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


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.


CONCLUSIONS
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.
Department of Cell Biology and Anatomy, University of South Carolina School of Medicine, 6439 Garners Ferry Road, Columbia, SC 29208, USA.
Jinqing
J
Li
Cheng
C
Zhang
Yifan
Y
Xing
Joseph S
JS
Janicki
Masayuki
M
Yamamoto
Xing Li
XL
Wang
Dong-Qi
DQ
Tang
Taixing
T
Cui
D000804:Angiotensin II / Q000494:pharmacology; D000818:Animals; D001794:Blood Pressure / Q000187:drug effects / Q000502:physiology; D006332:Cardiomegaly / Q000139:chemically induced / Q000378:metabolism* / Q000503:physiopathology*; D002478:Cells, Cultured; D050760:Cyclin-Dependent Kinase Inhibitor p27 / Q000235:genetics / Q000378:metabolism*; D025461:Feedback, Physiological / Q000502:physiology; D008297:Male; D051379:Mice; D032383:Myocytes, Cardiac / Q000166:cytology / Q000378:metabolism; D051267:NF-E2-Related Factor 2 / Q000235:genetics / Q000378:metabolism*; D018384:Oxidative Stress / Q000502:physiology; D010636:Phenols / Q000378:metabolism; D010936:Plant Extracts / Q000378:metabolism; D012323:RNA Processing, Post-Transcriptional / Q000502:physiology; D034741:RNA, Small Interfering; D051381:Rats; D015854:Up-Regulation / Q000502:physiology; D014662:Vasoconstrictor Agents / Q000494:pharmacology
C493961:Cdkn1b protein, mouse; D051267:NF-E2-Related Factor 2; C495636:Nfe2l2 protein, mouse; D010636:Phenols; D010936:Plant Extracts; D034741:RNA, Small Interfering; D014662:Vasoconstrictor Agents; C501911:antioxidant biofactor AOB; D000804:Angiotensin II; D050760:Cyclin-Dependent Kinase Inhibitor p27