Hypertension caused by transgenic overexpression of Rac 1

Reactive oxygen species, including superoxide, are important mediators of the pathophysiology of hypertension. In the vasculature, superoxide antagonizes nitric oxide (NO center dot) 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 O-2(center dot-) in the blood vessel wall. An hypothesis is that Rac1 may act as an important regulator of vascular O-2(center dot-) production, contributing to the balance between O-2(center dot-) and NO center dot 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 alpha-actin promoter. The RacCA transgenic had excessive amounts of O-2(center dot-) in the vessel wall that, which led to heightened production of peroxynitrite, as detected by increased protein nitration and reduced NO center dot 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.