STAT3 balances myocyte hypertrophy vis-à-vis autophagy in response to Angiotensin II by modulating the AMPKα/mTOR axis.
STAT3 balances myocyte hypertrophy vis-à-vis autophagy in response to Angiotensin II by modulating the AMPKα/mTOR axis.
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DOI：
10.1371/journal.pone.0179835
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发表时间：
2017
期刊：
影响因子：
3.7
通讯作者：
Dawn B
中科院分区：
文献类型：
--
作者：
Chen L;Zhao L;Samanta A;Mahmoudi SM;Buehler T;Cantilena A;Vincent RJ;Girgis M;Breeden J;Asante S;Xuan YT;Dawn B
信号转导和转录激活子3(STAT3)参与多种心血管信号转导通路，包括心肌肥大和细胞保护。然而，STAT3信号在心肌细胞自噬中的作用尚不清楚。我们测试了血管紧张素II(Ang II)诱导的心肌细胞肥大的假说，至少部分是通过STAT3介导的抑制细胞自噬来实现的。在H9c2细胞中，Ang II以剂量依赖的方式诱导STAT3激活和细胞肥大。Ang II增强自噬作用，但不影响AMPKATP/mTOR信号转导或细胞内α/ATP值。WP1066药物抑制STAT3可抑制血管紧张素Ⅱ诱导的心肌细胞肥大及肥大相关基因ANP和β-MHcmRNA的表达。这些分子事件在带有STAT3基因敲除的细胞中被重现。基因或药物抑制STAT3可显著增加心肌细胞腺苷三磷酸/三磷酸腺苷比值，并通过AMPKα/mTOR信号通路促进自噬。药物激活和抑制AMPKα分别减弱和夸大了Ang II对ANP和β-MHC基因表达的影响，而同时抑制STAT3则增强了对肥大的抑制作用。综上所述，这些数据表明，STAT3的新的非基因组效应影响心肌细胞的能量状态，并调节AMPKα/MTOR信号和自噬，以平衡对Ang II刺激的转录肥大反应。这些发现可能与Ang II信号介导的各种心血管病理过程有重要的相关性。
Signal transducers and activators of transcription 3 (STAT3) is known to participate in various cardiovascular signal transduction pathways, including those responsible for cardiac hypertrophy and cytoprotection. However, the role of STAT3 signaling in cardiomyocyte autophagy remains unclear. We tested the hypothesis that Angiotensin II (Ang II)-induced cardiomyocyte hypertrophy is effected, at least in part, through STAT3-mediated inhibition of cellular autophagy. In H9c2 cells, Ang II treatment resulted in STAT3 activation and cellular hypertrophy in a dose-dependent manner. Ang II enhanced autophagy, albeit without impacting AMPKα/mTOR signaling or cellular ADP/ATP ratio. Pharmacologic inhibition of STAT3 with WP1066 suppressed Ang II-induced myocyte hypertrophy and mRNA expression of hypertrophy-related genes ANP and β-MHC. These molecular events were recapitulated in cells with STAT3 knockdown. Genetic or pharmacologic inhibition of STAT3 significantly increased myocyte ADP/ATP ratio and enhanced autophagy through AMPKα/mTOR signaling. Pharmacologic activation and inhibition of AMPKα attenuated and exaggerated, respectively, the effects of Ang II on ANP and β-MHC gene expression, while concomitant inhibition of STAT3 accentuated the inhibition of hypertrophy. Together, these data indicate that novel nongenomic effects of STAT3 influence myocyte energy status and modulate AMPKα/mTOR signaling and autophagy to balance the transcriptional hypertrophic response to Ang II stimulation. These findings may have significant relevance for various cardiovascular pathological processes mediated by Ang II signaling.