Expression cloning of cardiotrophin 1, a cytokine that induces cardiac myocyte hypertrophy.

Pennica, Diane; King, Kathleen L.; Shaw, Kenneth J.; Luis, Elizabeth; Rullamas, J; Luoh, Shiuh-Ming; Darbonne, Walter C.; Knutzon, Deborah S.; Yen, Randy; Chien, Kenneth R.

doi:10.1073/pnas.92.4.1142

Cited by 491 publications

(279 citation statements)

References 43 publications

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“…Cardiotrophin-1 (CT-1) is a member of the IL-6 family of cytokines that was originally isolated from cardiac tissue and identified by its ability to induce hypertrophy in cardiomyocytes [4]. Its receptor consists of a heterodimer made of glycoprotein 130 (GP130) receptor and leukaemia inhibitory factor receptor (LIFR), together with a yet to be described third component [5].…”

Section: Introductionmentioning

confidence: 99%

Cardiotrophin 1 protects beta cells from apoptosis and prevents streptozotocin-induced diabetes in a mouse model

et al. 2013

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Aims/hypothesis Cardiotrophin 1 (CT-1) is a recently described cytokine originally isolated from the heart where it has been shown to play an important role in apoptotic protection of cardiomyocytes and heart hypertrophy. Its beneficial properties have also been described in other organs such as liver and neuromuscular tissue. In the present study, we investigated whether CT-1 can confer protection against pro-apoptotic stimuli in pancreatic beta cells, and its role in insulin secretion and diabetes development.Methods The effects of CT-1 on apoptosis and function were studied using MIN6B1 cells and freshly isolated murine pancreatic islets. The impact on the development of diabetes was evaluated in Ct1-null (Ct1 −/− ) mice (the gene Ct1 is also known as Ctf1) using two streptozotocin (STZ)-induced models of diabetes. Results CT-1 has a protective effect in MIN6B1 cells and murine islets under the pro-apoptotic stimulus of serum deprivation, which correlates with the expression of B cell lymphoma-extra large, or following exposure to a mixture of cytokines. In addition, CT-1 enhances glucose-stimulated insulin secretion in MIN6B1 cells and this was repressed by inhibitors of phospholipase C. Furthermore, Ct1 −/− mice were more prone to develop diabetes, and their glucose tolerance test showed impaired plasma glucose clearance which correlated with decreased pancreatic insulin secretion. Conclusions/interpretation The results obtained from both in vitro and in vivo experiments show that CT-1 improves beta cell function and survival, and protects mice against STZ-induced diabetes.

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Section: Introductionmentioning

confidence: 99%

Cardiotrophin 1 protects beta cells from apoptosis and prevents streptozotocin-induced diabetes in a mouse model

et al. 2013

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“…The hearts were immediately removed and rinsed with ice-cold phosphate-buffered saline, and total cellular Okuno et al RNA was isolated by the acid-guanidinium thiocyanatephenol-chloroform method (Chomczynski and Sacchi, 1987). A CT-1 cDNA was obtained by reverse transcription (RT)-polymerase chain reaction (PCR) methods using specific oligonucleotides primers (sense, 5Ј-GAGACAGTGCTGGCCGGCGCTG-3Ј; anti-sense, 5Ј-AGAGGAGAGCAGAAGAGAGAGA-3Ј) synthesized based on the nucleotide sequence of mouse CT-1 cDNA (Pennica et al, 1995). Resulting products of 345 bp in size were subcloned into pGEM (Promega, Madison, Wisconsin) and linealized by digestion with NcoI.…”

Section: Rnase Protection Assaymentioning

confidence: 99%

Expressional Patterns of Cytokines in a Murine Model of Acute Myocarditis: Early Expression of Cardiotrophin-1

Okuno

Nakagawa

Shimada

et al. 2000

Laboratory Investigation

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SUMMARY:To determine the role of cytokines in acute myocarditis, we examined expressional patterns of cardiotrophin-1 (CT-1), TNF-␣, and IL-1␣ in a murine model of acute myocarditis. Ten-day-old Institute of Cancer Research mice were injected with Coxsackievirus B3 and killed on Days 1, 2, 3, 4, 5, 7, 10, 14, and 28 of injection. TNF-␣ and IL-1␣ expressions were investigated on histological sections from each heart, and mRNA expression of TNF-␣, IL-1␣, and CT-1 in the heart was examined by reverse transcription-polymerase chain reaction and RNase protection assay. To determine myocardial regeneration, cardiomyocytic DNA synthesis was investigated using bromodeoxyuridine on Days 3, 5, 7, and 10, and the labeling index was calculated in each heart. Age-matched uninfected mice were used as controls. TNF␣ and IL-1␣ expression was first detected in the cardiomyocytes on Day 3 and reached the maximum level on Day 7, when inflammatory changes were most prominent. Although an increased expression of TNF␣ and IL-1␣ mRNA was also detected on Day 3, CT-1 mRNA expression was distinctly augmented on Day 2. The labeling indices in the hearts with myocarditis were significantly higher than in those of the controls in all of the time points examined. CT-1 expression preceded TNF-␣ and IL-1␣ expressions and active DNA synthesis in a murine model of acute myocarditis. All CVB3-infected mice with anti-glycoprotein-130 antibody treatment died within 6 days. CT-1 may exert a protective role by modulating cytokine production and by inducing cardiomyocytic proliferation in CVB3-infected murine hearts. (Lab Invest 2000, 80:433-440).V iral myocarditis results from a viral infection that induces myocardial necrosis and triggers a series of immune responses to eliminate the viral agent. Although several studies have examined the crucial roles of cytokines and the induction of apoptosis in the myocardium, the pathogenic mechanisms of myocarditis remain unclear

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“…CT-1 was identified based on its ability to promote hypertrophy in cardiac myocytes [1]. Mice lacking the CT-1 receptor component gp130 die during embryogenesis due in part to severe ventricular hypoplasia [10], and ventricular wall thickness is also diminished in mice lacking postnatal expression of gp130 [11].…”

Section: Discussionmentioning

confidence: 99%

“…Cardiotrophin-1 (CT-1) is a cytokine originally identified for its ability to stimulate cardiac myocyte hypertrophy in vitro [1,2]. CT-1 is part of a larger family of cytokines that includes Interleukin-6 (IL-6), Leukemia Inhibitory Factor (LIF), Ciliary Neurotrophic Factor (CNTF), Oncostatin-M (OSM), Interleukin-11 (IL-11), Cardiotrophin-Like Cytokine (CLC), and Neuropoietin/Cardiotrophin-2 (NP/CT-2).…”

Section: Introductionmentioning

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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Expression cloning of cardiotrophin 1, a cytokine that induces cardiac myocyte hypertrophy.

Abstract: Heart failure continues to be a leading cause of mortality worldwide. A hallmark of this disease is dilated cardiac hypertrophy, which is accompanied by a reactivation of genes expressed in fetal heart development.

Cited by 491 publications

References 43 publications

Cardiotrophin 1 protects beta cells from apoptosis and prevents streptozotocin-induced diabetes in a mouse model

Cardiotrophin 1 protects beta cells from apoptosis and prevents streptozotocin-induced diabetes in a mouse model

Expressional Patterns of Cytokines in a Murine Model of Acute Myocarditis: Early Expression of Cardiotrophin-1

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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