HMG-CoA reductase inhibitors reduce vascular monocyte chemotactic protein-1 expression in early lesions from hypercholesterolemic swine independently of their effect on plasma cholesterol levels

Atherosclerosis. 2001 Nov;159(1):27-33. doi: 10.1016/s0021-9150(01)00469-5.

Abstract

Inhibitors of 3-hydroxy-3-methylglutaryl coenzyme A reductase are widely used in the treatment of dyslipemias and have shown beneficial effects in primary and secondary prevention of cardiovascular diseases. There is new information that seems to suggest that the beneficial effects observed may not be solely attributable to plasma cholesterol reduction. Our objective has been to evaluate the effect of two statins at similar dose, although unequivalent plasma lipid lowering potential, on vessel wall expression of two proteins involved in atherosclerotic lesion progression. We have studied the effects of treatment on vessel wall expression of monocyte chemotactic protein-1 (MCP-1) and the inducible form of nitric oxide synthase (NOS II). Atherosclerosis was induced in pigs by feeding a high cholesterol and saturated fatty acid diet for 50 days. Mild atherosclerotic lesions were found at this early stage of induction. Animals were simultaneously treated with atorvastatin (3 mg/kg/day), pravastatin (3 mg/kg/day) or placebo. Non-HDL-cholesterol levels induced by diet were reduced in the atorvastatin-treated group (63+/-8%, P=0.03) and not as much in the pravastatin treated group (44+/-3, P=0.08). The average MCP-1 expression in carotid, femoral and thoracic aorta was significantly reduced with both statins by 37% (P<0.05), while NOS II expression was unaffected. Therefore, vascular MCP-1 expression was downregulated by statins regardless of their lipid lowering potential and lipo/hydrophilic characteristics. Early downregulation of MCP-1 could attenuate the inflammation within the vascular wall and prevent the development of atherosclerotic lesions.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Aorta / metabolism
  • Aorta / pathology
  • Arteries / metabolism*
  • Arteries / pathology
  • Arteriosclerosis / metabolism*
  • Arteriosclerosis / pathology
  • Atorvastatin
  • Carotid Arteries / metabolism
  • Chemokine CCL2 / biosynthesis*
  • Chemokine CCL2 / genetics
  • Cholesterol / blood*
  • Coronary Vessels / pathology
  • Down-Regulation
  • Femoral Artery / metabolism
  • Gene Expression
  • Heptanoic Acids / pharmacology*
  • Hydroxymethylglutaryl-CoA Reductase Inhibitors / pharmacology*
  • Hypercholesterolemia / metabolism*
  • Iliac Artery / pathology
  • Immunohistochemistry
  • Nitric Oxide Synthase / biosynthesis
  • Nitric Oxide Synthase / genetics
  • Nitric Oxide Synthase Type II
  • Pravastatin / pharmacology*
  • Pyrroles / pharmacology*
  • RNA, Messenger / analysis
  • Reverse Transcriptase Polymerase Chain Reaction
  • Swine

Substances

  • Chemokine CCL2
  • Heptanoic Acids
  • Hydroxymethylglutaryl-CoA Reductase Inhibitors
  • Pyrroles
  • RNA, Messenger
  • Cholesterol
  • Atorvastatin
  • Nitric Oxide Synthase
  • Nitric Oxide Synthase Type II
  • Pravastatin