Hypertension Caused by Transgenic Overexpression of Rac1

Abstract

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^• levels. RacCA mice developed moderate hypertension, which was corrected by N-acetyl-L-cysteine (NAC). RacCA transgenic mice also developed left ventricular hypertrophy as a secondary effect of pressure overload. The data suggest that Rac1 is a critical regulator of the redox state of blood vessels and homeostasis of blood pressure.