Objective-Angiotensin II contributes to atherogenesis, mainly through oxidative stress and inflammation. Recent data suggest that aldosterone is implicated in some effects of angiotensin II. We hypothesized that aldosterone could directly contribute to oxidative stress and atherosclerotic lesion formation. Methods and Results-Male apolipoprotein E-deficient mice 6 weeks of age were placed on a normal diet or 1.25%high-cholesterol diet. After 6 weeks of the high-cholesterol diet, a marked increase in atherosclerotic lesion formation was observed in the aorta, accompanied by significant elevation of plasma cholesterol level. Production of superoxide anion and expression of NAD(P)H oxidase subunit p47 phox , tumor necrosis factor-␣, and monocyte chemoattractant protein-1 in the aorta were increased with the high-cholesterol diet. Eplerenone (1.67 g/kg in high-cholesterol diet) did not affect blood pressure or plasma cholesterol but decreased the atherosclerotic area by nearly 70% (PϽ0.05), associated with attenuation of oxidative stress and inflammatory response. Valsartan (0.5 mg/kg per day) also decreased the atherosclerotic lesion, whereas coadministration of valsartan and eplerenone further decreased it. Moreover, aldosterone (0.1 mol/L) enhanced NADPH oxidase activity in cultured vascular smooth muscle cells. Conclusions-These results suggest that aldosterone may play a critical role in atherogenesis subsequent to oxidative stress in part independent of angiotensin II-mediated signaling, and that eplerenone could prevent atherosclerosis by attenuating oxidative stress and inflammation. , and a low molecular weight G-protein, rac-1.Angiotensin II (Ang II) is the principal vasoactive substance of the renin-angiotensin system, which has a variety of physiological actions including vasoconstriction, aldosterone release, and cell growth. In various vascular cell types, Ang II is a potent mediator of oxidative stress through activation of NADPH oxidase, 6 which contributes to the development of atherosclerosis. Recently, several lines of data have suggested that aldosterone is implicated in some of the effects of Ang II. Aldosterone potentiates ROS-dependent extracellular signal-regulated kinase (ERK) and c-Jun N-terminal kinase signaling induced by Ang II in vascular smooth muscle cells (VSMCs). 7 Animal studies using hypercholesterolemic rabbits, 8 Ang II-treated rats, 9 and aldosterone-treated mice 10 showed that an aldosterone receptor antagonist reduced oxidative stress and attenuated vascular changes. These observations suggest that aldosterone is involved in the pathogenesis of atherosclerosis in part independent of Ang II-mediated signaling. However, the direct effect of aldosterone on oxidative stress and how aldosterone contributes to spontaneous atherosclerosis are still unclear.In the present study, we hypothesized that aldosterone could directly induce oxidative stress and contribute to the pathogenesis of spontaneous atherosclerosis. To test this hypothesis, we examined the effect of eplerenone, a sele...

We examined whether amlodipine, an L-type calcium channel blocker (CCB), has an inhibitory effect on oxidative stress and inflammatory response, and thereby atherosclerosis, in apolipoprotein E-deficient

Abstract-To explore the role of angiotensin II Type 1 receptor-associated protein (ATRAP) in vascular remodeling, we developed transgenic mice for mouse ATRAP cDNA and examined remodeling after inflammatory vascular injury induced by polyethylene cuff placement. In ATRAP transgenic (ATRAP-Tg) mice, ATRAP mRNA was increased 3-to 4-fold in the heart, aorta, and femoral artery. ATRAP-Tg mice showed no significant change in body weight, systolic blood pressure, heart rate, and heart/body weight ratio. However, cell proliferation and neointimal formation in the injured artery were attenuated in ATRAP-Tg mice. The increase in NADPH oxidase activity and the expression of p22 phox , a reduced nicotinamide-adenine dinucleotide/reduced nicotinamide-adenine dinucleotide phosphate oxidase subunit, after cuff placement was also attenuated in ATRAP-Tg mice. Moreover, activation of extracellular signal-regulated kinase, signal transducer and activator of transcription 1, and signal transducer and activator of transcription 3 after cuff placement was significantly reduced in ATRAP-Tg mice. Pressor response and cardiac hypertrophy induced by angiotensin II infusion and pressure overload were also attenuated in ATRAP-Tg mice. These results suggest that ATRAP plays an important role in vascular remodeling as a negative regulator. Previous reports indicate that the intracellular carboxylterminal tail of the receptor plays an important role in activation of receptor-coupled G protein and internalization of the AT 1 receptor. [1][2][3][4][5][6] We cloned a novel AT 1 receptorassociated protein (ATRAP) using a yeast 2-hybrid screening system. 7 ATRAP has 3 transmembrane domains and interacts with the intracellular carboxyl-terminal domain of the AT 1 receptor, but it does not interact with the AT 2 receptor, m 3 muscarinic receptor, bradykinin B 2 receptor, endothelin ETB receptor, or ␤ 2 -adrenergic receptor. It is reported that ATRAP modulates AT 1 receptor function in COS-7 cells, human embryonic kidney 293 cells, and cultured mouse cardiomyocytes. Overexpression of ATRAP significantly decreases the number of AT 1 receptors on the cell surface and also decreases the degree of p38 mitogen-activated protein kinase phosphorylation, activity of the c-fos promoter, and protein synthesis on Ang II treatment. [7][8][9] We also reported that overexpression of ATRAP in cultured vascular smooth muscle cells (VSMCs) enhanced internalization of the AT 1 receptor and attenuated DNA synthesis and activation of extracellular signal-regulated kinase (ERK), Akt, and signal transducer and activator of transcription (STAT) induced by Ang II. 10 Polyethylene cuff placement around the femoral artery induces inflammatory vascular injury and remodeling responses accompanied by an increase in AT 1 and AT 2 receptor expression. VSMC proliferation, neointimal formation, inflammatory response, and oxidative stress in vascular injury were significantly attenuated in AT 1 a receptor-deficient mice. [11][12][13] Moreover, administration of an AT 1 receptor bloc...

These results suggest that the co-administration of calcium antagonists and ARB synergistically blunts oxidative stress at least partly through the inhibition of Akt activity and enhances the beneficial effects of these drugs on atherosclerosis compared with monotherapy.