Intermedin is upregulated and has protective roles in a mouse ischemia/reperfusion model

Zhang, Heng-Yu; Jiang, Wei; Liu, Jianying; Li, Yan; Chen, Chunlin; Xin, Hong‐Bo; Huang, Daixin

doi:10.1038/hr.2009.120

Cited by 27 publications

(23 citation statements)

References 32 publications

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“…There are several evidences of increased IMD expression in the hypertrophic rat heart (7, 13) but more importantly of its antihypertrophic effects in isolated rat cardiomyocytes upon hypertrophic stimuli (2). Furthermore, there is evidence of IMD cardioprotective action in ischemia-reperfusion injury, associated to its negative inotropic action and antioxidant properties (10,37). Our results, demonstrating for the first time that the myocardial effects of IMD are dependent on NO production, suggest an additional potential role for IMD in the pathophysiology of endothelial dysfunction, which is present in numerous cardiovascular diseases.…”

Section: Discussionmentioning

confidence: 99%

“…However, there is a study (33) describing IMD expression in endothelial microvascular cells in mice. More importantly, there are several reports documenting not only increased expression of IMD in different cardiac disease models (2, 13) but also a cytoprotective role in ischemic injury (37), indicating therefore a pathophysiological and cardioprotective function for IMD similar to ADM.…”

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confidence: 99%

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Intermedin elicits a negative inotropic effect in rat papillary muscles mediated by endothelial-derived nitric oxide

Pires

Pinho

Sena

et al. 2012

American Journal of Physiology-Heart and Circulatory Physiology

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Pires AL, Pinho M, Sena CM, Seica R, Leite-Moreira AF. Intermedin elicits a negative inotropic effect in rat papillary muscles mediated by endothelial-derived nitric oxide. Am J Physiol Heart Circ Physiol 302: H1131-H1137, 2012. First published January 6, 2011; doi:10.1152/ajpheart.00877.2011.-Intermedin (IMD) is a novel vasoactive peptide from the calcitonin gene-related peptide (CGRP) implicated in cardiac regulation, yet the contractile effects of IMD remain controversial, since previous studies in vivo and isolated cardiomyocytes documented contradictory results. We hypothesized cardiac endothelial cells involvement in IMD modulation of cardiac function as an explanation for these opposing observations. With this in mind, we investigated the direct action of increasing concentrations of IMD (10 Ϫ8 to 10 Ϫ6 M) on myocardial performance parameters in rat left ventricular (LV) papillary muscles with and without endocardial endothelium (EE) and in presence of receptor antagonists and intracellular pathways inhibitors. In LV papillary muscles with intact EE, IMD induced a concentration-dependent negative inotropic action (%decrease relative to baseline, at IMD concentration of 10 Ϫ6 M, active tension of 14 Ϯ 4%, and maximum velocity of tension rise of 10 Ϯ 4%). These effects were blunted by EE removal, AM receptor antagonist (AM22-52), and CGRP receptor antagonist (CGRP8-37). Additionally, nitric oxide (NO) synthase inhibition with N G -nitro-Larginine (L-NAME) in muscles with and without EE and guanylyl cyclase inhibition with {1H-[1,2,4]oxadiazole-[4,4-a]-quinoxalin-1-one} not only blunted the negative inotropic action of IMD but also unmasked IMD-positive inotropic effect dependent on CGRP receptor PKA activation. Western blot quantification of phosphorylated cardiac troponin I (P-cTnI) in IMD-treated papillary muscles revealed a significant increase in P-cTnI when compared with untreated muscles, while in L-NAME-pretreated papillary muscles IMD failed to increase P-cTnI. Finally, we found that stimulation of both EE and microvascular endothelial cells with IMD significantly increased NO production by 40 Ϯ 3 and 38 Ϯ 3%, respectively, suggesting the role of cardiac endothelial cells in NO production upon IMD stimulation. Our findings establish IMD negative inotropic effect in isolated myocardium due to NO/cGMP pathway activation with concomitant thin myofilament desensitization by increase in cTnI phosphorylation and provide a coherent explanation for the previously reported contradictory results.neurohormones; contractile effect; nitric oxide synthase; cardiac endothelial cells; myofilament desensitization; adrenomedullin-2 OVERWHELMING DATA SUPPORT the role of neurohumoral regulation in the cardiovascular system, as illustrated by the fact that some neurohumoral agents due to their pathophysiological function in cardiac disease have become important therapeutic targets (22). In this context, numerous studies have continued to search for new neurohormones. Among the targeted peptide families is the calcitonin...

