Deletion of the mouse α-calcitonin gene-related peptide gene increases the vulnerability of the heart to ischemia-reperfusion injury

Abstract

Huang R, Karve A, Shah I, Bowers MC, DiPette DJ, Supowit SC, Abela GS. Deletion of the mouse ␣-calcitonin gene-related peptide gene increases the vulnerability of the heart to ischemia-reperfusion injury. Am J Physiol Heart Circ Physiol 294: H1291-H1297, 2008. First published January 11, 2008 doi:10.1152/ajpheart.00749.2007.-Calcitonin gene-related peptide (CGRP), a potent vasodilator released from capsaicin-sensitive C-fiber and A␦-fiber sensory nerves, has been suggested to play a beneficial role in myocardial ischemia-reperfusion (I/R) injury. Because most previous studies showing a cardioprotective role of CGRP employed pharmacological experiments, the purpose of this study was to utilize a genetic approach by using mice with a targeted deletion of the ␣-CGRP gene to determine whether this neuropeptide had a modulatory function on the severity of I/R injury. To accomplish this goal, isolated, perfused hearts from ␣-CGRP knockout (KO) and wild-type (WT) mice were subjected to 30 min of ischemia followed by 5, 15, and 30 min of reperfusion. Cardiac functional parameters, including coronary flow rates, left ventricular developed pressure, maximum rates of pressure development, and left ventricular end-diastolic pressure, were measured before and after I/R injury, as were levels of creatine kinase, to assess myocardial damage, and malonaldehyde, to assess oxidative stress. Following I/R injury, cardiac performance was significantly reduced in the hearts from the ␣-CGRP KO mice compared with their WT counterparts. The marked reduction in myocardial function in the ␣-CGRP KO hearts compared with WT hearts after I/R injury was associated with a significant elevation in creatine kinase release into the perfusates and malonaldehyde production in the cardiac tissue. Therefore, these data indicate that, in this in vitro setting, deletion of ␣-CGRP makes the heart more vulnerable to I/R injury, possibly due, at least in part, to increased oxidative stress. genetically modified mice; cardiac; isolated perfused heart preparations; sensory nervous system CALCITONIN GENE-RELATED PEPTIDE (CGRP), a 37-amino acid neuropeptide, is derived from the tissue-specific splicing of the primary transcript of the calcitonin/␣-CGRP gene (6,8,13,38). Whereas calcitonin is produced mainly in the C cells of the thyroid, CGRP synthesis is limited almost exclusively to specific regions of the central and peripheral nervous systems. There is a second CGRP gene (␤-CGRP) that does not produce calcitonin, which is also synthesized primarily in neuronal tissues. The two CGRP genes, ␣ and ␤ in the rat and I and II in humans, differ in their protein sequences by one and three amino acids, respectively, and the biological activities of the two peptides are quite similar in most vascular beds. However, ␣-CGRP is by far the predominant product in dorsal root ganglia sensory neurons and appears to be the CGRP gene product that has markedly greater activity in the regulation of cardiovascular function (5, 11, 31).Immunoreactive CGRP and its receptor are...

An Ongoing Role of α-Calcitonin Gene–Related Peptide as Part of a Protective Network Against Hypertension, Vascular Hypertrophy, and Oxidative Stress

“…The concomitant hypertrophy in αCGRPKOs and loss of increased GPX-1 gene expression at 28 days is in keeping with studies using GPX-1 KO mice which revealed protection against AngII-induced artery functional and cardiac remodeling changes. 37,39 We provide novel evidence linking αCGRP with vascular protection against enhanced oxidative stress in a model of hypertension, consistent with evidence from cardiac models 8,40 and an atherosclerosis model. 41 We further provide evidence of enhanced ROS generation in αCGRPKO-AngII mice at day 28, as shown recently in a wire-induced vascular injury model.…”

“…CGRP acts via a G-protein-coupled receptor (calcitonin-like receptor) when dimerized with a single transmembrane-spanning receptor activity-modifying protein RAMP1 2 signaling via cAMP and other pathways. 3,4 CGRP does not play a primary role in the regulation of basal blood pressure (BP) in normal individuals 5,6 but is suggested to have protective properties, in cardiovascular disease, 7,8 including attenuation of vascular smooth muscle proliferation, 9 hyperplasia, 10,11 and stimulation of endothelial cell proliferation 12 and endothelial progenitor cells. 13 Evidence indicates the importance of CGRP in aggressive models of rodent hypertension that are centered on the kidney.…”

Degeneration of capsaicin sensitive sensory nerves enhances myocardial injury in acute myocardial infarction in rats

“…The increases in the infarct size of myocardium by antagonisms of endogenous CGRP receptor may indicate the cardioprotective property of the afferent nerves are mediated by the neuropeptide, which was supported by previous reports showing the exogenous CGRP protecting myocardium [20], enhancement of myocardial injury after knockout of the gene encoding the synthesis of CGRP [36], reduction of infarct size by lipoxygenase, an agonist of transient receptor potential vanilloid 1 (TRPV1) [2,37] and increase of infarct size [22], mortality rate and tissue apoptosis [38,39] by TRPV1 gene knockout. However there was opposite report showing exogenously administered CGRP caused systemic hypotension and augmented post-ischemic coronary flow, in which no cardioprotective effect of CGRP could be proven [2].…”

Renal denervation attenuates aldosterone expression and associated cardiovascular pathophysiology in angiotensin II-induced hypertension

“…These diseases are associated with the dysregulation of renin-angiotensin-aldosterone system (RAAS). Afferent nerve-derived calcitonin gene-related peptide (CGRP) is identified as a potent vasodilator and a hypotensive peptide [12], which has protective properties in cardiovascular disease [13, 14]. CGRP release is stimulated by mechanisms that include angiotensin II and sympathetic nerve reflexes [12, 15].…”