Background— Atherosclerotic renovascular disease may augment deterioration of renal function and ischemic nephropathy compared with other causes of renal artery stenosis (RAS), but the underlying mechanisms remain unclear. This study was designed to test the hypothesis that concurrent early atherosclerosis and hypoperfusion might have greater early deleterious effects on the function and structure of the stenotic kidney. Methods and Results— Regional renal hemodynamics and function at baseline and during vasoactive challenge (acetylcholine or sodium nitroprusside) were quantified in vivo in pigs by electron-beam computed tomography after a 12-week normal (n=7) or hypercholesterolemic (HC, n=7) diet, RAS (n=6), or concurrent HC and a similar degree of RAS (HC+RAS, n=7). Flash-frozen renal tissue was studied ex vivo. Basal cortical perfusion and single-kidney glomerular filtration rate (GFR) were decreased similarly in the stenotic RAS and HC+RAS kidneys, but tubular fluid reabsorption was markedly impaired only in HC+RAS. Perfusion responses to challenge were similarly blunted in the experimental groups. Stimulated GFR increased in normal, HC, and RAS (38.3±3.6%, 36.4±7.6%, and 60.4±9.3%, respectively, P <0.05), but not in HC+RAS (6.5±15.1%). These functional abnormalities in HC+RAS were accompanied by augmented perivascular, tubulointerstitial, and glomerular fibrosclerosis, inflammation, systemic and tissue oxidative stress, and tubular expression of nuclear factor-κB and inducible nitric oxide synthase. Conclusions— Early chronic HC+RAS imposes distinct detrimental effects on renal function and structure in vivo and in vitro, evident primarily in the tubular and glomerular compartments. Increased oxidative stress may be involved in the proinflammatory and progrowth changes observed in the stenotic HC+RAS kidney, which might potentially facilitate the clinically observed progression to end-stage renal disease.
Simvastatin Preserves the Structure of Coronary Adventitial Vasa Vasorum in Experimental Hypercholesterolemia Independent of Lipid Lowering
Background — Previous studies have demonstrated that experimental hypercholesterolemia leads to neovascularization in the coronary artery vasa vasorum (VV). Recent evidence suggests that HMG-CoA reductase inhibitors (statins) have beneficial effects independent of lipid lowering. We aimed to determine the effect of simvastatin on coronary VV neovascularization, in the absence of cholesterol lowering. Methods and Results — Pigs were randomized to 3 groups fed a normal (N), high cholesterol (HC), or HC+simvastatin (HC+S) diet for 12 weeks. The proximal left anterior descending artery was isolated, scanned with micro-CT, and reconstructed. Quantification of the VV density in serial cross-sections along the vessel was then performed. LDL cholesterol was similarly increased in HC and HC+S compared with N. There was an increase in both VV density (4.7±0.3 versus 2.7±0.2 n/mm 2 ; P <0.05) and vessel wall area (3.1±0.2 versus 1.8±0.1 mm 2 ; P <0.05) in HC compared with N. The VV density in HC+S was preserved compared with HC (3.0±0.2 n/mm 2 ; P <0.05), despite similar increase in vessel wall area compared with N (2.5±0.1 mm 2 ; P <0.05). Coronary artery tissue expression of VEGF was increased in HC but not in HC+S compared with N. In parallel, immunoreactivity for HIF-1α, VEGF, MMP-2, and MMP-9 was accentuated in the outer media in HC but not in HC+S compared with N. Conclusions — This study demonstrates that simvastatin attenuates hypoxia in the coronary artery wall and VV neovascularization in experimental hypercholesterolemia, despite no change in plasma lipids. These data are consistent with an additional mechanism for the vascular effects of the statins, independent of cholesterol lowering.
Oxidation-Sensitive Transcription Factors and Molecular Mechanisms in the Arterial Wall
Restenosis after percutaneous transluminal coronary angioplasty is caused by neointimal hyperplasia, which involves impairment of nitric oxide (NO)-dependent pathways, and may be further exacerbated by a concomitant aging process. We compared the effects of NO-releasing-aspirin (NCX-4016) and aspirin (ASA) on experimental restenosis in both adult and elderly rats. Moreover, to ascertain the efficacy of NCX-4016 during vascular aging, we fully characterized the release of bioactive NO by the drug. Sprague–Dawley rats aged 6 and 24 months were treated with NO releasing-aspirin (55 mg/kg) or ASA (30 mg/kg) for 7 days before and 21 days after standard carotid balloon injury. Histological examination and immunohistochemical double-staining were used to evaluate restenosis. Plasma nitrite and nitrate and S -nitrosothiols were determined by a chemiluminescence-based assay. Electron spin resonance was used for determining nitrosylhemoglobin. Treatment of aged rats with NCX-4016 was associated with increased bioactive NO, compared with ASA. NO aspirin, but not ASA, reduced experimental restenosis in old rats, an effect associated with reduced vascular smooth muscle cell proliferation. NCX-4016, but not ASA, was well tolerated and virtually devoid of gastric damage in either adult or old rats. Thus, impairment of NO-dependent mechanisms may be involved in the development of restenosis in old rats. We suggest that an NCX-4016 derivative could be an effective drug in reducing restenosis, especially in the presence of aging and/or gastrointestinal damage.