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ABSTRACT: Aim: Previous studies have revealed that blockade of the renin angiotensin system attenuates plaque vulnerability and reduces cardiovascular events; however, few studies have compared the effects of an angiotensin-converting enzyme inhibitor (ACEI) with an angiotensin receptor blocker (ARB) and evaluated combination therapy. The objective of this study was to compare the efficacy and mechanisms of plaque stabilization by ACEI or ARB and to determine the effects of combination therapy.Methods: Twenty-eight male Japanese white rabbits were fed a high-cholesterol diet after balloon injury of the carotid arteries, then separated into ACEI (n= 7; imidapril 0.5 mg/kg/day), ARB (n= 7; TA606 4.5 mg/kg/day), combination (n= 7; imidapril 0.5 mg/kg/day+TA606 4.5 mg/kg/day), and vehicle (n= 7) groups.Results: No difference in plaque volume was identified among the 4 groups. ACEI or ARB increased the thickness of the fibrous cap, collagen content and the number of smooth muscle cells in the intima (% smooth muscle cell in intima: ACEI, 36.3%; ARB, 36.4%; vehicle, 14.9%), and reduced the accumulation of macrophages (% macrophages in intima: ACEI, 20.1%; ARB, 24.0%; vehicle, 37.9%), suggesting the plaque-stabilizing effects of each drug. ACEI reduced matrix metalloproteinase (MMP)-9 expression and gelatinolytic activity in the intima. While ARB did not change gelatinolytic activity, accumulation ot T cell in the intima was suppressed. Combination therapy did not show additive effects.Conclusion: These results suggest that ACEIs and ARBs have similar, but not additive, plaque-stabilizing effects. Each agent showed specific effects, with ACEIs decreasing gelatinolytic activity and ARBs suppressing T cell accumulation.
Journal of atherosclerosis and thrombosis 11/2012; · 2.69 Impact Factor
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ABSTRACT: BACKGROUND: Valvular aortic stenosis (AS) is not an infrequent condition in the aged population. Activation of renin-angiotensin system (RAS) is presumed to be involved in the development of AS; however, but direct evidence seems to be limited. We herein examined the effect of the administration of angiotensin II (Ang II) on the development of aortic valve thickening in apolipoprotein-E (ApoE)-deficient mice. METHODS AND RESULTS: Male ApoE-deficient mice were divided into three groups: control (saline, n = 8), mice that were administered low-dose Ang II (500 ng/kg/min, n = 11), and those with high-dose Ang II (1000 ng/kg/min, n = 11) administration for 4 weeks. Administration of high-dose, but not low-dose, Ang II significantly induced aortic valve thickening. It was found that in the aortic valve leaflets of high-dose Ang II group, integrity of endothelial cells was impaired and the number of myofibroblasts was increased. These phenomena induced by high-dose Ang II were suppressed by Ang II type 1 receptor blocker olmesartan (n = 15), but not by the dilatator, hydralazine (n = 13). Olmesartan also suppressed dilatation of aortic diameter, although it did not significantly affect the plaque area, in the abdominal aorta in ApoE-deficient mice. CONCLUSION: Administration of Ang II to genetically hyperlipidemic mice induced aortic valve thickening by a pressor-independent mechanism. Role of RAS activation in the development of AS in dyslipidemic patients should further be investigated.
Atherosclerosis 11/2012; · 3.79 Impact Factor
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ABSTRACT: We investigated the effects of hypercholesterolemia on optic nerve head (ONH) blood flow, visual function, and retinal histology in a rabbit model. Hypercholesterolemia was induced in rabbits by feeding them a high cholesterol (1%) diet for 12 weeks. Changes in blood pressure, intraocular pressure (IOP), and ONH blood flow were monitored at 6 and 12 weeks after treatment. The autoregulation of ONH blood flow as detected by laser speckle flowgraphy was verified by an artificial elevation of IOP at 12 weeks. Visually evoked potentials (VEPs) were also recorded and analyzed at 6 and 12 weeks. Finally, a histological examination as well as immunohistochemistry to endothelial nitric oxide synthase (eNOS) and inducible nitric oxide synthase (iNOS) was performed. In the hypercholesterolemic rabbits, blood pressure, IOP, and ONH blood flow did not alter significantly throughout this study. The autoregulation of ONH blood flow against IOP elevation was found to be impaired at 12 weeks. The amplitudes of the first negative peak of VEPs were diminished. Both the density of the retinal ganglion cells and the thickness of the inner nuclear layer and photoreceptor cell layer were reduced. Immunoreactivity to eNOS was reduced and that to iNOS was enhanced in the hypercholesterolemic rabbits compared to those in the normal control rabbits. The results of this study show that hypercholesterolemia induces impairment in the autoregulation of ONH blood flow and deterioration in visual function and histology. Downregulation of eNOS activity might be one of the causes for impairment of the autoregulation. Enhanced activity of iNOS might be involved in the impaired visual function and histology.
Experimental Eye Research 12/2011; 93(6):818-24. · 3.26 Impact Factor
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Circulation 04/2011; 123(14):e400-2. · 14.74 Impact Factor
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ABSTRACT: Vascular or valvular calcification is a manifestation of atherosclerosis. The aim of this study was to clarify the association between calcification in the vascular or valvular area and significant coronary stenosis; that is, the requirements of coronary revascularization (CR), and to analyze the most associated marker among those valuables.
A total of 253 consecutive patients underwent multi-detector spiral computed tomography (MDCT) to diagnose coronary artery stenosis. We quantitatively and qualitatively analyzed calcification in vascular (coronary artery, thoracic ascending and descending aorta) and valvular (mitral and aortic valve) areas. Of 253 patients, 56 with suspected coronary artery stenosis or who had heavy calcification that precluded a diagnosis of lumen stenosis underwent selective coronary angiography. Coronary artery stenosis was significant in 47 patients, of whom 40 underwent CR. The calcification score revealed a significant association between any two sites. Univariate analysis revealed that CR patients showed significantly more calcification at sites other than the aortic valve and a significantly higher calcium score at 3 vascular beds. Multivariate analysis revealed that the presence of calcification in the ascending aorta and a calcium score > 103.8, a cut-off value determined by receiver-operating characteristics (ROC) curve analysis, for the coronary artery were independent factors for CR.
Calcification at sites other than the aortic valve was significantly related to CR (+). The presences of calcification in the ascending aorta and a calcium score > 103.8 for the coronary artery were independently associated with CR.
Journal of atherosclerosis and thrombosis 09/2009; 16(4):346-54. · 2.69 Impact Factor
