Signal transducer and activator of transcription 3 in the heart transduces not only a hypertrophic signal but a protective signal against doxorubicin-induced cardiomyopathy

Abstract

The signal transducer and activator of transcription (STAT) 3, a transcriptional factor downstream of several cytokines, is activated by Janus kinase families and plays a pivotal role in cardiac hypertrophy through gp130. To determine the physiological significance of STAT3 in vivo, transgenic mice with cardiac-specific overexpression of the Stat3 gene (STAT3-TG) were generated. STAT3-TG manifested myocardial hypertrophy at 12 wk of age with increased expression of the atrial natriuretic factor (ANF), ␤-myosin heavy chain (MHC), and cardiotrophin (CT)-1 genes. The animals were injected i.p. with 15 mg͞kg doxorubicin (Dox), an antineoplastic drug with restricted use because of its cardiotoxicity. The survival rates after 10 days were 25% (5͞20) for control littermates (WT), but 80% (16͞20) for STAT3-TG (P < 0.01). WT showed increased expression of ␤-MHC and ANF mRNAs in the hearts 1 day after Dox treatment; this expression peaked at 3 days, suggesting that the WT suffered from congestive heart failure. Although the expression of these mRNAs was elevated in STAT3-TG hearts before Dox treatment, no additional increase was observed after the treatment. Dox administration significantly reduced the expression of the cardiac ␣-actin and Stat3 genes in WT hearts but not in STAT3-TG. These results provide direct evidence that STAT3 transduces not only a hypertrophic signal but also a protective signal against Dox-induced cardiomyopathy by inhibiting reduction of cardiac contractile genes and inducing cardiac protective factors. Signal transducer and activator of transcription (STAT) proteins, which consist of six members, are known to play important roles in cytokine signaling pathways (1). STATs are activated by the Janus kinase (JAK) family after cytokine binding to their specific receptors (2-6). Previous studies revealed that STAT3 was important for the growth, differentiation, and cell death or survival in various kinds of cells (7)(8)(9)(10)(11). Recently, we have demonstrated that STAT3 is expressed in cardiac myocytes, immediately activated by the IL-6 family of cytokines, and plays a crucial role in generating the hypertrophic signal through gp130 (12, 13). In addition, activation of gp130 has been shown to induce bcl-xL expression by means of STAT1 in cardiac myocytes, resulting in a cytoprotective effect (14). Although recent reports provide evidence of STAT phosphorylation in a pressure-overload model (15) and an acute myocardial infarction model of rat hearts (16), the physiological function of STAT in the heart has not been clarified yet. Doxorubicin (Dox), an antitumor drug, is effective for a variety of soft and solid human malignancies, but its long-term use is limited because of the development of cardiomyopathy. Several proposals regarding the pathogenesis of Dox-induced cardiac toxicity have been made, including a generation of oxygen-free radicals (17, 18), from which damage is inhibited by free-radical scavengers, and an intercalation of the drug to DNA (19), which is not affected by free-radical sc...

Convergence of Protein Kinase C and JAK-STAT Signaling on Transcription Factor GATA-4

“…Several studies support this conclusion. First, STAT proteins have been reported to transduce cardioprotective signals (29,37,83). Although the mediators of this beneficial effect are not defined, interaction of STAT with GATA-4, a cardioprotective transcription factor (3), and activation of ANF and/or VEGF may explain at least part of STAT cardioprotective effects.…”

“…Others found that overexpression of STAT3 leads to cardiac hypertrophy but also protects against druginduced cardiotoxicity (37). More recently, mice with cardiacspecific inactivation of STAT6 were generated and found to have an impaired response to pressure overload (29).…”

Cardiac-specific Activation of Signal Transducer and Activator of Transcription 3 Promotes Vascular Formation in the Heart

“…Generation of Transgenic Mice Expressing STAT3 Mutants-Transgenic mice with cardiac-specific overexpression of the caSTAT3 gene, caSTAT3 TG, were generated as described previously (15). caSTAT3 cDNA was subcloned into SalI site of pBSIISK(ϩ)-␣-MHC plasmid, a kind gift from Dr. J. Robbins (Children's Hospital, Cincinnati, OH) (25).…”

“…The stimulation of GP130 activates Janus kinase/STAT, mitogen activated protein kinase, and phosphatidylinositol 3-kinase/Akt pathways (11,12). The signals through GP130 transduce cell survival signals as well as hypertrophic signals (13)(14)(15)(16). Mice with GP130 gene knocked out in a cardiac-specific manner showed the decompensation in response to pressure overload (17), suggesting that the GP130/Janus kinase/STAT pathway is critical for adaptation in response to extracellular stresses.…”

Molecular mechanisms of cardiotoxicity of tyrosine kinase inhibition

“…STAT3 seems to be crucial to maintaining cardiac capillary density through several mechanisms, including direct regulation of VEGF expression, induction of proangiogenic cytokines and suppression of anti-angiogenic gene programmes in the heart. Mice lacking STAT3 in the heart are also more susceptible to doxorubicin-induced cardiotoxicity, and overexpression of STAT3 protects against this [85][86][87] . Although JAK1 or tyrosine kinase 2 (TYK2) might be able to compensate for the inhibition of JAK2 in the heart (JAK3 is not expressed), these findings raise concerns about possible cardiotoxicity of JAK2 inhibitors, particularly if they have activity against several JAK family kinases.…”