Objective:
The interactions between the renin-angiotensin system and neovascularization in atherosclerotic plaque development are unclear. We investigated the effects of 3-hydroxy-3-methylglutaryl-coenzyme a reductase inhibition with pitavastatin in the pathogenesis of atherosclerosis in ApoE-/- mice with special focus on plaque neovascularization.
Methods and Results:
Ten-week-old male ApoE-/- mice fed a high-fat diet were randomly assigned into two groups and administered vehicle (0.5% carboxymethyl cellulose) or pitavastatin (PiS, 1 mg/kg daily) for 12 weeks. Quantification of plaque areas at the aortic roots and in the thoracic and abdominal aortas revealed that, in all three regions, AT1R antagonism reduced the intimal neovessel density and the mRNA levels of toll-like receptor (TLR) 2 and TLR4. PiS increased the contents of collagen and elastin, lessened the macrophage component as well as the level of monocyte chemoattractant protein-1 and osteopontin protein in aortic roots, and reduced the mRNA and activity levels of matrix metalloproteinase (MMP)-2 and MMP-9 in aortic roots and thoracic aortas. Neointimal vessel density, the extent of atherosclerotic lesions, and the levels of TLR2 and TLR4 mRNA, were lower in ApoE-/-MMP-2-/- mice than in controls. The amounts of TNF-α and IL-1β protein as well as the levels of MMP2, MMP-9, TLR2, and TLR4 mRNA were increased by exposure to ox-LDL and lipopolysaccharide. These effects were diminished by PiS and small interfering RNAs targeting TLR2 or TLR4 in cultured macrophages.
Conclusions:
3-hydroxy-3-methylglutaryl-coenzyme a reductase inhibition appears to inhibit intimal neovascularization in ApoE-/- mice, partly by reducing TLR2/TLR4-mediated inflammation and MMP activation, thus decreasing atherogenic plaque growth and instability.
Properties of 3-hydroxy-3-methylglutaryl-coenzyme A reductase in villous and crypt cells of the rat small intestine.
