STAT3 balances myocyte hypertrophy vis-à-vis autophagy in response to Angiotensin II by modulating the AMPKα/mTOR axis

• Published in: PloS one 2017-07, Vol.12 (7), p.e0179835
• Main Authors: Chen, Lei, Zhao, Lin, Samanta, Anweshan, Mahmoudi, Seyed Morteza, Buehler, Tanner, Cantilena, Amy, Vincent, Robert J, Girgis, Magdy, Breeden, Joshua, Asante, Samuel, Xuan, Yu-Ting, Dawn, Buddhadeb
• Format: Article
• Language: English
• Subjects: Activation; Adenosine diphosphate; Adenosine Diphosphate - metabolism; Adenosine Triphosphate - metabolism; Alzheimer's disease; Alzheimers disease; AMP-Activated Protein Kinases - biosynthesis; AMP-Activated Protein Kinases - genetics; Angiotensin; Angiotensin II; Angiotensin II - administration & dosage; Angiotensin II - genetics; Animals; ATP; Attenuation; Autophagy; Autophagy - drug effects; Autophagy - genetics; Biology and Life Sciences; Blood pressure; Cardiomyocytes; Cell death; Disease Models, Animal; Energy balance; Fatty acids; Gene expression; Gene Expression Regulation - drug effects; Gene Knockdown Techniques; Heart attacks; Heart diseases; Heart failure; Homeostasis; Humans; Hypertrophy; Hypertrophy - genetics; Hypertrophy - metabolism; Hypertrophy - pathology; Inhibition; Kinases; Major histocompatibility complex; Medicine and Health Sciences; Myocytes, Cardiac - drug effects; Myocytes, Cardiac - metabolism; Myocytes, Cardiac - pathology; Pathways; Peptides; Phagocytosis; Pharmacology; Protein synthesis; Proteins; Pyridines; Rats; Research and Analysis Methods; Rodents; Scholarships & fellowships; Signal Transduction; Stat3 protein; STAT3 Transcription Factor - antagonists & inhibitors; STAT3 Transcription Factor - biosynthesis; STAT3 Transcription Factor - genetics; Stimulation; TOR protein; TOR Serine-Threonine Kinases - biosynthesis; TOR Serine-Threonine Kinases - genetics; Transcription factors; Transducers; Tyrphostins
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0179835

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.