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(Circulation Research. 2004;95:902.)
© 2004 American Heart Association, Inc.

Molecular Medicine

Apurinic/Apyrmidinic Endonuclease 1 Regulates Endothelial NO Production and Vascular Tone

Byeong Hwa Jeon, Gaurav Gupta, Young Chul Park, Bing Qi, Azeb Haile, Firdous A. Khanday, Yan-Xia Liu, Jin-Man Kim, Michitaka Ozaki, Anthony R. White, Dan E. Berkowitz, Kaikobad Irani

From the Division of Cardiology, Department of Medicine (B.H.J., Y.C.P., B.Q., A.H., F.A.K., Y.-X.L., K.I.) and Department of Anesthesiology (G.G., A.R.W., D.E.B.), Johns Hopkins University School of Medicine, Baltimore, Md; Departments of Physiology (B.H.J.) and Pathology (J.-M.K.), Chungnam National University, Daejon, South Korea; Department of Microbiology and Immunology (Y.C.P.), Pusan National University, South Korea; and Department of Surgery (M.O.), Hokkaido University, Sapporo, Japan.

Correspondence to Kaikobad Irani, Department of Medicine, Johns Hopkins University, Ross 1023, 720 Rutland Ave, Baltimore, MD 21214. E-mail kirani{at}jhmi.edu

The dual-function protein apurinic/apyrmidinic endonuclease/redox factor-1 (APE1/ref-1) is essential for DNA repair and also governs the reductive activation of many redox-sensitive transcription factors. We examined the role of APE1/ref-1 in regulation of endothelium-dependent tone and systemic blood pressure. APE1/ref-1^+/– mice have impaired endothelium-dependent vasorelaxation, reduced vascular NO levels, and are hypertensive. APE1/ref-1 upregulates H-ras expression and leads to H-ras-mediated, phosphoinositide-3 kinase/Akt kinase-dependent calcium sensitization of endothelial NO synthase (eNOS), stimulating NO production. The reducing property of APE1/ref-1 is essential for upregulation of H-ras and for the calcium sensitization of eNOS. These findings uncover a novel physiological role for APE1/ref-1 in regulating vascular tone by governance of eNOS activity and bioavailable NO.

Key Words: eNOS • redox • hypertension • H-ras

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