Effects of cardiotrophin-1 on hemodynamics and endocrine function of the heart

Hamanaka, Ichiro; Saito, Yoshihiko; Nishikimi, Toshio; Magaribuchi, Tatsuo; Kamitani, Shigeki; Kuwahara, Koichiro; Ishikawa, Masahiro; Miyamoto, Yoshihiro; Hara, Masaki; Ogawa, Emiko; Kajiyama, Noboru; Takahashi, Naoya; Izumi, Tohru; Shirakami, Gotaro; Mori, Kenjiro; Inobe, Yoshito; Kishimoto, Ichiro; Masuda, Izuru; Fukuda, Kazuhiko; Nakao, Kazuwa

doi:10.1152/ajpheart.2000.279.1.h388

Cited by 29 publications

(22 citation statements)

References 42 publications

(37 reference statements)

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“…Echocardiographic examination of LV function for 6 h after administration of CT-1 alone revealed it to have no positive or negative inotropic effects (data not shown). This is consistent with our recent findings that CT-1 has no effect on the maximum rate of rise (dP/dT) in LV developed pressure and perfusion pressure in the isolated perfused rat heart, 30 and confirms that the inhibitory effect of CT-1 on LPS-induced LV dysfunction is indirect.…”

Section: Ct-1 Pretreatment Protects Lps-induced LV Dysfunctionsupporting

confidence: 93%

SOCS1/JAB Likely Mediates the Protective Effect of Cardiotrophin-1 Against Lipopolysaccharide-Induced Left Ventricular Dysfunction In Vivo

Tanimoto¹,

Saito²,

Hamanaka³

et al. 2005

Circ J

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roinflammatory cytokines are involved in the pathogenesis of various heart diseases, such as septic shock, myocarditis, some cases of dilated cardiomyopathy, ischemic heart disease and cardiac hypertrophy. [1][2][3][4][5][6][7] The effects of some cytokines, which act in an autocrine or paracrine manner, on the heart have been extensively studied. Contributing to the profound cardiocirculatory abnormalities in septic shock is myocardial depression, which some evidence suggests can be attributed to circulating inflammatory cytokines such as tumor necrosis factor (TNF)-, interleukin (IL)-1 and interferon (IFN)-. 8 These mediators activate nuclear factor (NF)-B in cardiomyocytes, which in turn leads to upregulation of inducible nitric oxide synthase (iNOS) expression, resulting in acute left ventricular (LV) dysfunction caused by the negative inotropic effect of nitric oxide (NO). 9,10 Induction of iNOS in cardiomyocytes was likewise demonstrated in an animal model in which septic shock was produced by administration of lipopolysaccharide (LPS) or endotoxin derived from gram-negative bacterial membranes. 11,12 The suppressor of cytokine signaling (SOCS) family is a recently identified group of proteins (SOCS1 to SOCS7 and cytokine-inducible SH2-containing protein) that function in a negative feedback loop that regulates signaling mediated by cytokine receptors via the Janus kinase (JAK)-signal transducers and activators of transcription (STAT) pathway. [13][14][15] SOCS proteins appear to use several mechanisms to inhibit cytokine signaling. 16 For instance, SOCS1/ JAB (JAK binding protein), which is activated by phosphorylated STAT1 and STAT3, binds directly to the kinase domain of JAK1 and JAK2, thereby inhibiting STAT signal transduction. SOCS1 also suppresses LPS signal transduction through one of the Toll-like receptors (TLRs), TLR4, via which LPS triggers innate immune responses. 17,18 In addition, SOCS1 reportedly inhibits signaling by mediators other than JAK-STAT, including TNF-, insulin and Vav. [19][20][21][22] Although the SOCS1 target molecule in TLR4 signaling has not yet been identified, collectively the available data suggest that induction of SOCS1 could play a protective role during septic shock by modulating the cardiovascular response.We recently reported that intravenous injection of cardiotrophin-1 (CT-1), a cytokine in the IL-6 family, into Wistar rats induces phosphorylation of STAT3 and expression of SOCS1 and SOCS3 in various tissues. 23 In addition, injection of CT-1 induced resistance to a second CT-1 injection; that is, it lead to attenuation of the STAT3 phosphorylation, iNOS mRNA expression and blood pressure reduction seen otherwise. In the present report we show that induction of Background Suppressor of cytokine signaling 1 (SOCS1) is a negative regulator of cytokine signaling whose expression is induced in the rat heart by cardiotrophin-1 (CT-1). Sepsis-induced myocardial depression results from the expression of inducible nitric oxide synthase (iNOS) evoked by inflammatory cytoki...

