Expression of the Counter-Regulatory Peptide Intermedin is Augmented in the Presence of Oxidative Stress in Hypertrophied Cardiomyocytes

Bell, David; Zhao, Yifang; McCoy, Francis; Devine, Adrian; McDermott, Barbara

doi:10.1159/000129633

Cited by 19 publications

(14 citation statements)

References 51 publications

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“…20 The factors involved in cardiac ischemic diseases, including catecholamines, angiotensin II, endothelin-1 and numerous cytokines, might upregulate IMD gene expression. 4,5 Bell et al 12 reported that the local concentration and action of IMD may be further enhanced by the downregulation of neutral endopeptidase, a membrane-bound metallopeptidase that may degrade IMD in local tissues. Further studies are needed to confirm the regulation of IMD expression by hypoxia and the change in the activity of neutral endopeptidase in local ischemic tissues.…”

Section: Discussionmentioning

confidence: 99%

“…10 Recently, there has been increased interest in the role of endogenous IMD in cardiovascular diseases. 10,12 The robust expression of IMD in the diseased cardiovascular system suggests an important influence on cardiovascular pathology. 10,12 It has been reported that IMD protects the myocardium from the deleterious effects of oxidative stress 10 and hypertrophic stimuli, 12 which indicates an important cytoprotective role of IMD as an endogenous counter-regulatory peptide in the cardiovascular system.…”

Section: Introductionmentioning

confidence: 99%

“…10,12 The robust expression of IMD in the diseased cardiovascular system suggests an important influence on cardiovascular pathology. 10,12 It has been reported that IMD protects the myocardium from the deleterious effects of oxidative stress 10 and hypertrophic stimuli, 12 which indicates an important cytoprotective role of IMD as an endogenous counter-regulatory peptide in the cardiovascular system. 9,10,12 Alterations in not only IMD but also its receptor complexes have been further studied to reveal the underlying signal transduction in cardiovascular diseases.…”

Section: Introductionmentioning

confidence: 99%

“…10,12 It has been reported that IMD protects the myocardium from the deleterious effects of oxidative stress 10 and hypertrophic stimuli, 12 which indicates an important cytoprotective role of IMD as an endogenous counter-regulatory peptide in the cardiovascular system. 9,10,12 Alterations in not only IMD but also its receptor complexes have been further studied to reveal the underlying signal transduction in cardiovascular diseases. 10,13,14 Hirose et al 15 investigated the expression of IMD and the receptor complex components (CRLR, three types of RAMP) in the hearts of rats with congestive heart failure.…”

Section: Introductionmentioning

confidence: 99%

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

et al. 2009

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Intermedin (IMD), a new calcitonin/calcitonin gene-related peptide family peptide with vasodilatory and positive inotropic properties, has multiple functions in regulating cardiovascular homeostasis and is of particular interest in the pathophysiology of myocardial ischemia/reperfusion (MI/R). We created a mouse model of MI/R by ligating the cardiac left anterior descending artery to study the possible pathophysiological role of IMD and its receptor complexes in MI/R. Compared with the control, infarcted mice showed increased content, mRNA and protein expression of IMD in plasma and cardiac tissue. The mRNA expression of the receptor activity-modifying protein 3 (RAMP3) gene increased very early, and the calcitonin receptor-like receptor and RAMP2 mRNA levels increased later after reperfusion. However, the RAMP1 gene expression did not change. The tissue IMD content was positively correlated with the diastolic blood pressure and negatively correlated with pulse pressure. In addition, exogenous IMD treatment significantly ameliorated the MI/R injury by rescuing the pulse pressure, inhibiting neutrophil infiltration in the peri-infarction area, and decreasing the creatine kinase and lactate dehydrogenase activities in plasma. Our results indicated that IMD was upregulated in the ischemic myocardium and may induce important beneficial cytoprotection against cardiac ischemic injury.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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

et al. 2009

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“…4 In addition, higher IMD expression in hypertrophied left ventricular cardiomyocytes suggests an important role for the peptide in the response to chronic hypertension. 5 In an investigation published in this issue, Zhang et al 6 use a mouse model to study the effects of IMD in relation to the important clinical problem of myocardial ischemiareperfusion injury. The role of IMD in this pathological condition remains poorly understood, and little is known with regard to changes in the expression of IMD and the receptor components.…”

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confidence: 99%

Toward revealing the roles for intermedin in the community of vasoactive peptides

