Z.; Ke, Z.; Hu, K. Calcineurin Suppresses Cardiomyocyte-protective Autophagy Under Chronic Intermittent Hypoxia by Downregulating the AMPK Pathway. Preprints 2021, 2021060605

Abstract

Calcineurin plays a key role in cardiovascular pathogenesis by exerting pro-apoptotic effects in cardiomyocytes; however, its involvement in the regulation of cardiomyocyte autophagy under chronic intermittent hypoxia (CIH) remains largely unknown. Here we showed that CIH induced calcineurin activity in H9C2 cells, resulting in the attenuation of adenosine monophos-phate-activated protein kinase (AMPK) signaling and inhibition of H9C2 cell autophagy. Au-tophagy, LC3-II levels, and AMPK phosphorylation were significantly elevated in response to CIH in H9C2 cells by day 3; however, these effects were reversed, and calcineurin activity and apoptosis were significantly increased by day 5. The calcineurin inhibitor, FK506, restored AMPK activation and LC3 protein levels, and reduced CIH-induced H9C2 cell apoptosis, while calcineurin overexpression significantly attenuated the increase in LC3 levels and enhanced H9C2 cell apop-tosis. Calcineurin inhibition failed to induce autophagy or alleviate apoptosis in H9C2 cells ex-pressing a dominant negative K45R AMPK mutant. Autophagy downregulation abrogated the protective effects of FK506-mediated calcineurin inhibition. These results indicated that calcineurin suppressed adaptive autophagy during CIH by downregulating AMPK activation. Our findings showed the underlying mechanisms of calcineurin and autophagy regulation during H9C2 cell survival in response to CIH, and suggested a new strategy for preventing CIH-induced cardiomyocyte damage.

Subject Areas

chronic intermittent hypoxia; autophagy; apoptosis; cardiomyocyte damage; calcineurin

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