Adrenomedullin Protects Against Myocardial Apoptosis After Ischemia/Reperfusion Through Activation of Akt-GSK Signaling

Yin, Hang; Chao, Lee; Chao, Julie

doi:10.1161/01.hyp.0000103696.60047.55

Cited by 117 publications

(66 citation statements)

References 43 publications

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“…10 In fact, CGRP and ADM have been reported to be upregulated in plasma and cardiovascular tissues in cardiac ischemic diseases. 16,23,24 They effectively antagonize the deleterious actions of angiotensin II 25,26 and endothelin 26,27 in different cardiovascular diseases, which indicates that IMD might counteract vicious stimuli in a similar way. 10 Although the IMD gene delivery technique has not been applied to ameliorate conditions of cardiac ischemia, Hagiwara et al 28 have fully shown that a delivered human IMD gene not only produced a sustained reduction of blood pressure but also attenuated renal dysfunction in DOCA-salt hypertensive rats by inhibition of oxidative stress and proinflammatory mediator pathways.…”

Section: Discussionmentioning

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: Discussionmentioning

confidence: 99%

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

et al. 2009

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“…Furthermore, this protection from apoptosis was inhibited by dominant-negative Akt or active GSK-3β mutant and mimicked by pharmacological inhibitors of GSK-3β. 69,[94][95][96][97][98] Transgenic mice that cardio-specifically express dominantnegative GSK-3β showed significantly fewer apoptotic cardiomyocytes after pressure overloading by aortic constriction. 99 These findings indicate that GSK-3β activity determines the fate of cardiomyocytes exposed to apoptosis inducers.…”

Section: Role Of Gsk-3β In Apoptosis Of Cardiomyocytesmentioning

confidence: 99%

“…Although the role of GSK-3β in apoptosis of cardiomyocytes has not been fully clarified, evidence to date supports its significant contribution to apoptosis induced by ischemia/ reperfusion, 69,[94][95][96] hypoxia/re-oxygenation, 97 β-adrenoceptor activation 98 and pressure overload. 99 Apoptosis by these insults was suppressed by overexpression of the adrenomedullin gene 95 or kallikrein gene 96 or treatment with statins, 97 all of which induced phosphorylation of GSK-3β.…”

Section: Role Of Gsk-3β In Apoptosis Of Cardiomyocytesmentioning

confidence: 99%

“…99 Apoptosis by these insults was suppressed by overexpression of the adrenomedullin gene 95 or kallikrein gene 96 or treatment with statins, 97 all of which induced phosphorylation of GSK-3β. Furthermore, this protection from apoptosis was inhibited by dominant-negative Akt or active GSK-3β mutant and mimicked by pharmacological inhibitors of GSK-3β.…”

Section: Role Of Gsk-3β In Apoptosis Of Cardiomyocytesmentioning

confidence: 99%

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GSK-3.BETA., a Therapeutic Target for Cardiomyocyte Protection