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Section: Ct-1 Pretreatment Protects Lps-induced LV Dysfunctionsupporting

confidence: 93%

SOCS1/JAB Likely Mediates the Protective Effect of Cardiotrophin-1 Against Lipopolysaccharide-Induced Left Ventricular Dysfunction In Vivo

Tanimoto¹,

Saito²,

Hamanaka³

et al. 2005

Circ J

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“…20 We therefore tested whether in addition to attenuating STAT3 activation, pretreatment with CT-1 would also inhibit an integrated biological response, such as decline in BP. Figure 6A shows that whereas the first injection of CT-1 (20 g/kg body weight) elicited a clear decline in BP, a second injection 60 minutes later had a significantly smaller effect.…”

Section: Pretreatment With Ct-1 Inhibits the Hypotension Induced By Amentioning

confidence: 99%

“…13 CT-1 binds to the gp130-LIF receptor complex in myocytes, activating the JAK-STAT pathway and inducing hypertrophic responses. 14 -18 Other investigators 19 and we 20 recently reported additionally that the intravenous injection of CT-1 induces nitric oxide (NO)-dependent hypotension dosedependently in conscious rats. Taken together, these findings strongly suggest that CT-1 acts as a cytokine with a variety of important actions in the cardiovascular system.…”

mentioning

confidence: 96%

Induction of JAB/SOCS-1/SSI-1 and CIS3/SOCS-3/SSI-3 Is Involved in gp130 Resistance in Cardiovascular System in Rat Treated With Cardiotrophin-1 In Vivo

Hamanaka

Saito

Yasukawa

et al. 2001

Circulation Research

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Abstract-CIS (cytokine-inducible SH2 protein), SOCS (suppressor of cytokine signaling), or SSI (signal transducers and activators of transcription [STAT]-induced STAT inhibitor) proteins are a family of cytokine-inducible negative regulators of cytokine signaling via Janus kinase (JAK)-STAT pathways. Given the evidence that the JAK-STAT pathway plays a critical role in the cardiovascular system, the primary objective of this study was to assess the effects of the CIS family on JAK-STAT signaling in the cardiovascular system in rats treated with cardiotrophin-1 (CT-1), an interleukin-6 family of cytokines. Intravenous injection of 20 g/kg body weight of CT-1 induced a transient, marked increase in STAT3 activation in various tissues, including heart and lung, and subsequent upregulation of 2 members of the CIS family, JAK-binding protein (JAB)/SOCS-1/SSI-1 and CIS3/SOCS-3/SSI-3, in the same tissues. It was also observed that CIS3 was directly associated with JAK2 in vivo. Pretreatment with the same dose of CT-1 60 minutes before significantly attenuated the STAT3 activation induced by a second injection of CT-1. We previously reported that intravenous injection of CT-1 results in the nitric oxide (NO)-dependent hypotension accompanied by the induction of inducible NO synthase mRNA. In rats pretreated with CT-1, the induction of inducible NO synthase mRNA or hypotension by subsequent CT-1 injection was not observed. he Janus kinase (JAK)-signal transducer and activator of transcription (STAT) pathway is activated in a rapid, transient manner and has been shown to be critical in many biological responses to cytokines. 1,2 Recently, a family of proteins that functions in a negative feedback loop to regulate signaling by cytokine receptors via JAK-STAT pathway has been identified by several groups and is referred to as the CIS (cytokine-inducible SH2-containing protein), 3 SOCS (suppressor of cytokine signaling), 4 or SSI (STAT-induced STAT inhibitor) 5 family. Presently, the CIS/SOCS/SSI family consists of at least 7 members of proteins and shares 2 homologous domains, an SH2 domain and a C-terminal-conserved domain called CIS homology domain. 6,7 Most CISs seem to be induced by several cytokines, and at least 3 CIS family members, CIS, JAB/SOCS-1/SSI-1, and CIS3/SOCS-3/ SSI-3, are proved to block JAK-STAT signaling by binding cytokine receptors or JAKs. 6 JAB and CIS3 directly bind to the kinase domain of JAKs and thereby inhibit interferon (IFN)-mediated STAT1 signaling and leukemia inhibitory factor (LIF)-mediated or interleukin (IL)-6 -mediated STAT3 activation in mouse myeloid leukemia M1 cells. 8 CIS3 is also found to bind to gp130 and regulate the signaling. 9 -11 Thus, evidence was accumulated that JAB or CIS3 exerts negative regulators of JAK-STAT signaling in hematopoietic and immune systems. 8,12 However, the significance of the negative regulatory mechanism of JAK-STAT pathway in cardiovascular system is little understood.Cardiotrophin-1 (CT-1), a member of the IL-6 superfamily, is substantially expresse...

