Regression of atherosclerosis by amlodipine via anti-inflammatory and anti-oxidative stress actions.

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 (ApoEKO) mice. Adult male ApoEKO mice (6 weeks of age) were fed a high-cholesterol diet (HCD) for 8 or 10 weeks with or without oral administration of amlodipine (3 mg/kg/day) for 10 weeks or for only the last 2 weeks of the HCD. After HCD feeding, atherosclerotic lesion formation, in situ superoxide production and nicotinamide-adenine dinucleotide phosphate (NADPH) oxidase activity were evaluated in the proximal aorta. The expressions of NADPH oxidase subunits (p47(phox) and rac-1), monocyte chemoattractant protein-1 (MCP-1), intercellular adhesion molecule-1 (ICAM-1), and vascular cell adhesion molecule-1 (VCAM-1) were determined with immunohistochemistry and quantitative real-time reverse-transcription polymerase chain reaction. After 8 to 10 weeks of HCD administration to ApoEKO mice, marked atherosclerotic lesion formation was observed in the proximal aorta. In the atherosclerotic lesion, superoxide production, the expression of NADPH oxidase subunits, and NADPH oxidase activity were enhanced, and the expressions of MCP-1, ICAM-1, and VCAM-1 were increased. These changes were suppressed in mice that were treated with amlodipine for 10 weeks concomitant with HCD administration, with no significant change in blood pressure and plasma cholesterol level. We also observed that treatment with amlodipine for only the last 2 weeks regressed the atherosclerotic lesions with a decrease in oxidative stress and vascular inflammation. Inhibition of the atherosclerotic lesion area and lipid area in the proximal aorta by amlodipine was correlated with its inhibitory actions on oxidative stress, inflammation and the production of adhesive molecules. These results suggest that amlodipine not only inhibits atherosclerotic lesion formation, but also regresses atherosclerosis, and that these effects are at least partly due to inhibition of oxidative stress and inflammatory response.

Attenuation of inflammatory vascular remodeling by angiotensin II type 1 receptor-associated protein.

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.