CRH-like peptides protect cardiac myocytes from lethal ischaemic injury

Brar, Bhawanjit K.; Stephanou, Anastasis; Okosi, A; Lawrence, Kevin M.; Knight, Richard; Marber, Michael; Latchman, David S.

doi:10.1016/s0303-7207(99)00183-5

Cited by 111 publications

(84 citation statements)

References 27 publications

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“…They expand on earlier findings that cardiac myocytes release Ucn2 from intracellular stores and Ucn2 mRNA abundance increases during simulated ischemia/reperfusion (33). We found that neutralizing Ucn2 antibody, which selectively binds extracellular Ucn2, blunts the activation of AMPK during hypoxia.…”

Section: Discussionsupporting

confidence: 88%

Urocortin 2 autocrine/paracrine and pharmacologic effects to activate AMP-activated protein kinase in the heart

Qi²,

Cheng

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

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Urocortin 2 (Ucn2), a peptide of the corticotropin-releasing factor (CRF) family, binds with high affinity to type 2 CRF receptors (CRFR2) on cardiomyocytes and confers protection against ischemia/reperfusion. The mechanisms by which the Ucn2-CRFR2 axis mitigates against ischemia/reperfusion injury remain incompletely delineated. Activation of AMP-activated protein kinase (AMPK) also limits cardiac damage during ischemia/reperfusion. AMPK is classically activated by alterations in cellular energetics; however, hormones, cytokines, and additional autocrine/paracrine factors also modulate its activity. We examined the effects of both the endogenous cardiac Ucn2 autocrine/paracrine pathway and Ucn2 treatment on AMPK regulation. Ucn2 treatment increased AMPK activation and downstream acetyl-CoA carboxylase phosphorylation and glucose uptake in isolated heart muscles. These actions were blocked by the CRFR2 antagonist anti-sauvagine-30 and by a PKCe translocation-inhibitor peptide (eV1-2). Hypoxia-induced AMPK activation was also blunted in heart muscles by preincubation with either anti-sauvagine-30, a neutralizing anti-Ucn2 antibody, or eV1-2. Treatment with Ucn2 in vivo augmented ischemic AMPK activation and reduced myocardial injury and cardiac contractile dysfunction after regional ischemia/reperfusion in mice. Ucn2 also directly activated AMPK in ex vivo-perfused mouse hearts and diminished injury and contractile dysfunction during ischemia/reperfusion. Thus, both Ucn2 treatment and the endogenous cardiac Ucn2 autocrine/paracrine pathway activate AMPK signaling pathway, via a PKCe-dependent mechanism, defining a Ucn2-CRFR2-PKCe-AMPK pathway that mitigates against ischemia/reperfusion injury. metabolism | cardiac function

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Section: Discussionsupporting

confidence: 88%

Urocortin 2 autocrine/paracrine and pharmacologic effects to activate AMP-activated protein kinase in the heart

Qi²,

Cheng

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

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“…This suggests that endogenous urocortins may also act via an autocrine/paracrine cardioprotective mechanism. Indeed, supernatants from primary cultures of rat cardiomyocytes exposed to I/R are cardioprotective and these cardioprotective effects of ischemia-preconditioned media are inhibited by CRH-R antagonists [8]. In addition, we have shown that both myocyte apoptosis and urocortin expression are increased in human hearts exposed to cardioplegic arrest, a common iatrogenic form of I/R, and all urocortin positive cells are viable, while apoptotic cells are urocortinnegative [9].…”

Section: Introductionmentioning

confidence: 78%

Retracted: Cardiac release of urocortin precedes the occurrence of irreversible myocardial damage in the rat heart exposed to ischemia/reperfusion injury

Knight¹,

Chen‐Scarabelli²,

Yuan³

et al. 2008

FEBS Letters

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This study evaluates whether cardiac ischemia induces release of urocortin, before and independently from myocyte cell death. Urocortin levels rose after 5-min ischemia and peaked after 10-min ischemia, when cell death was not detected. However, myocyte apoptosis and/or necrosis occurred following 20-and 30-min ischemia, which paralleled a fall in urocortin levels, suggesting that urocortin expression and release are mainly sustained by metabolically challenged, though still viable myocytes. Hence, since cardiac release of urocortin, unlike that of conventional biomarkers, occurs before and apart from cell death, urocortin levels may be clinically useful in the diagnosis of sublethal myocardial ischemia.

