Cardiac ischemic preconditioning promotes cMyBP-C phosphorylation by inhibiting the calpain-mediated proteolysis

  • Exp Cell Res. 2023 Nov 22:113859. doi: 10.1016/j.yexcr.2023.113859.
Cheng Liang  1 ,  Zulibiya Aisa  2 ,  Longfei Sun  3 ,  Baojian Zhang  4
Affiliations
  • 1. State Key Laboratory of Pathogenesis, Prevention and Treatment of High Incidence Diseases in Central Asia, Urumqi, China; Department 2 of Cardiology, Affiliated Hospital of Traditional Chinese Medicine of Xinjiang Medical University, Urumqi, China.
  • 2. State Key Laboratory of Pathogenesis, Prevention and Treatment of High Incidence Diseases in Central Asia, Urumqi, China; Department 5 of Cardiology, Affiliated Hospital of Traditional Chinese Medicine of Xinjiang Medical University, Urumqi, China.
  • 3. State Key Laboratory of Pathogenesis, Prevention and Treatment of High Incidence Diseases in Central Asia, Urumqi, China; Department 4 of Cardiology, Affiliated Hospital of Traditional Chinese Medicine of Xinjiang Medical University, Urumqi, China.
  • 4. State Key Laboratory of Pathogenesis, Prevention and Treatment of High Incidence Diseases in Central Asia, Urumqi, China; Department 5 of Cardiology, Affiliated Hospital of Traditional Chinese Medicine of Xinjiang Medical University, Urumqi, China. Electronic address: [email protected].
PMID: 38000772 DOI: 10.1016/j.yexcr.2023.113859
Abstract

Ischemic preconditioning (IPC) has been considered as the most important mean to protect against ischemia/reperfusion (I/R) induced heart injury. It has been reported that cardiac Myosin binding protein-C (cMyBP-C) phosphorylation plays an essential role in cardiac protection against I/R-induced heart injury. However, it is still obscured whether IPC-mediated cardiac protection is causally related to cMyBP-C phosphorylation and proteolysis and, if so, what the underlying mechanism is. In this study, IPC was found to increase the phosphorylation level of cMyBP-C, companying with the decreased calpain activity in the collected perfusate samples. Mechanistically, we confirmed that IPC promoted cMyBP-C phosphorylation and inhibited calpain-mediated cMyBP-C proteolysis. Moreover, inhibition of calpain activity significantly increased the phosphorylated cMyBP-C level by using calpain inhibitor (MG-101), and subsequently promoted stabilization and secretion of cMyBP-C. Functionally, adeno-associated virus (AAV)-mediated overexpression of mutated phosphorylation motif site of cMyBP-C exhibited impaired IPC-mediated cardiac protection via proteolysis of the full-length cMyBP-C protein. We concluded that IPC promoted cMyBP-C phosphorylation via inhibition of calpain-mediated proteolysis and participated in IPC-mediated protection against I/R induced heart injury.

Keywords
Calpain; Cardiac myosin binding protein-C; Ischemia/reperfusion; Ischemic preconditioning; Phosphorylation.
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