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

• Published in: Biomedicine & pharmacotherapy Vol. 179; p. 117342
• Main Authors: Jiang, Zefeng, Wen, Xiaowei, Mao, Qin, Wang, Gang, Wang, Zhuo, Yan, Yu, Gao, Shan, Sun, Xiaoqian, Zhang, Miao, Liu, Jiajing, Zhang, Rong, Yang, Baofeng
• Format: Journal Article
• Language: English
• Published: France Elsevier Masson SAS 01.10.2024; Elsevier
• Subjects: 13-Methylpalmatine; Animals; Apoptosis - drug effects; Berberine Alkaloids - pharmacology; Calcium - metabolism; CHOP; Endoplasmic Reticulum - drug effects; Endoplasmic Reticulum - metabolism; Endoplasmic reticulum stress; Endoplasmic Reticulum Stress - drug effects; Inositol 1,4,5-Trisphosphate Receptors - metabolism; Male; Mice; Mice, Inbred C57BL; Mitochondria - drug effects; Mitochondria - metabolism; Mitochondria, Heart - drug effects; Mitochondria, Heart - metabolism; Mitochondrial Ca2+ overload; Myocardial infarction; Myocardial Infarction - drug therapy; Myocardial Infarction - metabolism; Myocardial Infarction - pathology; Myocytes, Cardiac - drug effects; Myocytes, Cardiac - metabolism; Myocytes, Cardiac - pathology; Rats, Sprague-Dawley; Transcription Factor CHOP - metabolism; Myocardial infarction; IP3R; ERS; CK-MB; CTnT; LVIDd; LV; PERK; FS; Endoplasmic reticulum stress; LDH; NRVCs; TUNEL; ΔΨm; LVPWs; UPR; IRE1; CCK-8; CHOP; PLT; MI; EF; LVAWs; LVPWd; 13-Methylpalmatine; GRP78; ER; LVAWd; 13-Me-PLT; LVIDs; VDAC1; MPTP; ATF6; HE; TEM; Mitochondrial Ca2+ overload; Mitochondrial Ca(2+) overload
• ISSN: 0753-3322; 1950-6007; 1950-6007
• DOI: 10.1016/j.biopha.2024.117342

Myocardial infarction (MI) is a leading cause of morbidity and mortality worldwide, and endoplasmic reticulum stress (ERS) and mitochondrial Ca2+ 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 Ca2+ overload and structural and functional injuries to mitochondria. Our data revealed mitigating mitochondrial Ca2+ overload and apoptosis by inhibiting CHOP-mediated Ca2+ transfer between inositol 1,4,5-trisphosphate receptor (IP3R) 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/IP3R/VDAC1 signaling pathway mediates ER-mitochondrial Ca2+ transfer and 13-Me-PLT activates this axis to maintain cellular and organellar Ca2+ homeostasis, protecting against ischemic myocardial injury. These findings may offer an opportunity to develop new agents for the therapy of ischemic heart disease. [Display omitted] •13-Me-PLT ameliorates ER stress and apoptosis in cardiomyocytes of mice with MI.•13-Me-PLT inhibits the crosstalk between the ER and mitochondria in cardiomyocytes of mice with MI.•The CHOP/IP3R/VDAC1 signalling pathway mediates the axis of ER-mitochondrial Ca2+ transfer.