Miura

Miki

2009

Circ J

130

112

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lycogen synthase kinase-3β (GSK-3β) is a constitutively active 47-kDa Ser/Thr protein kinase that was purified more than 2 decades ago as a kinase that reduces glycogen synthase activity. However, GSK-3β is now known as a multifunctional kinase having more than 40 substrates, playing roles not only in glycogen metabolism but also cell proliferation, growth and death. [1][2][3] To properly execute its functions, GSK-3β has multiple regulatory mechanisms including phosphorylation at Ser and Tyr residues, complex formation with scaffold proteins, priming of substrates and intracellular translocation. Recently, pathophysiological roles of GSK-3β have also received attention because it is involved in common and serious diseases such as Alzheimer's disease, bipolar mood disorder, cancer and ischemia/reperfusion injury. 1,3 In the cardiovascular system, GSK-3β has major roles in glucose metabolism, 4 cardiomyocyte hypertrophy 5 and cell death. The roles of GSK-3β in hypertrophy have recently been reviewed by Sugden et al 5 , so therefore we have focused on the roles of this protein kinase in myocyte death, particularly that after ischemia/ reperfusion. We first briefly overview mechanisms of ischemia/reperfusion injury and then discuss the contribution of GSK-3β to cardiomyocyte death and manipulation of GSK-3β for myocardial protection. Mechanisms of Cardiomyocyte Necrosis During Ischemia/ReperfusionWhen myocardial blood perfusion is interrupted, for example by occluding the coronary artery, ischemic cardiomyocytes suffer from several critical intracellular events that can lead to cell necrosis and/or prime the cells to reperfusion-induced necrosis. First, intracellular level of highenergy phosphate is reduced due to oxygen deficiency. Although ischemic cardiomyocytes cease contraction within a few minutes after the onset of ischemia, adenosine triphosphate (ATP) consumption continues during ischemia mainly by mitochondrial ATPase for maintenance of mitochondrial membrane potential. 6,7 Anaerobic glycolysis supplies ATP during the early period of ischemia, but it is ultimately halted by inhibition of glyceraldehyde phosphate dehydrogenase due to accumulated H + and NADH. 7,8 Second, intracellular Na + accumulates due to Na + influx via Na + -H + exchangers and Na + channels and due to reduced Na + efflux via the Na + -K + pump. [9][10][11] This Na + overload predisposes ischemic cardiomyocytes to Ca 2+ influx by the Na + -Ca 2+ exchanger. Third, Ca 2+ influx via the Na + -Ca 2+ exchanger, reduced Ca 2+ uptake into the sarcoplasmic reticulum and reduced Ca 2+ efflux via the sarcolemmal Ca 2+ pump induce Ca 2+ overload in ischemic cardiomyocytes. 9-12 However, elevation of intracellular Ca 2+ is modest during ischemia because acidosis inhibits the Na + -Ca 2+ exchanger and cytosolic Ca 2+ is taken up by the mitochondria as long as its membrane potential is maintained by use of ATP. [9][10][11]13 Severely ischemic cardiomyocytes ultimately 'starve to death', although sarcolemmal damage by detergent actions of accumulated...

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“…25 In addition, age-matched male C57BL/6 (wild type, WT) mice were purchased from Charles River (Wilmington, MA, USA). Studies were performed in: (i) sham-operated (normal) mice and (ii) WT or a-CGRP KO mice that (immediately after BDL) were treated with saline or the CGRP receptor antagonist, CGRP (0.55 mg/kg body weight/day by IP-implanted Alzet s minipumps) 26 for 3 or 7 days. BDL was performed as described.…”

Section: Animal Modelsmentioning

confidence: 99%

Knockout of α-calcitonin gene-related peptide reduces cholangiocyte proliferation in bile duct ligated mice

Glaser

Ueno

DeMorrow

et al. 2007

Laboratory Investigation

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The role of sensory innervation in the regulation of liver physiology and the pathogenesis of cholestatic liver disease are undefined. Biliary proliferation has been shown to be coordinately controlled by parasympathetic and sympathetic innervation of the liver. The aim of our study was to address the role of the sensory neuropeptide calcitonin gene-related peptide (a-CGRP) in the regulation of cholangiocyte proliferation during cholestasis induced by extrahepatic bile duct obstruction (BDL). Our study utilized a knockout (KO) mouse model, which lacks the sensory neuropeptide a-CGRP. Wildtype (WT) and a-CGRP KO mice were subjected to sham surgery or BDL for 3 and 7 days. In addition, immediately after BDL, WT and KO mice were administered the CGRP receptor antagonist (CGRP 8-37 ) for 3 and 7 days by osmotic minipumps. Liver sections and isolated cholangiocytes were evaluated for proliferation markers. Isolated WT BDL (3 days) cholangiocytes were stimulated with a-and b-CGRP and evaluated for proliferation and cAMP-mediated signaling. Lack of a-CGRP inhibits cholangiocyte proliferation induced by BDL at both 3 and 7 days. BDL-induced cholangiocyte proliferation in WT mice was associated with increases of circulating a-CGRP levels. In vitro, a-and b-CGRP stimulated proliferation in purified BDL cholangiocytes, induced elevation of cAMP levels, and stimulated the activation of cAMPdependent protein kinase A and cAMP response element binding protein DNA binding. In conclusion, sensory innervation of the liver and biliary expression of a-CGRP play an important role in the regulation of cholangiocyte proliferation during cholestasis.

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Adrenomedullin Protects Against Myocardial Apoptosis After Ischemia/Reperfusion Through Activation of Akt-GSK Signaling

Cited by 117 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

GSK-3.BETA., a Therapeutic Target for Cardiomyocyte Protection

Knockout of α-calcitonin gene-related peptide reduces cholangiocyte proliferation in bile duct ligated mice

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