Differential Expression of Components of the Cardiomyocyte Adrenomedullin/Intermedin Receptor System following Blood Pressure Reduction in Nitric Oxide-Deficient Hypertension

Zhao, Yifang; Bell, David; Smith, Lisa R.; Zhao, Li; Devine, Adrian; McHenry, Eugene M.; Nicholls, D. P.; McDermott, Barbara

doi:10.1124/jpet.105.092783

Cited by 47 publications

(69 citation statements)

References 43 publications

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“…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. They showed that the mRNA expression levels of IMD and the receptor complex components were increased, indicating that IMD signaling has a certain pathophysiological role in heart failure.…”

Section: Introductionmentioning

confidence: 99%

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: Introductionmentioning

confidence: 99%

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

et al. 2009

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“…The presence of IMD in diseased myocardium has also been observed [18]. To determine whether IMD level is altered in myocardial tissue in SAP rats, we measured myocardial IMD protein using RIA assay, and IMD mRNA using quantitative PCR.…”

Section: Increase Of Imd Was Observed In Sap Ratsmentioning

confidence: 99%

“…Expression of receptor-activity-modifying proteins (RAMPs) in SAP rats without or with IMD treatment IMD interacts with a receptor complex consisting of calcitonin receptor-like receptor (CL) and RAMPs. Three subsets of RAMP have been defined, RAMP1, RAMP2, and RAMP3, which have differential expression levels in different tissues and distinguish signaling transduction activity [18,21,22]. To determine the expression of RAMPs in heart tissue, we examined their mRNA expressions using QPCR.…”

Section: Imd Inhibits Myocardial Apoptosis Through Regulating Pro-andmentioning

confidence: 99%

Protective effect of intermedin on myocardial cell in a rat model of severe acute pancreatitis

Cao

Xue

et al. 2011

Cellular and Molecular Biology Letters

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Abstract:Severe acute pancreatitis (SAP) is a common disease with a poor prognosis. Heart failure is one cause of SAP patient death. Intermedin (IMD) is a potent endogenous cardio-protective substance. Administration of exogenous IMD showed beneficial effects in cardiovascular diseases. The aim of this study was to investigate the myocardial damage in SAP and to determine the therapeutic potential of IMD for SAP. Using an SAP rat model, we examined endogenous IMD expression following SAP induction, and determined the effect of IMD on myocardial function, histological morphology, apoptosis-related gene expression, and prognosis. Our results indicated that the cardiac function and histological structure were significantly disrupted in SAP rats. Infusion of exogenous IMD significantly preserved cardiac function and ameliorated myocardial damage. Terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling (TUNEL) revealed that myocardial apoptosis was extensively present in SAP rats, and IMD infusion led to increased expression of the prosurvival factor Bcl-2, but decreased pro-apoptotic factors Bax and caspase-3. In addition, IMD infusion also reversed the change of IMD receptor systems in SAP rat heart tissue. Furthermore, we found that IMD infusion greatly decreased mortality of SAP rats. In conclusion, administration of SAP produced therapeutic effects in SAP through modulating apoptotic and pro-survival gene expression, inhibiting myocardial apoptosis, preserving cardiac function, and ultimately increasing survival. The current study suggests that IMD may be a useful therapeutic agent for SAP, and provides us an insight for a clinical trial of IMD for treating human severe acute pancreatitis.

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“…(13) IMD is expressed by endothelial cells, smooth muscle cells and cardiomyocytes at a basal level with enhanced expression in response to hypoxic stress (14) or high blood pressure. (15) In addition, IMD can be induced by hypoxia-inducible factors (HIF) 1a and 1b in hypoxic hepatocytes. (14) The calcitonin peptide family, of which IMD is a member, has a common secondary structure with an N-terminal ring structure and an amidated carboxyl terminus.…”

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confidence: 99%

Intermedin is overexpressed in hepatocellular carcinoma and regulates cell proliferation and survival

et al. 2012

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Angiogenesis is one of the hallmarks of tumor growth and metastasis. Identification of tumor angiogenic factors has been a critical component in understanding cancer biology and treatment. Intermedin (IMD) has been reported to promote angiogenesis in a rat ischemic model and human umbilical vascular endothelial cells. Our study sought to determine the role of IMD in human hepatocellular carcinoma tumor progression. High IMD mRNA expression levels were observed in human hepatocellular carcinoma tumors, even in early stage disease, by real-time RT-PCR. Immunohistochemical analysis of hepatocellular carcinoma clinical samples demonstrated that the tumor regions were significantly more immunoreactive for IMD than adjacent benign liver. Inhibition of IMD expression using RNA interference reduced cell proliferation in SK-Hep-1 and SNU-398 cells. Blockage of IMD signaling using either an antagonist peptide or a neutralizing antibody inhibited growth in a dose-dependent manner with concomitant induction of apoptosis, causing cleavage of caspase-8 and downregulation of Gli1 and Bcl2. Conversely, addition of IMD active peptide increased the phosphorylation level of extracellular signal-regulated kinase. Thus, IMD might play an important role in cell proliferation and survival of hepatocellular carcinoma. Our data suggests that IMD is a potential biomarker and therapeutic target for hepatocellular carcinoma. (Cancer Sci 2012; 103: 1474-1480 H epatocellular carcinoma (HCC) is the fifth most common cancer worldwide, and the third leading cause of cancer death.(1) The majority (>80%) of liver cancers are HCC.Conventional chemotherapy and hormonal therapies have minimal response rates. (3) Therapeutic agents targeting angiogenesis, which is required for tumor growth and metastasis, are currently in development. (4,5) Of the known angiogenic factors, vascular endothelial growth factor (VEGF) is the most potent pro-angiogenic factor and is secreted by nearly all solid cancers.(5) Sorafenib, an inhibitor targeting the VEGF and platelet-derived growth factor receptors, is the standard of care in patients with advanced HCC.(6) Promising novel inhibitors are under investigation.(7) The key to targeting angiogenesis successfully in the future may be to use a combination of multiple inhibitors against multiple targets. Intermedin (IMD, adrenomedullin-2), is a secreted peptide that belongs to the calcitonin/calcitonin gene-related peptide family.(9) IMD regulates diverse physiological processes. For example, IMD is required for rat normal fetoplacental growth, (10) functions as a vasodilator and reduces blood pressure in both normal and hypertensive rats.(11) IMD is expressed in every endocrine organ of the hypothalamo-pituitary-adrenal axis together with its receptor, calcitonin receptor-like receptor (CRLR). (12) The signaling of IMD is mediated by the interaction of CRLR in association with receptor activity modifying protein 3 (RAMP3).(13) IMD is expressed by endothelial cells, smooth muscle cells and cardiomyocytes at a basal leve...

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Differential Expression of Components of the Cardiomyocyte Adrenomedullin/Intermedin Receptor System following Blood Pressure Reduction in Nitric Oxide-Deficient Hypertension

Cited by 47 publications

References 43 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

Protective effect of intermedin on myocardial cell in a rat model of severe acute pancreatitis

Intermedin is overexpressed in hepatocellular carcinoma and regulates cell proliferation and survival

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