NF-κB (p65) negatively regulates myocardin-induced cardiomyocyte hypertrophy through multiple mechanisms.

Abstract

Myocardin is well known to play a key role in the development of cardiomyocyte hypertrophy. But the exact molecular mechanism regulating myocardin stability and transactivity to affect cardiomyocyte hypertrophy has not been studied clearly. We now report that NF-κB (p65) can inhibit myocardin-induced cardiomyocyte hypertrophy. Then we explore the molecular mechanism of this response. First, we show that p65 can functionally repress myocardin transcriptional activity and also reduce the protein expression of myocardin. Second, the function of myocardin can be regulated by epigenetic modifications. Myocardin sumoylation is known to transactivate cardiac genes, but whether p65 can inhibit SUMO modification of myocardin is still not clear. Our data show that p65 weakens myocardin transcriptional activity through attenuating SUMO modification of myocardin by SUMO1/PIAS1, thereby impairing myocardin-mediated cardiomyocyte hypertrophy. Furthermore, the expression of myocardin can be regulated by several microRNAs, which play important roles in the development and function of the heart and muscle. We next investigated potential role of miR-1 in cardiac hypotrophy. Our results show that p65 can upregulate the level of miR-1 and miR-1 can decrease protein expression of myocardin in cardiac myocytes. Notably, miR-1 expression is also controlled by myocardin, leading to a feedback loop. These data thus provide important and novel insights into the function that p65 inhibits myocardin-mediated cardiomyocyte hypertrophy by downregulating the expression and SUMO modification of myocardin and enhancing the expression of miR-1.

• Authors: Xing-Hua Liao, Nan Wang, Dong-Wei Zhao, De-Liang Zheng, Li Zheng, Wen-Jing Xing, Hao Zhou, Dong-Sun Cao, Tong-Cun Zhang
• Journal: Cellular signalling (Cell Signal) Vol. 26 Issue 12 Pg. 2738-48 (Dec 2014) ISSN: 1873-3913 [Electronic] England
• PMID: 25152367 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2014 Elsevier Inc. All rights reserved.

Chemical References

• MicroRNAs
• NF-kappa B
• Nuclear Proteins
• Protein Inhibitors of Activated STAT
• SUMO-1 Protein
• Trans-Activators
• myocardin

Topics

• Animals
• Cells, Cultured
• Down-Regulation (physiology)
• Hypertrophy (metabolism)
• MicroRNAs (metabolism)
• Myocytes, Cardiac (metabolism)
• NF-kappa B (metabolism)
• Nuclear Proteins (metabolism)
• Protein Inhibitors of Activated STAT (metabolism)
• Rats
• Rats, Sprague-Dawley
• SUMO-1 Protein (metabolism)
• Trans-Activators (metabolism)
• Transcription, Genetic (physiology)
• Transcriptional Activation (physiology)
• Up-Regulation (physiology)