NF-κB mediated miR-21 regulation in cardiomyocytes apoptosis under oxidative stress

Abstract

Oxidative stress, defined as an excess production of reactive oxygen species (ROS), is shown to play an important role in the pathophysiology of cardiac remodeling including cell death and contractile dysfunction. Therefore, the balance between ROS production and removal of excess ROS is essential in maintaining the redox state and homeostasis balance in the cell. The increased ROS further activates nuclear factor-κB (NF-κB), a redox-sensitive transcription factor and promotes cell death. Recently, microRNAs (miRNAs) have been identified as critical regulators of various pathophysiological processes of cardiac remodeling; however, NF-κB-mediated miRNA's role in cardiomyocytes under oxidative stress remains undetermined. The miR-21 has been implicated in diverse cardiac remodeling; but, NF-κB-mediated miR-21 modulation in oxidative stress is currently unknown. Neonatal cardiomyocytes were transfected with IκBα mutant, miR-21 mimetic, and inhibitors separately, and were challenged with H₂O₂. The target gene, programmed cell death 4 (PDCD4), ROS activity, and NF-κB translocation were analyzed. Our results indicated that NF-κB positively regulated miR-21 expression under oxidative stress, and PDCD4 was a direct target for miR-21. NF-κB further regulated the expression of PDCD4 in H₂O₂-induced oxidative stress. Moreover, H₂O₂-induced ROS activity and cardiomyocytes apoptosis were partly protected by overexpression of miR-21 and displayed an important role in ROS-mediated cardiomyocytes injury. We evaluated a critical role of NF-κB-mediated miR-21 modulation in H₂O₂-induced oxidative stress in cardiomyocytes by targeting PDCD4. Our data may provide a new insight of miR-21's role in cardiac diseases primarily mediated by ROS.

Keywords::

• miR-21
• NF-κB
• cardiac apoptosis
• oxidative stress

Acknowledgments

The authors acknowledge to Central Texas Veterans Affairs Health Care System for providing research facility to complete this work.

Declaration of interest

The authors report no conflicts of interest. The authors alone are responsible for the content and writing of the paper.

This study was partly supported by start-up funds from the Texas A & M Health Science Center, College of Medicine, by an American Heart Association-National Scientist Development Grant (0835227N) to S. Gupta (SG).