Urocortin, a Newly Identified Corticotropin-Releasing Factor-Related Mammalian Peptide, Stimulates Atrial Natriuretic Peptide and Brain Natriuretic Peptide Secretions from Neonatal Rat Cardiomyocytes

Ikeda, Keiichi; Tojo, Katsuyoshi; Sato, Shigeaki; Ebisawa, Takanori; Tokudome, Goro; Hosoya, Tatsuo; Hara, Masaki; Nakagawa, Osamu; Nakao, Kazuwa

doi:10.1006/bbrc.1998.9297

Cited by 72 publications

(31 citation statements)

References 35 publications

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“…2B). These studies indicate that endogenous Ucn2 was released during ischemia and are consistent with previous results in isolated cardiomyocytes during hypoxia (18). We also measured serum Ucn2 concentrations during in vivo regional ischemia.…”

Section: Resultssupporting

confidence: 91%

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: Resultssupporting

confidence: 91%

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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“…Ang II markedly increased the secretion of Ucn I up to 12 h, with a temporal increase of Ucn I mRNA followed by suppression. The increase in Ucn I levels in the culture medium may result in an increase in intracellular cAMP (Ikeda et al 1998), leading to the induction of a family of cAMP-responsive nuclear factors, including inducible cAMP early repressor (Sassone-Corsi 1998). Consequently, due to the presence of a cAMP responsive element (CRE) in the Ucn I promoter region (Zhao et al 1998), the decrease in the expression of Ucn I mRNA may be attributed to the binding of inducible cAMP early repressor to the CRE after an initial increase in the expression of Ucn I mRNA.…”

Section: Discussionmentioning

confidence: 99%

“…Urocortin (murine urocortin: Ucn, human urocortin: UCN) I, Ucn II, and Ucn III, the members of corticotropin-releasing hormone (CRH)-related peptides, have various actions on the cardiovascular system via cAMP-dependent pathways and the extracellularly regulated kinase 1/2 pathway (Ikeda et al 1998, 2002, 2005a, Brar et al 2004a, Honjo et al 2006. We previously reported the pathophysiological involvement of UCN I in cardiomyopathies (Ikeda et al 2003), in which a patient's plasma concentration of tumor necrosis factor (TNF)-a increased (Matsumori et al 1994).…”

Section: Introductionmentioning

confidence: 99%

“…TNF-a can produce various deleterious effects when expressed in large amounts and it is produced in the heart by both cardiomyocytes and resident macrophages under conditions of cardiac stress (Sarzi-Puttini et al 2005). In addition, Ucn I was up-regulated by TNF-a in human umbilical vein endothelial cells (Honjo et al 2006), and, in turn, CRH type 2 receptor (CRH-R2) was down-regulated by lipopolysaccarides (LPS) and TNF-a in the mouse heart (Ikeda et al 1998, Coste et al 2001. Because CRH-R2 was also downregulated by Ucn I in mouse cardiomyocytes (Heldwein et al 1997, Coste et al 2001 and in the mouse heart (Asaba et al 2000), we hypothesize that LPS and TNF-a may stimulate the release of endogenous ligand(s) for CRH-R2, such as CRH, Ucn I, Ucn II, and/or Ucn III, from the heart.…”

Section: Introductionmentioning

confidence: 99%

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Regulation of urocortin I and its related peptide urocortin II by inflammatory and oxidative stresses in HL-1 cardiomyocytes

