13-Methylpalmatine improves myocardial infarction injury by inhibiting CHOP-mediated cross-talk between endoplasmic reticulum and mitochondria.

Myocardial infarction (MI) is a leading cause of morbidity and mortality worldwide, and endoplasmic reticulum stress (ERS) and mitochondrial Ca ²⁺ overload have been involved in apoptotic cardiomyocyte death during MI. 13-Methylpalmatine (13-Me-PLT) is a natural isoquinoline alkaloid isolated from Coptis chinensis and has not been systematically studied for their potential pharmacological effects in cardiovascular diseases. We conducted the present study to elucidate whether 13-Me-PLT modulates MI pathology in animal MI and cellular hypoxic models, employing state-of-the-art molecular techniques. The results demonstrated that 13-Me-PLT preserved post-ischemic cardiac function and alleviated cardiomyocyte apoptosis. 13-Me-PLT decreased ERS and the communication between ER and mitochondria, which serves as a protective mechanism against mitochondrial Ca ²⁺ overload and structural and functional injuries to mitochondria. Our data revealed mitigating mitochondrial Ca ²⁺ overload and apoptosis by inhibiting CHOP-mediated Ca ²⁺ transfer between inositol 1,4,5-trisphosphate receptor (IP ₃ R) in ER and VDAC1 in mitochondria as an underlying mechanism for 13-Me-PLT action. Furthermore, 13-Me-PLT produced superior effects in alleviating cardiac dysfunction and apoptosis post-MI to diltiazem and palmatine. Collectively, our research suggests that the CHOP/IP ₃ R/VDAC1 signaling pathway mediates ER-mitochondrial Ca ²⁺ transfer and 13-Me-PLT activates this axis to maintain cellular and organellar Ca ²⁺ homeostasis, protecting against ischemic myocardial injury. These findings may offer an opportunity to develop new agents for the therapy of ischemic heart disease.
Competing Interests: Declaration of Competing Interest All the authors declare no competing financial interest.
(Copyright © 2024 The Authors. Published by Elsevier Masson SAS.. All rights reserved.)