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Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

Intermedin elicits a negative inotropic effect in rat papillary muscles mediated by endothelial-derived nitric oxide

Pires

Pinho

Sena

et al. 2012

American Journal of Physiology-Heart and Circulatory Physiology

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“…In a mouse model of myocardial I/R injury, both the mRNA level and protein content of IMD increased, and the mRNA expression of CRLR, RAMP2 and RAMP3 was also upregulated. However, the RAMP1 gene expression did not change [ 19 ] and the change of CRLR and RMAPs protein expression, and the eff ect of endogenous IMD on myocardial I/R injury were still unknown. Recently, protein level of IMD and its receptors in the rat model of myocardial I/R injury, and eff ects of endogenous IMD on neonatal myocardiocytes hypoxia/reoxygenation (H/R) injury was also studied.…”

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confidence: 92%

Downregulation of Endogenous Intermedin Augmented Myocardial Injury in Rats with Ischemia/Reperfusion

et al. 2012

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tonin/calcitonin gene-related peptide (CGRP) family [ 5 , 6 ]. The human IMD gene encodes a prepropeptide of 148 amino acids with a signal peptide for secretion at the N terminus. IMD 1-53 can be generated from prepro-IMD by proteolytic cleavage at Arg93-Arg94 [ 7 , 8 ]. Two other bioactive polypeptides, IMD 1-47 and IMD 8-47 , are generated from prepro-IMD. The biological action of IMD is mediated by calcitonin receptor-like receptor (CRLR, the 7 transmembrane G proteincoupled receptor) and receptor activity-modifying proteins (RAMPs). IMD is a potent systemic and pulmonary vasodilator, infl uences regional blood fl ow and augments cardiac contractility [ 9 ]. IMD was found to dose-dependently augment cardiac perfusion and function and increase blood fl ow of the mesenterium, kidney, and hind limb [ 10 , 11 ]. IMD 1-53 inhibited cardiac fi broblast activation induced by angiotensin II [ 12 ] and improved viability of human aortic endothelial cells by inhibiting apoptosis and increasing the density of capillaries and arterioles in the ischemic hind limb of rats [ 13 , 14 ]. IMD stabilized pulmonary microvascular permeability that was increased during infl ammation and hypoxia. Furthermore, IMD decreased the generation of oxy-* These authors contributed equally to this manuscript.

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“…Rats' blood samples were prepared as previously described (Zhang et al, 2009). Plasma was loaded to a Sep-Pak C18 cartridge (Phoenix, AZ, USA) and pre-equilibrated with 0.5 mM acetic acid (Xilong, China).…”

Section: Determination Of Plasma Imd Levelsmentioning

confidence: 99%

Intermedin protects against myocardial ischemia-reperfusion injury in hyperlipidemia rats

Yang

Liu

2014

Genet. Mol. Res.

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ABSTRACT. Hyperlipidemia is a well-established risk factor for the development of coronary atherosclerosis, while intermedin (IMD) has been identified as a novel calcitonin/calcitonin gene-related peptide family member involved in cardiovascular protection. However, whether IMD protects against hyperlipidemia-associated myocardial ischemia/reperfusion (MI/R) injury is unknown. We established a hyperlipidemia model using Sprague-Dawley rats, and created a MI/R condition by ligating the cardiac left circumflex artery. The possible pathophysiological role of IMD and its physiological function in MI/R was further studied. The level of IMD significantly decreased in hyperlipidemia rats (P < 0.05). After MI/R, the IMD level was increased both in the plasma and myocardial tissue of hyperlipidemia rats compared to the sham-operated rats (P < 0.001). As evaluated by the activity of LDH, CK-MB, MDA and SOD, additional IMD was revealed to alleviate MI/R heart injury in hyperlipidemia rats (P < 0.05). By regulating the process of cardiomyocyte apoptosis and inflammatory reaction, IMD could perform an important role in cardio-protection, especially against hyperlipidemia-associated MI/R injury. Additional IMD could protect cardiac myocytes against MI/R injury via reduction of apoptosis and inflammation in the hyperlipidemia rat model, and thus, it may play a potential role as a novel therapeutic target for cardiac ischemic injury in hyperlipidemic patients.

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Intermedin is upregulated and has protective roles in a mouse ischemia/reperfusion model

Cited by 27 publications

References 32 publications

Intermedin elicits a negative inotropic effect in rat papillary muscles mediated by endothelial-derived nitric oxide

Intermedin elicits a negative inotropic effect in rat papillary muscles mediated by endothelial-derived nitric oxide

Downregulation of Endogenous Intermedin Augmented Myocardial Injury in Rats with Ischemia/Reperfusion

Intermedin protects against myocardial ischemia-reperfusion injury in hyperlipidemia rats

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