CGRP mitigates myocardial ischemia-reperfusion injury by attenuating ferroptosis through the inhibition of MAMs and mitochondrial division.

Ferroptosis of cardiomyocytes is a key factor in myocardial ischemia-reperfusion injury (MIRI), but its regulatory mechanisms and intervention targets have not been fully clarified. Calcitonin gene-related peptide (CGRP) is a key regulatory factor released from peripheral vascular nerve endings, with powerful vasodilatory, positive chronotropic, and inotropic effects. In this study, the effects of CGRP on myocardial ischemia/reperfusion injury (I/R) and hypoxia/reoxygenation (H/R) were investigated in a rat model of left anterior descending coronary artery ligation and reperfusion. We found that the endogenous CGRP concentration in the serum of I/R rats was significantly decreased. While exogenous CGRP improved the viability of H/R cardiomyocytes in a concentration-dependent manner, inhibited the release of lactate dehydrogenase, down-regulated the expression of ferroptosis executive protein ACSL4, up-regulated the expression of GPX4, and reduced the accumulation of reactive oxygen species and lipid peroxide. Mechanistically, CGRP alleviates H/R-induced mitochondrial dynamics imbalance, improving mitochondrial morphology and membrane potential. In addition, CGRP inhibited abnormal expression of key proteins (IP3R, GRP75, and VDAC) at mitochondrial endoplasmic reticulum contact sites (MAMs) and reduced ferroptosis signaling. In vivo experiments demonstrated that nitroglycerin and cinnamaldehyde, a TRPA1 agonist, reduced myocardial infarction size by activating the TRPA1-CGRP pathway, while blocking the CGRP receptor could counteract this protective effect. In conclusion, our study demonstrates that CGRP mitigates myocardial ferroptosis through the regulation of mitochondrial dynamics and MAMs interactions. These findings establish CGRP as a promising therapeutic target and provide a solid theoretical foundation for combating myocardial I/R injury.