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“…In in vitro cultures of primary rat cardiac myocytes exposed to simulated hypoxia/ ischemia followed by reoxygenation, exogenous UCN reduces cardiac myocyte cell death when added after the simulated hypoxia/ischemia and during the reoxygenation/reperfusion period as well as when added prior to the simulated hypoxia/ ischemia (20). Moreover, in the ischemic/reperfused isolated heart ex vivo, UCN is also cardioprotective when added to the perfusate after ischemia and during reperfusion.…”

Section: Discussionmentioning

confidence: 99%

Section: Urocortin (Ucn)mentioning

confidence: 97%

“…Moreover, cardiac CRF-R2␤ expression is modulated by endotoxin, a potent inducer of cardiovascular dysregulation, further suggesting a possible link between UCN and the cardiovascular response to stress (19). Indeed, in previous studies, we have shown that UCN mRNA expression increases in cardiac cells exposed to thermal and simulated hypoxic/ischemic injury stress in vitro (9) and that endogenous UCN peptide protects cardiac myocytes from cell death when administered prior to the stress (20).A number of studies have implicated the mitogen-activated protein kinase (MAPK) pathway as a survival pathway in both cardiac cells (21-23) and other cell types (24 -29). The extracellular signal-related kinases (ERKs), belonging to one subfamily of MAPKs, are composed of 42-and 44-kDa kinases named p42 ERK and p44 ERK, respectively.…”

mentioning

confidence: 98%

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Urocortin Protects against Ischemic and Reperfusion Injury via a MAPK-dependent Pathway

Brar

Jonassen

Stephanou

et al. 2000

Journal of Biological Chemistry

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233

193

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Urocortin (UCN) is a peptide related to hypothalamic corticotrophin-releasing hormone and binds with high affinity to corticotrophin-releasing hormone receptor-2␤, which is expressed in the heart. In this study, we report that UCN prevented cell death when administered to primary cardiac myocyte cultures both prior to simulated hypoxia/ischemia and at the point of reoxygenation after simulated hypoxia/ischemia. UCN-mediated cell survival was measured by trypan blue exclusion, 3-OH end labeling of DNA (TUNEL), annexin V, and fluorescence-activated cell sorting. To explore the mechanisms that could be responsible for this effect, we investigated the involvement of MAPK-dependent pathways. UCN caused rapid phosphorylation of ERK1/2-p42/ 44, and PD98059, which blocks the MEK1-ERK1/2-p42/44 cascade, also inhibited the survival-promoting effect of UCN. Most important, UCN reduced damage in isolated rat hearts ex vivo subjected to regional ischemia/reperfusion, with the protective effect being observed when UCN was given either prior to ischemia or at the time of reperfusion after ischemia. This suggests a novel function of UCN as a cardioprotective agent that could act when given after ischemia, at reperfusion. Urocortin (UCN)1 is a peptide related to the hypothalamic hormone corticotrophin-releasing factor (CRF), the central mediator of the hypothalamic-pituitary-adrenal axis and stress response in mammals (1-3). UCN and CRF share 45% homology at the amino acid level, and both are synthesized as precursors, which are subsequently processed to the mature biologically active peptides (in the case of UCN, a 40-amino acid molecule) (4, 5). Although UCN was originally identified in restricted areas of the brain, it has also been found in the placenta, lymphocytes, and heart (6 -9).The CRF family of peptides bind two types of CRF receptors, CRF-R1 and CRF-R2. CRF-R2 exists in three alternative splice variant forms, CRF-R2␣, CRF-R2␤, and CRF-R2␥ (10 -12); and CRF-R2 binds UCN with a higher affinity than CRF both in ligand binding studies (4) and as shown by the effects of ligand on intracellular cAMP (13). In contrast, the R1 receptors show little ligand selectivity for UCN versus CRF. R2 receptors are the only type of CRF receptor found in the heart: the ␣ form in man (14) and the ␤ form in the rat (15). The CRF family of peptides have been shown to stimulate adenylate cyclase activity in cardiac myocytes (16), and changes in CRF-R2 expression have been reported in the hearts of spontaneously hypertensive rats (17).The coincident expression of CRF-R2 receptors with their preferred UCN ligand in the heart suggests that UCN may have physiological cardiac properties. Indeed UCN, but not CRF, induces a dose-dependent increase in heart rate, cardiac output, and coronary blood flow (18). Moreover, cardiac CRF-R2␤ expression is modulated by endotoxin, a potent inducer of cardiovascular dysregulation, further suggesting a possible link between UCN and the cardiovascular response to stress (19). Indeed, in previous studies, we have...

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CRH-like peptides protect cardiac myocytes from lethal ischaemic injury

Cited by 111 publications

References 27 publications

Urocortin 2 autocrine/paracrine and pharmacologic effects to activate AMP-activated protein kinase in the heart

Urocortin 2 autocrine/paracrine and pharmacologic effects to activate AMP-activated protein kinase in the heart

Retracted: Cardiac release of urocortin precedes the occurrence of irreversible myocardial damage in the rat heart exposed to ischemia/reperfusion injury

Urocortin Protects against Ischemic and Reperfusion Injury via a MAPK-dependent Pathway

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