Evans

2009

Hypertens Res

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T he potential of intermedin (IMD) as a regulator of cardiovascular activity is well established. For example, studies have shown that IMD exhibits vasodilatory activity 1 and decreases blood pressure. 2,3 In pathophysiological states, it has been reported that the expression of IMD is enhanced during heart failure. 4 In addition, higher IMD expression in hypertrophied left ventricular cardiomyocytes suggests an important role for the peptide in the response to chronic hypertension. 5 In an investigation published in this issue, Zhang et al. 6 use a mouse model to study the effects of IMD in relation to the important clinical problem of myocardial ischemiareperfusion injury. The role of IMD in this pathological condition remains poorly understood, and little is known with regard to changes in the expression of IMD and the receptor components. In the current investigation, the authors use a mouse model involving ligation of the left descending artery. They report that there are changes induced in pulse pressure and heart rate following induction of infarction and reperfusion. With respect to furthering our understanding of ischemia-reperfusion, it is important to note that there were also changes in factors associated with IMD. Observations included raised levels of IMD in plasma and of expression in the infarcted area. In addition, there was modulation of receptor activity-modifying protein (RAMP)2 and RAMP3 expression. The peptide was administered to consider the effects of IMD, and these included reduction in the size of the necrotic area. Furthermore, levels of IMD in blood were positively associated with diastolic blood pressure and negatively associated with pulse pressure. These results are consistent with a cardioprotective function.The authors have supplied new information on the response and potential role of IMD in myocardial ischemia-reperfusion injury. This is important in light of the knowledge that there are a number of endogenous bioactive factors involved in cardiovascular control. These include the peptides endothelin-1, CNP, angiotensin-II, urocortin and adrenomedullin (ADM), among others. To understand (and therefore control) the system, it is necessary to delineate the distinct effects of the different peptides. The activities and responses of the peptides will potentially complement each other in physiological functioning by being activated in different circumstances.The relationship between IMD and ADM is of particular interest because of their structural similarity and the possibility that they comprise a distinct family within the calcitonin gene-related peptide superfamily. 3 It has been observed that the effects of IMD on the cardiovascular system can indeed sometimes be similar to those of ADM, so perhaps in some circumstances we could expect the effects to be additive in vivo. Even with regard to ischemia-reperfusion injuries, cardio-protective activity has been reported for both ADM and IMD. 7 The current study has observed that IMD reduces neutrophil infiltration and has an increase...

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Inhibition of endoplasmic reticulum stress by intermedin1–53 protects against myocardial injury through a PI3 kinase–Akt signaling pathway

et al. 2011

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Intermedin (IMD) is a novel member of the calcitonin/calcitonin gene-related peptide family. We aimed to explore whether the cardioprotective effect of IMD is mediated by inhibiting myocardial endoplasmic reticulum (sarcoplasmic reticulum) stress (ERS). In vitro, IMD(1-53) (10(-9), 10(-8), and 10(-7) mol/l) directly inhibited the upregulation of ERS markers such as glucose-regulated protein 78, CCAAT/enhancer binding protein homologous protein, and caspase-12 induced by the ERS inducers tunicamycin (Tm, 10 mg/ml) or dithiothreitol (DTT, 2 mmol/l) in cardiac tissue. IMD(1-53) also inhibited Tm- or DTT-induced upregulation of cleaved activating transcription factor 6 and 4. These inhibitory effects of IMD(1-53) were abolished by the IMD receptor antagonist IMD(17-47) (10(-6) mol/l) and phosphoinositide 3-kinase inhibitor LY294002 (10 μmol/l). However, preincubation with PD98059 (20 μmol/l), an extracellular signal-regulated protein kinase inhibitor, and H89 (10 μmol/l), a protein kinase A inhibitor, could not block the ERS-inhibiting effects of IMD(1-53). Furthermore, in an in vivo model of myocardium ischemia/reperfusion (I/R) in rats, administration of IMD(1-53) (20 nmol/kg, intravenously) greatly attenuated ERS and ameliorated myocardium impairment induced by I/R. IMD(1-53) could exert its cardioprotective effect by inhibiting myocardial ERS, which might be mediated by the phosphoinositide 3-kinase/Akt signaling pathway.

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Expression of the Counter-Regulatory Peptide Intermedin is Augmented in the Presence of Oxidative Stress in Hypertrophied Cardiomyocytes

Cited by 19 publications

References 51 publications

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

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

Toward revealing the roles for intermedin in the community of vasoactive peptides

Inhibition of endoplasmic reticulum stress by intermedin1–53 protects against myocardial injury through a PI3 kinase–Akt signaling pathway

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