Abstract 1122: α-Calcitonin Gene-Related Peptide (α-CGRP) Protects Myocardial Cells Against Oxidative Stress Through a Mitochondrial-Dependent Pathway
α-calcitonin gene-related peptide (α-CGRP) is a 37-amino acid peptide primarily synthesized in sensory neurons, and released in peripheral organs, such as the heart. In various cardiac models, α-CGRP is shown to induce coronary vasodilation, and play a role in ischemic preconditioning in isolated hearts. The objective of this proposal was to determine whether α-CGRP can directly protect cardiomyocytes against oxidant-induced death and whether mitochondria are involved in this process. Neonatal rat cardiomyocytes (NRCM) were cultured for 5–10 days, pretreated with α-CGRP (50 nM for 24 hrs) and subjected to oxidative stress 100 μM of H2O2 for 2 hrs). Mitochondrial membrane potential (MMP) and cell viability were assessed by flow cytometry using tetramethylrhodamine ethyl ester (TMRE) and by trypan blue staining. Pretreatment of cells with α-CGRP significantly attenuated MMP loss and cell viability in response to H2O2. In order to assess the role of mitochondrial channels in this process, we added α-CGRP to NRCM followed by treatment with modulators of the mitochondrial permeability transition pore (mPTP) or the mitochondrial ATP-dependent K+ channel (mitoKATP). Diamide, an mPTP opener, significantly reduced MMP and cell viability, while α-CGRP reversed both of these effects. Furthermore, glybenclamide (Gly, an inhibitor of mitoKATP) attenuated the protective effects of α-CGRP against H2O2. These results provide primary evidence that α-CGRP plays a major role in the cellular protection against oxidant stress through a mitochondrial dependent pathway, identifying this protein as a potential cardioprotective target in ischemic heart disease.