Abstract
The vascular endothelium is the inner lining of blood vessels and servers as an important autocrine/paracrine organ, which regulates vascular tone. Balance of reactive oxygen species and nitric oxide (NO) plays a pivotal role in governing the overall redox state of the vascular cellular systems. Apurinic/apyrimidinic endonuclease-1/redox factor-1 (Ref-1) is a ubiquitous multifunctional protein involved in the base excision repair of oxidative DNA damage. In addition, Ref-1 has been implicated in the redox regulation of transcription factor DNA binding activity of several transcription factors. We studied the role of Ref-1 on the regulation of nitric oxide production, endothelium-dependent tone, and systemic blood pressure. Ref-1+/- mice have impaired endothelium-dependent vasorelaxation, reduced vascular NO levels, and are hypertensive. 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 Ref-1 is essential for upregulation of H-ras and for the calcium sensitization of eNOS. Overexpression of Ref-1 suppressed the expression of vascular cell adhesion molecule-1 and superoxide production induced by TNF-alpha, suggesting Ref-1 has a protective property against monocyte adhesion in the vascular system. These findings uncover a novel physiological role for Ref-1 in regulating vascular tone by governance of eNOS activity and bioavailable NO and in regulating monocyte adhesion by modulating of vascular adhesion molecules [Jpn J Physiol 55 Suppl:S52 (2005)]
