Brief review
A Novel Role for STAT3 in Cardiac Remodeling

https://doi.org/10.1016/S1050-1738(01)00066-4Get rights and content

Abstract

The binding of ligands to gp130 activates the JAK/STAT signal transduction pathway, where STAT3 plays a central role in transmitting signals from the membrane to the nucleus. STAT3 is essential for gp130-mediated cardiac myocyte hypertrophy. Cardiac-specific disruption of gp130 was shown to present heart failure in response to mechanical stress accompanied by an increase in apoptosis. Thus, the inactivation of STAT3 resulting from the loss of gp130 may be a key event in the transition from cardiac hypertrophy to heart failure. Proper vascular growth is essential for normal cardiac development and remodeling process. Recently, bcl-xL and VEGF have identified as target genes of STAT and together can promote cardiac myocyte survival by prevention of apoptosis and restoration of energy deprivation. In this review, STAT3 is highlighted as a regulator of angiogenic factors, and activation of STAT-mediated signaling in the cardiac myocyte is proposed as a novel therapeutic strategy for the prevention of heart failure.

Section snippets

gp130/STAT3 in the Prevention of Heart Failure

A growing body of evidence suggests the possibility that cytokines which operate via gp130 pathway might play a critical role in the onset of cardiac failure Chien 1999, Yamauchi-Takihara and Kishimoto 2000. The ligands that activate gp130 play an important physiological role in regulating survival of terminally differentiated cell types (Sendtner et al. 1990). A recent study has provided direct evidence that activation of gp130 can promote the survival of cardiac myocytes via activation

Role of STAT3 in Ischemic Heart Disease

In the case of acute myocardial infarction, a large number of cardiac myocytes are known to die as a result of apoptosis as well as of necrosis Gottlieb et al. 1994, Itoh et al. 1995, Kajstura et al. 1996. The heart suffering from acute myocardial infarction is a complex of various stressful states characterized by a reduction in oxygen supply followed by inflammatory responses and mechanical stretching. This implies that two main cellular events induce apoptosis, that is, hypoxia and

Role of STAT3 in gp130-mediated Cardiac Myocyte Hypertrophy

An in vitro study using an adenovirus vector to address the importance of STAT3 in inducing cardiac myocyte hypertrophy was designed to both overexpress and inhibit STAT3 activity in cardiac myocytes. Wild-type STAT3 or DNSTAT3 was overexpressed in cultured cardiac myocytes and gp130 was activated by using LIF. Although STAT3 phosphorylation was not observed in wild-type STAT3 transfected cells before LIF stimulation, augmented phosphorylation was observed after the stimulation. In contrast,

A Novel Role for STAT3 in Vascularization

Several studies indicate that the expression of a growing number of genes is induced by hypoxic stimulation in cardiac myocytes and vascular endothelial cells Karakurum et al. 1994, Yamauchi-Takihara et al. 1995, Yan et al. 1995. Interestingly, recent studies indicate that hypoxic stimulation induces the expressions of IL-6, CT-1 and vascular endothelial growth factor (VEGF) in cardiac myocytes Hishinuma et al. 1999, Ladoux and Frelin 1993, Yamauchi-Takihara et al. 1995. VEGF is involved in

Conclusions

Investigations of signaling pathways through gp130 in cardiac myocytes can be expected to result in the discovery of novel mechanisms of cardiac myocyte growth and survival. Although recent investigations have addressed the participation of cytokines in various cardiovascular diseases, we have but a limited understanding of their underlying functions and mechanisms. Hypertrophic and cytoprotective signals through gp130, especially through STAT3, can be expected to provide new insights into the

Acknowledgements

Cardiac research from KYT's lab is supported by a Grant-in Aid for Scientific Research on priority Areas from the Ministry of Education, Science Sports and Culture of Japan and grants from the Ministry of Health and Welfare of Japan and Takeda Science Foundation. We thank Drs. Hisao Hirota, Keita Kunisada and Yasushi Fujio for insightful discussions.

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