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CELLULAR METABOLISM

Involvement of oxidants and AP-1 in angiotensin II-activated NFAT3 transcription factor

Department of Pharmacology, Arizona Cancer Center, College of Medicine, University of Arizona, Tucson, Arizona

Submitted 13 December 2005 ; accepted in final form 4 November 2006

Cardiomyocyte hypertrophy is associated with multiple pathophysiological cardiovascular conditions. Recent studies have substantiated the finding that oxidants may contribute to the development of cardiomyocyte hypertrophy. Activation of the nuclear factor of activated T cells-3 (NFAT3) transcription factor has been shown to result from endocrine inducers of cardiomyocyte hypertrophy such as angiotensin II (ANG II) and serves as an important molecular regulator of cardiomyocyte hypertrophy. In this study, we found that antioxidant enzyme catalase and antioxidants N-acetyl-L-cysteine, -phenyl-N-tert-butylnitrone, and lipoic acid prevent ANG II from activating NFAT3 promoter-luciferase. H₂O₂ induces a time- and dose-dependent activation of NFAT3 transcription factor. A dominant negative form of NFAT3 transcription factor inhibited H₂O₂ from activating NFAT3 promoter. An inhibitor of ERKs, but not phosphoinositide 3-kinase or p38 MAPKs, blocked NFAT3 activation by H₂O₂. The NFAT3 binding site in the promoters of most genes contains a weak activator protein-1 (AP-1) binding site adjacent to the core consensus NFAT binding sequence. ERK inhibitor PD98059 was found previously to inhibit AP-1 activation by H₂O₂. Inactivation of AP-1 transcription factor by cotransfection of a dominant negative c-Jun, TAM67, prevented H₂O₂ or ANG II from activating NFAT3 promoter. NFAT3 promoter containing the core NFAT cis-element without AP-1 binding site failed to show activation by H₂O₂ treatment. Our data suggest that hypertrophy inducers ANG II and H₂O₂ may activate NFAT3 in cardiomyocyte through an AP-1 transcription factor-dependent mechanism.

activator protein-1; nuclear factor of activated T cells-3; cardiomyocytes; hypertrophy; antioxidants

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