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STAT3 Suppression Is Involved in the Protective Effect of SIRT6 Against Cardiomyocyte Hypertrophy
Xiaoying Zhang1, Wei Li, Peiye Shen
1*Department of Pharmacology and Toxicology, National and Local United Engineering Lab of Druggability and New Drugs Evaluation, School of Pharmaceutical Sciences, Sun Yat-Sen University, Guangzhou, China; †Department of Pharmacology, School of Medicine, Xizang Minzu University, Shaanxi, China; and ‡Department of Anesthesiology, Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou, China.
Insights
Sirtuin 6 (SIRT6) protects the heart by inhibiting signal transducer and activator of transcription 3 (STAT3) activation. This study shows SIRT6 suppresses STAT3, reducing cardiac hypertrophy and contributing to heart protection.
Area of Science:
- Cardiovascular Biology
- Molecular Cardiology
- Epigenetics
Background:
- Signal transducer and activator of transcription 3 (STAT3) activation is crucial in cardiac hypertrophy and heart failure.
- Sirtuin 6 (SIRT6) is known to protect cardiomyocytes from hypertrophy.
Purpose of the Study:
- To investigate the association between SIRT6 and STAT3 in regulating cardiomyocyte hypertrophy.
- To elucidate the mechanism by which SIRT6 exerts its cardioprotective effects.
Main Methods:
- Utilized phenylephrine (PE)-induced hypertrophic cardiomyocyte and isoprenaline-induced cardiac hypertrophy rat models.
- Assessed mRNA and protein expression, phosphorylation levels (P-STAT3), and nuclear localization of STAT3.
- Investigated the effects of SIRT6 overexpression and knockdown on STAT3 activation and hypertrophic biomarkers.
Main Results:
- PE treatment significantly increased STAT3 activation and P-STAT3 levels, while weakening SIRT6 deacetylation activity.
- SIRT6 overexpression repressed STAT3 activation, decreasing its mRNA/protein levels and transcriptional activity.
- SIRT6's protective effect against hypertrophy was dependent on STAT3 suppression, as evidenced by biomarker expression changes.
Conclusions:
- SIRT6 prevents phenylephrine-induced STAT3 activation in cardiomyocyte hypertrophy.
- The inhibitory effect of SIRT6 on STAT3 contributes significantly to cardiac protection.
- Targeting the SIRT6-STAT3 pathway may offer a therapeutic strategy for cardiac hypertrophy.
Abstract:
The activation of signal transducer and activator of transcription 3 (STAT3) is critical for the development of cardiac hypertrophy and heart failure. Sirtuin 6 (SIRT6) protects cardiomyocytes from hypertrophy. This study focused on the association between SIRT6 and STAT3 in the regulation of cardiomyocyte hypertrophy. In the phenylephrine (PE)-induced hypertrophic cardiomyocyte model and in the hearts of isoprenaline-induced cardiac hypertrophic rat model, the mRNA and protein expressions of STAT3 and its phosphorylated level at tyrosine 705 (P-STAT3) were significantly increased. By contrast, the deacetylation activity of SIRT6 was weakened without altering its protein expression. In addition, the nuclear localization of STAT3 and P-STAT3 was enhanced by PE, suggesting that STAT3 was activated in cardiomyocyte hypertrophy. Adenovirus infection-induced SIRT6 overexpression repressed the activation of STAT3 by decreasing its mRNA and protein levels, by suppressing its transcriptional activity, and by hindering the expressions of its target genes. Moreover, the effect of SIRT6 overexpression on eliminating PE-induced expressions of hypertrophic biomarkers, such as atrial natriuretic factor and brain natriuretic peptide, was reversed by STAT3 overexpression. Likewise, SIRT6 knockdown-induced upregulation of atrial natriuretic factor and brain natriuretic peptide was reversed by STAT3 silencing. These observations suggest that the antihypertrophic effect of SIRT6 involves STAT3 suppression. In conclusion, SIRT6 prevents PE-induced activation of STAT3 in cardiomyocyte hypertrophy; the inhibitory effect of SIRT6 on STAT3 contributes to cardiac protection.