Ikeda¹,

Tojo²,

Inada³

et al. 2009

Journal of Molecular Endocrinology

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Despite our knowledge on the regulation of urocortin (Ucn) I and its related peptides in the heart, the possible involvement of cardiovascular stress substances, such as cytokines or angiotensin II (Ang II), on this regulation remains to be fully elucidated. We therefore evaluated the potential role of cardiovascular stress substances on the regulation of the Ucn-corticotropin-releasing hormone (CRH) receptor system in HL-1 cardiomyocytes using a Ucn I-specific RIA, conventional reverse transcription-PCR (RT-PCR) and quantitative real-time RT-PCR. Ucn I mRNA levels were shown to be up-regulated by lipopolysaccarides (LPS), tumor necrosis factor-a (TNF-a), Ang II, H 2 O 2 , and pyrrolidinedithiocarbamate (PDTC). The LPS-and Ang II-induced increase in Ucn I mRNA levels was abolished by tempol. In addition, the secretion of Ucn I from HL-1 cardiomyocytes was stimulated by LPS and TNF-a. On the contrary, Ucn II mRNA was increased by TNF-a alone and Ang II with tempol, and the TNF-a-induced increase in Ucn II mRNA was abolished by erythromycin and PDTC. These results suggested that Ucn I mRNA may be up-regulated by oxidative stress, whereas Ucn II mRNA may be up-regulated by the activated nuclear factor-kB, i.e. inflammatory stress. CRH-R2 mRNA may be negatively regulated by the increase in expression of Ucn I and/or Ucn II mRNA. In conclusion, the Ucn-CRH receptor system may be regulated by two major forms of cardiac stresses, i.e. oxidative and inflammatory stress, and may play a critical role in cardiac stress adaptation in heart diseases.

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“…It was found that urocortin, another Urocortin 2 inhibits [Camember of CRF family, stimulated Ca 2 + uptake in skin cells (Wiesner et al, 2003). In addition, urocortin-induced increase of ANP and BNP secretion was completely abolished by a-helical CRF, a specific CRFR2 antagonist, and partially inhibited by diltiazem, another L-type VGCC blocker in cultured neonatal cardiomyocytes (Ikeda et al, 1998). In the same paper, the authors also stated that urocortin caused cAMP accumulation, which may lead to activation of L-type VGCC.…”

Section: Urocortin 2 Inhibits [Ca 2 + ] I In Pc12 Cells J Tao Et Almentioning

confidence: 99%

Expression of Urocortin 2 and its Inhibitory Effects on Intracellular Ca2+ Via L-Type Voltage-Gated Calcium Channels in Rat Pheochromocytoma (PC12) Cells

Tao

Zhang

Soong

et al. 2006

Neuropsychopharmacol

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Urocortin 2, a new member of the corticotrophin-releasing factor (CRF) neuropeptide family, was reported to be widely expressed in the central nervous system and peripheral tissues. Here, we detected urocortin 2 mRNA in PC12 cells using reverse transcriptionpolymerase chain reaction (RT-PCR). Furthermore, we observed its effects on intracellular Ca 2 + concentration ([Ca 2 + ] i ) using confocal microscopy and flow cytometry and on voltage-gated calcium channel (VGCC) currents using whole-cell patch clamp. Our results showed that urocortin 2 mRNA was coexpressed with CRF, and CRF receptor (CRFR) 2b in undifferentiated PC12 cells, but not CRFR1 or CRFR2a. KCl (40 mM) or Bay K8644 (1 mM), an L-type VGCC activator, increased [Ca 2 + ] i . Pretreatment of the cells with urocortin 2 significantly diminished the effect of Bay K8644 or KCl. Urocortin 2 showed no influence on [Ca 2 + ] i in tyrode's solution containing EGTA or Ca 2 + -free tyrode's solution. It reversibly inhibited the VGCC currents in a concentration-dependent manner, but had no apparent effects on the cells treated with nifedipine (1 mM), an L-type VGCC blocker. Urocortin 2 up-shifted the current-voltage curves. No frequency-dependence of urocortin 2 effects on I Ba was observed. The inhibitory effects of urocortin 2 on VGCC currents or [Ca 2 + ] i were not affected by astressin 2B, an antagonist of CRFR2. As calcium overload play a key role in some neuronal degenerative diseases such as Alzheimer's and Parkinson's diseases, our results suggest that urocortin 2 may be a potentially interesting agent for the treatment of these diseases.

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Urocortin, a Newly Identified Corticotropin-Releasing Factor-Related Mammalian Peptide, Stimulates Atrial Natriuretic Peptide and Brain Natriuretic Peptide Secretions from Neonatal Rat Cardiomyocytes

Cited by 72 publications

References 35 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

Regulation of urocortin I and its related peptide urocortin II by inflammatory and oxidative stresses in HL-1 cardiomyocytes

Expression of Urocortin 2 and its Inhibitory Effects on Intracellular Ca2+ Via L-Type Voltage-Gated Calcium Channels in Rat Pheochromocytoma (PC12) Cells

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