Cholesterol-lowering strategies reduce vascular LRP1 overexpression induced by hypercholesterolaemia

Abstract

Low density lipoprotein receptor-related protein (LRP1) plays a key role on vascular functionality and is upregulated by hypercholesterolemia and hypertension. To investigate the effect of cholesterol-lowering interventions on vascular LRP1 over expression and whether simvastatin influences LRP1 expression. Male New Zealand rabbits were recruited into various groups, one group was fed a normal chow diet for 28 days (control group, n = 6), other group (n = 24) was fed a hypercholesterolemic diet (HC), six rabbits were euthanized at day 28 to test the capacity of HC diet to induce early atherosclerosis and the rest at day 60 (n = 18) after receiving either HC diet (HC group, n = 6), HC diet with simvastatin (2·5 mg/kg.day) (HC+simv group, n = 6), or a normal chow diet (NC group, n = 6) for the last 32 days. High-cholesterol diet raised vascular LRP1 concomitantly with increased lipid, VSMC and macrophage content in the arterial intima. Simvastatin and return to normocholesterolemic diet significantly reduced systemic cholesterol levels and vascular lipid content. Interestingly, these interventions also downregulate LRP1 overexpression in the vascular wall although to a different extent (HC+simv: 75 ± 3·6%vs NC: 50 ± 3·5% versus, P = 0·002). Immunohistochemistry studies showed that LRP1 diminushion was associated to a reduction in the number of intimal VSMC in HC+simv.group. Simvastatin per se did not exert any significant effect on LRP1 expression in rabbit aortic smooth muscle cells (rSMC). Our results demonstrate that cholesterol-lowering interventions exerted down regulatory effects on vascular LRP1 over expression induced by hypercholesterolemia and that simvastatin did not influence LRP1 expression beyond its cholesterol-lowering effects.