Tone E, Kunisada K, Fujio Y, Matsui H, Negoro S, Oh H, Kishimoto T, Yamauchi-Takihara K
Department of Medicine III, Osaka University Medical School, Japan.
Biochem Biophys Res Commun. 1998 Dec 9;253(1):147-50. doi: 10.1006/bbrc.1998.9767.
Recently, we reported that leukemia inhibitory factor (LIF), a member of the interleukin (IL)-6 cytokine family, transduced hypertrophic and cytoprotective signals via Januas Kinase-signal transducer and activator of transcription (JAK-STAT) pathway in cardiac myocytes. Angiotensin II (AII) is also known to activate STATs and reported to induced apoptosis in adult rat ventricular myocytes. In the present study, we investigated potential interactions between gp130 dependent and AII signaling pathways, by examining AII regulation of LIF-induced anti-apoptotic effect and STAT3 activation in cardiac myocytes. Although LIF attenuated the DNA fragmentation induced by serum depletion, AII augmented the DNA fragmentation in cultured neonatal rat cardiac myocytes. Furthermore, LIF-mediated cytoprotective effect was inhibited by AII pretreatment. LIF rapidly and transiently tyrosine phosphorylated STAT3 in cardiac myocytes which was not observed by AII. AII pretreatment inhibited LIF-induced phosphorylation of STAT3 in a dose dependent manner. This inhibitory effect of AII on STAT3 activation was blocked by the AII type I (AT1) receptor antagonist CV11974. These results demonstrate that negative crosstalk between gp130 and AT1 receptor dependent signaling exists in cardiac myocytes. This crosstalk may contribute to the modulation of pathophysiological process in myocardial disease.
最近，我们报道了白血病抑制因子（LIF），白细胞介素（IL）-6细胞因子家族的一员，通过Januas激酶-信号转导子和转录激活子（JAK-STAT）途径在心肌细胞中传导肥大和细胞保护信号。已知血管紧张素II（AII）也可激活信号转导子和转录激活子，并报道其可诱导成年大鼠心室肌细胞凋亡。在本研究中，我们通过检测AII对LIF诱导的心肌细胞抗凋亡作用和STAT3激活的调节，研究了gp130依赖性信号通路和AII信号通路之间的潜在相互作用。尽管LIF减弱了血清饥饿诱导的DNA片段化，但AII增强了培养的新生大鼠心肌细胞中的DNA片段化。此外，AII预处理抑制了LIF介导的细胞保护作用。LIF可使心肌细胞中的STAT3迅速且短暂地酪氨酸磷酸化，而AII未观察到这种现象。AII预处理以剂量依赖性方式抑制LIF诱导的STAT3磷酸化。AII对STAT3激活的这种抑制作用被AII 1型（AT1）受体拮抗剂CV11974阻断。这些结果表明，心肌细胞中存在gp130和AT1受体依赖性信号通路之间的负性串扰。这种串扰可能有助于调节心肌疾病中的病理生理过程。
