NAD(P)H Oxidase Mediates Angiotensin II–Induced Vascular Macrophage Infiltration and Medial Hypertrophy

Abstract

Objective-Our preliminary data suggested that angiotensin II (Ang II)-induced reactive oxygen species are involved in intercellular adhesion molecule-1 (ICAM-1) expression and leukocyte infiltration in the rat thoracic aorta. Other reports demonstrating reactive oxygen species-induced cell growth suggested a potential role of NAD(P)H oxidase in vascular hypertrophy. In the present study, we postulate that NAD(P)H oxidase is functionally involved in Ang II-induced ICAM-1 expression, macrophage infiltration, and vascular growth, and that oxidase inhibition attenuates these processes independently of a reduction in blood pressure. Methods and Results-Rats were infused subcutaneously with vehicle or Ang II (750 g/kg per day) for 1 week in the presence or absence of gp91 docking sequence (gp91ds)-tat peptide (1 mg/kg per day), a cell-permeant inhibitor of NAD(P)H oxidase. Immunohistochemical staining for ICAM-1 and ED1, a marker of monocytes and macrophages, showed that both were markedly increased with Ang II compared with vehicle and were reduced in rats receiving Ang II plus gp91ds-tat. This effect was accompanied by an Ang II-induced increase in medial hypertrophy that was attenuated by coinfusion of gp91ds-tat; however, gp91ds-tat had no effect on blood pressure. Key Words: NADPH oxidoreductase Ⅲ NAD(P)H oxidase Ⅲ hypertrophy Ⅲ inflammation Ⅲ angiotensin II A ngiotensin II (Ang II) has been shown to increase vascular adhesion molecule expression by stimulating the production of reactive oxygen species (ROS). 1,2 Mediators of increased adhesion molecule expression include activation of nuclear factor-B (NF-B) and activator protein-1 transcription factors. 3 Ang II has been implicated in vascular dysfunction, acting via a variety of mechanisms, including (1) stimulation of superoxide anion (O 2 ·Ϫ ) production by large and small blood vessels 4 through activation of vascular NAD(P)H oxidases, 5,6 leading to impairment of endothelial function 7,8 ; (2) induction of adhesion molecules, such as vascular cell adhesion molecule-1, via activation of NF-Bdependent gene expression 9 ; and (3) hypertrophy and remodeling. 10,11 Conclusions-Ang See page 707There is substantial evidence indicating that the cellular actions of Ang II are proinflammatory and potentially injurious to the blood vessel. In hypertension, medial hypertrophy is a normal response, 12,13 yet the mechanisms mediating this hypertrophy are still not clear. Reports have demonstrated that Ang II can induce medial thickening and increase the vascular cross-sectional area independently of blood pressure elevation. 14 -16 In smooth muscle cell cultures, Ang II has been shown to induce hypertrophy, 17 which appears to be mediated by the stimulation of NAD(P)H oxidase-derived H 2 O 2 , which in turn activates proto-oncogenes, mitogenactivated protein kinases, and transcription factors, leading to the growth response. 5,18,19 A recent study by Wang et al 16 also posited an in vivo role for NAD(P)H oxidase in medial hypertrophy in response to Ang II, but this int...

Diabetes mellitus accelerates left ventricular diastolic dysfunction through activation of the renin–angiotensin system in hypertensive rats

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Myocardial fibrosis in response to Angiotensin II is preceded by the recruitment of mesenchymal progenitor cells

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Redox Control of Renal Function and Hypertension

“…This may be due to the difference in the animal model (DSS rat is a low-renin hypertension model). Another study showed a similar result, in which the BP was not affected by gp91ds-tat (190). This has been attributed to the use of 10-fold lower dilution of gp91ds-tat than that used in the original study by Rey et al (270).…”