Fluvastatin prevents renal dysfunction and vascular NO deficit in apolipoprotein E-deficient mice

Abstract

Objective - The objective of this study was to investigate the effects of fluvastatin on atherosclerosis, systemic and regional hemodynamics, and vascular reactivity in apolipoprotein E-deficient (ApoE-/-) mice. Methods and Results - Hemodynamics (fluospheres) and vasomotor responses of thoracic aorta and carotid artery were evaluated in male wild-type (WT) and untreated (ApoE-/- Control) or fluvastatin-treated (50 mg/kg per day for 20 weeks) ApoE-/- mice, all fed a Western-type diet. Plasma cholesterol and aortic root atherosclerotic lesions (ALs) were greater in ApoE-/- Control mice (19±1 mmol/L and 63 0176±38 785 μm2, respectively) than in WT mice (2 m±1 mmol/L and 1±1 μm2, respectively, Pα0.01). Fluvastatin significantly decreased plasma cholesterol (-53%) but failed to limit ALs. Renal blood flow was significantly reduced in ApoE-/- Control versus WT (-25%, P<0.05) mice. This reduction was prevented by fluvastatin. Aortic and carotid endothelium-dependent relaxations to acetylcholine were not altered in ApoE-/- Control versus WT mice. In carotid arteries from WT mice, these responses were abolished after nitro-L-arginine (L-NA), whereas those from ApoE-/- Control were only partially inhibited after L-NA but fully abolished after L-NA + diclofenac. Thus, in carotid arteries from ApoE-/- mice, vasodilating prostanoids compensate the deficit in NO availability. Fluvastatin prevented this carotid NO deficit. Conclusions - In ApoE-/- mice, chronic fluvastatin treatment preserved renal perfusion and vascular NO availability independently from atherosclerotic lesion prevention.