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SERCA2 regulates Piezo1 channel activation and contributes to the cardiac function and baroreflex in mice

Acta Pharmacologica Sinica (2025)Cite this article

Abstract

Piezo1 channels play important roles in physiological processes such as tactile sensation, blood pressure (BP) control, cardiac development, inflammatory responses as well as in disease processes. Sarco-endoplasmic reticulum Ca2+-transporting ATPase (SERCA) is the only active protein in the SR that orchestrates calcium homeostasis by translocation of Ca2+ from the cytoplasm to the sarcoplasmic reticulum. It has been shown that SERCA2 inhibits Piezo1 function in mammals by directly acting on the Piezo1 mechano-transduction module of mechanosensitive ion channels. In this study, we investigated whether SERCA2 regulates Piezo1 activation indirectly by modulating Ca2+ homeostasis. We showed that treatment with a Piezo1 agonist Yoda1 (5 µM) markedly increased the viability and ATP synthesis of primary cardiomyocytes as well as intracellular Ca2+ content through activation of Piezo1, and upregulated the expression of Piezo1 and SERCA2 in the cardiomyocytes. However, si-Piezo1 transfection resulted in downregulation of SERCA2 expression with opposite effects on viability and ATP synthesis and intracellular Ca2+ content that could not be reversed by application of Yoda1. Interestingly, application of a SERCA2 channel inhibitor paxilline (Pax, 10 µM) reversed the inhibitory effect of si-Piezo1 transfection on cardiomyocyte function. Using patch clamping and Ca2+ transient analyses in cardiomyocytes, we demonstrated that application of Pax inhibited Yoda1-mediated Ca2+ currents and APD50, confirming that Piezo1 activation by Yoda1 was significantly inhibited by Pax. Furthermore, application of Yoda1 was able to reverse si-SERCA2 transfection-induced impairment of myocardial function. Microinjection of Yoda1 and Pax into nodose ganglion (NG) in HFD-HTN model rats also demonstrated that the effect of Yoda1 was inhibited in the presence of Pax, thus confirming that Pax inhibited intracellular Ca2+ recycling by SERCA2. These results demonstrate for the first time that the application of Pax inhibits the recycling of intracellular Ca2+ by SERCA2 and reverses the reduction in cardiomyocyte function caused by downregulation of Piezo1 expression.

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Fig. 1: Direct effects of Yoda1 through Piezo1 on primary cardiomyocytes from neonatal rats.
Fig. 2: Effects of Yoda1 on primary cardiomyocyte function after si-Piezo1 transfection.
Fig. 3: Effects of SERCA2 inhibitor Paxilline and Yoda1 on cardiomyocytes function after si-Piezo1 transfection, respectively.
Fig. 4: Effects of SERCA2 inhibitor paxilline on cardiomyocytes function after siPiezo1 transfection.
Fig. 5: Effects of Yoda1 on cardiomyocytes function after si-SERCA2 transfection.
Fig. 6: Effects of Yoda1 and paxilline by microinjected into the NG on BP in HFD-HTN and control rats.
Fig. 7: Proposed mechanism of the activation of Piezo1 by Yoda1 was inhibited in the presence of Pax.

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Acknowledgements

This research was supported by the National Natural Science Foundation of China (81971326 and 81573431).

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Authors and Affiliations

  1. State Key Laboratory of Frigid Zone Cardiovascular Diseases (SKLFZCD), Department of Pharmacology (State Key Laboratory-Province Key Laboratories of Biomedicine-Pharmaceutics of China, Key Laboratory of Cardiovascular Research, Ministry of Education), College of Pharmacy, Harbin Medical University, Harbin, 150081, China

    Jia-xin Zhao, Yin-zhi Xu, Hui-xiao Fu, Jia-qun Li, Mao Yue, Zhao-yuan Xu, Xue-lian Li, Chang-peng Cui & Bai-yan Li

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  1. Jia-xin Zhao
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Contributions

CPC and JXZ designed research; JXZ and YZX performed research; YZX contributed new reagents or analytic tools; HXF, JQL, MY, ZYX and XLL analyzed data; CPC and BYL wrote the paper.

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Correspondence to Chang-peng Cui or Bai-yan Li.

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Zhao, Jx., Xu, Yz., Fu, Hx. et al. SERCA2 regulates Piezo1 channel activation and contributes to the cardiac function and baroreflex in mice. Acta Pharmacol Sin (2025). https://doi.org/10.1038/s41401-025-01610-x

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