Up-regulation of p27kip1 contributes to Nrf2-mediated protection against angiotensin II-induced cardiac hypertrophy

Jinqing Li, Cheng Zhang, Yifan Xing, Joseph S. Janicki, Masayuki Yamamoto, Xing Li Wang, Dong Qi Tang, Taixing Cui

Research output: Contribution to journalArticlepeer-review

56 Citations (Scopus)

Abstract

AimsNuclear 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 resultsLittermate 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 p27kip1 expression in the heart via a mechanism of post-transcriptional regulation. In contrast, adenoviral overexpression of Nrf2 increased p27kip1 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 p27kip1 in cultured cardiomyocytes.ConclusionThe Nrf2-p27kip1 pathway serves as a novel negative feedback mechanism in Ang II-induced pathogenesis of cardiac hypertrophy, independent of changes in blood pressure.

Original languageEnglish
Pages (from-to)315-324
Number of pages10
JournalCardiovascular Research
Volume90
Issue number2
DOIs
Publication statusPublished - 2011 May 1

Keywords

  • Angiotensin II
  • Cardiac hypertrophy
  • Nrf2
  • Oxidative stress
  • p27kip1

ASJC Scopus subject areas

  • Physiology
  • Cardiology and Cardiovascular Medicine
  • Physiology (medical)

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