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“…Infusion of exogenous CT-1 into adult animals provokes an acute decrease in blood pressure that stimulates a reflex increase in heart rate [32][33][34]. These acute effects of CT-1 do not include any changes in ventricular pressure or cardiac contractility.…”

Section: Discussionmentioning

confidence: 99%

The lack of cardiotrophin-1 alters expression of interleukin-6 and leukemia inhibitory factor mRNA but does not impair cardiac injury response

et al. 2006

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Cardiotrophin-1 (CT-1) was identified as a growth factor for cardiac myocytes, and CT-1 protects myocytes from cell death. Adult CT-1−/− mice exhibit neural deficits including the loss of preganglionic sympathetic neurons, but their autonomic and cardiac parameters have not been examined. We used these mice to determine if the absence of CT-1 or loss of preganglionic sympathetic input altered heart rate, left ventricular pressure, cardiac contractility (dP/dt), or cell death following ischemia-reperfusion. Basal heart rate was increased in CT-1−/− mice, and this difference was abolished by ganglionic block. Left ventricular pressure and dP/dt were unchanged. Dobutamine stimulated similar increases in heart rate and dP/dt in both genotypes, but ventricular pressure was significantly lower in CT-1 nulls. Cardiac expression of interleukin-6 (IL-6) mRNA was increased significantly in CT-1 null mice, while leukemia inhibitory factor (LIF) mRNA was unchanged. Infarct size normalized to area at risk was no different in CT-1 −/− mice (33.8±1.0 % vs. 37.7±3.2 % WT) 24 hours after ischemia-reperfusion. Induction of IL-6 mRNA after infarct was significantly abrogated in CT-1 null mice compared to wild type mice, but LIF mRNA induction remained significant in CT-1 null mice and might contribute to cardiac protection in the absence of CT-1.

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Effects of cardiotrophin-1 on hemodynamics and endocrine function of the heart

Cited by 29 publications

References 42 publications

SOCS1/JAB Likely Mediates the Protective Effect of Cardiotrophin-1 Against Lipopolysaccharide-Induced Left Ventricular Dysfunction In Vivo

SOCS1/JAB Likely Mediates the Protective Effect of Cardiotrophin-1 Against Lipopolysaccharide-Induced Left Ventricular Dysfunction In Vivo

Induction of JAB/SOCS-1/SSI-1 and CIS3/SOCS-3/SSI-3 Is Involved in gp130 Resistance in Cardiovascular System in Rat Treated With Cardiotrophin-1 In Vivo

The lack of cardiotrophin-1 alters expression of interleukin-6 and leukemia inhibitory factor mRNA but does not impair cardiac injury response

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