Up-regulation of p27(kip1) contributes to Nrf2-mediated protection against angiotensin II-induced cardiac hypertrophy.

Abstract

AIMS:

Nuclear factor erythroid-2-related factor 2 (Nrf2) appears to be a negative regulator of maladaptive cardiac remodelling and dysfunction; however, a potential of the Nrf2-mediated cardiac protection in diverse pathological settings remains to be determined. This study was aimed to explore the role of Nrf2 in angiotensin II (Ang II)-induced cardiac hypertrophy.

METHODS AND RESULTS:

Littermate wild-type (WT) and Nrf2 knockout (Nrf2(-/-)) mice were administered Ang II via osmotic mini-pumps for 2 weeks to induce cardiac hypertrophy. Elevation of blood pressure by the continuous Ang II infusion was comparable between WT and Nrf2(-/-) mice. Relative to WT mice, however, Nrf2(-/-) mice exhibited exaggerated myocardial oxidative stress with an impaired induction of a group of antioxidant genes and increased cardiac hypertrophy in response to the sustained Ang II stimulation. In cultured cardiomyocytes, adenoviral overexpression of Nrf2 shRNA enhanced Ang II-induced reactive oxygen species (ROS) production and protein synthesis, whereas adenoviral overexpression of Nrf2 exerted opposite effects. Moreover, Nrf2 deficiency exacerbated Ang II-induced down-regulation of p27(kip1) expression in the heart via a mechanism of post-transcriptional regulation. In contrast, adenoviral overexpression of Nrf2 increased p27(kip1) protein but not mRNA expression and reversed Ang II-induced down-regulation of p27(kip1) protein expression in cultured cardiomyocytes by suppressing ROS formation. Finally, the enhancement of Ang II-induced hypertrophic growth due to the Nrf2 deficiency was negated by overexpressing p27(kip1) in cultured cardiomyocytes.

CONCLUSION:

The Nrf2-p27(kip1) pathway serves as a novel negative feedback mechanism in Ang II-induced pathogenesis of cardiac hypertrophy, independent of changes in blood pressure.

• Authors: Jinqing Li, Cheng Zhang, Yifan Xing, Joseph S Janicki, Masayuki Yamamoto, Xing Li Wang, Dong-Qi Tang, Taixing Cui
• Journal: Cardiovascular research (Cardiovasc Res) Vol. 90 Issue 2 Pg. 315-24 (May 01 2011) ISSN: 1755-3245 [Electronic] England
• PMID: 21245055 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Cdkn1b protein, mouse
• NF-E2-Related Factor 2
• Nfe2l2 protein, mouse
• Phenols
• Plant Extracts
• RNA, Small Interfering
• Vasoconstrictor Agents
• antioxidant biofactor AOB
• Angiotensin II
• Cyclin-Dependent Kinase Inhibitor p27

Topics

• Angiotensin II (pharmacology)
• Animals
• Blood Pressure (drug effects, physiology)
• Cardiomegaly (chemically induced, metabolism, physiopathology)
• Cells, Cultured
• Cyclin-Dependent Kinase Inhibitor p27 (genetics, metabolism)
• Feedback, Physiological (physiology)
• Male
• Mice
• Myocytes, Cardiac (cytology, metabolism)
• NF-E2-Related Factor 2 (genetics, metabolism)
• Oxidative Stress (physiology)
• Phenols (metabolism)
• Plant Extracts (metabolism)
• RNA Processing, Post-Transcriptional (physiology)
• RNA, Small Interfering
• Rats
• Up-Regulation (physiology)
• Vasoconstrictor Agents (pharmacology)