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  3. Activation of transient receptor potential vanilloid 4 exacerbates myocardial ischemia-reperfusion injury via JNK-CaMKII phosphorylation pathway in isolated mice hearts

Activation of transient receptor potential vanilloid 4 exacerbates myocardial ischemia-reperfusion injury via JNK-CaMKII phosphorylation pathway in isolated mice hearts

  • Cell Calcium. 2021 Dec;100:102483. doi: 10.1016/j.ceca.2021.102483.
Shaoshao Zhang 1,  Kai Lu 1,  Shuaitao Yang 1,  Yuwei Wu 1,  Jie Liao 1,  Yang Lu 1,  Qiongfeng Wu 1,  Ning Zhao 1,  Qian Dong 1,  Lei Chen 2,  Yimei Du 3
Affiliations

Affiliations

  • 1 Department of Cardiology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China; Research Center of Ion Channelopathy, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China; Institute of Cardiology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China; Key Lab for Biological Targeted Therapy of Education Ministry and Hubei Province, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China.
  • 2 Department of Physiology, Nanjing Medical University, Nanjing, China. Electronic address: chenl@njmu.edu.cn.
  • 3 Department of Cardiology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China; Research Center of Ion Channelopathy, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China; Institute of Cardiology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China; Key Lab for Biological Targeted Therapy of Education Ministry and Hubei Province, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China. Electronic address: yimeidu@mail.hust.edu.cn.
PMID: 34628110 DOI: 10.1016/j.ceca.2021.102483
Abstract

Previous studies, including our own, have demonstrated that transient receptor potential vanilloid 4 (TRPV4) is involved in myocardial ischemia-reperfusion (IR) injury, yet its underlying molecular mechanism remains unclear. In this study, we isolated mice hearts for a Langendorff perfusion test and used HL-1 myocytes for in vitro assessments. We first confirmed that TRPV4 agonist (GSK101) enhanced myocardial IR injury, as demonstrated by the reduced recovery of cardiac function, larger myocardial infarct size, and more apoptotic cells. We also found that GSK101 could further increase the phosphorylation of JNK and CaMKII in isolated hearts during IR. Notably, GSK101 dose-dependently evoked the phosphorylation of JNK and CaMKII in isolated normal hearts. All above GSK101-induced effects could be significantly blocked by the pharmacological inhibition or genetic ablation of TRPV4. More importantly, JNK inhibition (with SP600125) or CaMKII inhibition (with KN93 or in transgenic AC3-I mice) could prevent GSK101-induced myocardial injury during IR. In HL-1 myocytes, GSK101 triggered CA2+ influx and evoked the phosphorylation of JNK and CaMKII but these effects were abolished by removing extracellular CA2+ or in the presence of a TRPV4 antagonist. Finally, we showed that in HL-1 myocytes and isolated hearts during IR, JNK inhibition significantly inhibited the phosphorylation of CaMKII induced by GSK101 but CaMKII inhibition had no effect on JNK activation induced by GSK101. Our data suggest that TRPV4 activation exacerbates myocardial IR injury via the JNK-CaMKII phosphorylation pathway.

Keywords

CaMKII; Calcium; Ischemia/reperfusion injury; JNK; Transient receptor potential vanilloid 4.

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