Hypertension caused by transgenic overexpression of Rac1.

Reactive oxygen species, including superoxide, are important mediators of the pathophysiology of hypertension. In the vasculature, superoxide antagonizes nitric oxide (NO•), resulting in increased vascular tone. The GTP binding protein Rac regulates a wide variety of cellular functions, including the activation of NADPH oxidase, the major source of O2 •− in the blood vessel wall. An hypothesis is that Rac1 may act as an important regulator of vascular O2 •− production, contributing to the balance between O2 •− and NO• and maintaining consequent homeostasis of blood pressure. To alter the activity of vascular NADPH oxidase, the authors developed a transgenic animal model that overexpresses the human cDNA of the constitutively active mutant of Rac1 (RacCA) in smooth muscle cells using the smooth muscle ±-actin promoter. The RacCA transgenic had excessive amounts of O2 •− in the vessel wall that, which led to heightened production of peroxynitrite, as detected by increased protein nitration and reduced NO• l...