Nrf2 protects against maladaptive cardiac responses to hemodynamic stress

Jinqing Li, Tomonaga Ichikawa, Luis Villacorta, Joseph S. Janicki, Gregory L. Brower, Masayuki Yamamoto, Taixing Cui

Research output: Contribution to journalArticlepeer-review

156 Citations (Scopus)

Abstract

BACKGROUND-: Reactive oxygen species (ROS) play an important role in the maintenance of cardiovascular homeostasis. The present study sought to determine whether nuclear factor erythroid-2 related factor 2 (Nrf2), a master gene of the endogenous antioxidant defense system, is a critical regulator of the cardiac hypertrophic response to pathological stress. METHODS AND RESULTS-: Cardiac hypertrophy and dysfunction were established in mice by transverse aortic constriction (TAC). Nrf2 expression was transiently increased and then declined to the basal level while impairment of cardiac function proceeded. The knockout of Nrf2 (Nrf2-/-) did not cause any apparent structural and functional abnormalities in the unstressed heart. However, Nrf2-/- mice after TAC developed pathological cardiac hypertrophy, significant myocardial fibrosis and apoptosis, overt heart failure, and increased mortality, which were associated with elevated myocardial levels of 4-hydroxy-2-nonenal and 8-hydroxydeoxyguanosine and a complete blockade of the myocardial expression of several antioxidant genes. Overexpression of Nrf2 dramatically inhibited hypertrophic factor-induced ROS production and growth in both cardiomyocytes and cardiac fibroblasts, whereas knockdown of Nrf2 exerted opposite effects in both cells. CONCLUSIONS-: These findings demonstrate that activation of Nrf2 provides a novel mechanism to protect the murine heart against pathological cardiac hypertrophy and heart failure via suppressing oxidative stress.

Original languageEnglish
Pages (from-to)1843-1850
Number of pages8
JournalArteriosclerosis, thrombosis, and vascular biology
Volume29
Issue number11
DOIs
Publication statusPublished - 2009 Nov

Keywords

  • Antioxidants
  • Apoptosis
  • Cardiomyopathies
  • Hypertrophy
  • Nrf2

ASJC Scopus subject areas

  • Cardiology and Cardiovascular Medicine

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