Introduction: Calcitonin gene-related peptide (CGRP), a 37 amino acid neuropeptide, is a potent vasodilator, and plays a critical role in the efferent functions of the sensory nervous system. A protective role for CGRP in cardiovascular diseases (hypertension, cardiac ischemia, and failure) has been well established by our laboratory and others. In the present study we determined whether long-term exogenous administration of α-CGRP protects against pressure-induced heart failure.
Method: Three groups of nine-week-old C57/BL6 mice were studied: one group received a sham procedure (n= 4) and two groups underwent transverse aortic constriction (TAC). Two days after TAC, one group had CGRP-filled osmotic pumps (4 mg/kg bwt/day) implanted subcutaneously (n= 7) while the second group was TAC-only (n=6). At day 28, all groups had echocardiography performed and were sacrificed and heart tissue collected.
Results: Echocardiographic and histological data showed that TAC markedly decreased fractional shortening (FS) and ejection fraction and increased heart and lung weight, cardiac hypertrophy, and fibrosis compared to sham. However, the TAC-CGRP mice had preserved cardiac function and less cardiac fibrosis (FS ±SEM: sham 46.2±1.8% vs TAC 25.4±1.1%, p< 0.001; and TAC 25.4±1.1% vs TAC-CGRP 36.6±1.2%, p< 0.001). CGRP significantly reduced apoptotic cell death and lipid peroxidation (an oxidative stress marker measured by malondialdehyde and 4-HNE staining) in the TAC hearts [malondialdehyde (nmol/mg protein) ±SEM: sham 3.5±0.19 vs TAC 14.3±0.57, p< 0.05; and TAC 14.3±0.57 vs TAC-CGRP 5.5±0.12, p< 0.05]. TAC alone decreased the level of p-ERK1/2 and increased p-JNK compared to sham. CGRP-TAC hearts had higher p-ERK1/2 levels but equal p-JNK levels compared to the TAC hearts. HIF1α and nrf2 protein levels were not different between experimental groups. Compared to TAC hearts, TAC-CGRP hearts had lower p-AMPK and nuclear Sirt1 level, regulatory proteins of energy metabolism.
Conclusion: Our results suggest that CGRP, mediated through energy metabolic, and oxidative stress pathways, decreases myocyte apoptosis and is protective in pressure-induced heart failure. Thus, CGRP is a potential therapeutic agent in preventing the progression of heart failure.