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.

Redox Control of Renal Function and Hypertension

“…In addition, NAD(P)H oxidase requires Rac1/Rac2 and Rap1 for activation in some cellular systems. These activating small-molecular-weight G proteins have been demonstrated in some studies to affect O 2 иϪ production and hypertension (115,240,355). The vascular and renal NAD(P)H oxidases share several characteristics with the multicomponent enzyme complex, as described in neutrophils in an earlier section (6).…”

Cardiomyocyte-specific overexpression of an active form of Rac predisposes the heart to increased myocardial stunning and ischemia-reperfusion injury

“…We have also shown that the constitutive overexpression of Rac1 in smooth muscle cells results in increased vascular O 2 ·Ϫ generation, hypertension and mild cardiac hypertrophy in transgenic mice (27). However, our novel ZmRacD-TG mouse model (19,20) is unique compared with Rac1 TG model (49), because, ZmRacD TG mice gradually develop cardiac phenotype with aging and provide an executable window to investigate the pathological conditions involved in the progression of Rac-induced cardiovascular diseases.…”

“…The small GTP-binding protein Rac1 of the Rho subfamily has been implicated in various cardiovascular disorders including vascular dysfunction, hypertension, and cardiac hypertrophy (12,27,29,35,55). Increased expression and/or activity of Rac1 were demonstrated in the blood vessels of diabetic rats (55) and in human saphenous vein smooth muscle cells secondary to thromboxane A 2 analogue (38).…”

“…Rac1 has been implicated in different cardiovascular disorders including vascular dysfunction (55), hypertension, and cardiac hypertrophy (12,27,29,35,55). We have reported that constitutive overexpression of human Rac1 in smooth muscle cells results in increased vascular O 2 ·Ϫ , hypertension, and mild cardiac hypertrophy in transgenic mice (27).…”

“…There is now growing evidence that Rac is activated in response to diverse extracellular stimuli such as growth factors (15), heavy metals (40), reoxygenation and reperfusion (31,41), and cytokines (48); and regulates the production of O 2 ·Ϫ by an NADPH oxidase in phagocytic as well as in nonphagocytic cells (1,29,35). Rac1 has been implicated in different cardiovascular disorders including vascular dysfunction (55), hypertension, and cardiac hypertrophy (12,27,29,35,55). We have reported that constitutive overexpression of human Rac1 in smooth muscle cells results in increased vascular O 2 ·Ϫ , hypertension, and mild cardiac hypertrophy in transgenic mice (27).…”