(3S-5S-6E)-7-[3-(4-fluorophenyl)-1-(propan-2-yl)-1H-indol-2-yl]-3-5-dihydroxyhept-6-enoic-acid and Aortic-Diseases

Atherosclerosis is driven by a diverse range of cellular and molecular processes. In the present study, we sought to better understand how statins mitigate proatherogenic inflammation. 48 male New Zealand rabbits were divided into eight groups, each including 6 animals. The control groups received normal chow for 90 and 120 days. Three groups underwent a hypercholesterolemic diet (HCD) for 30, 60, and 90 days. Another three groups underwent HCD for 3 months, followed by normal chow for one month, with or without rosuvastatin or fluvastatin. The cytokine and chemokine expressions were assessed in the samples of thoracic and abdominal aorta. Rosuvastatin significantly reduced MYD88, CCL4, CCL20, CCR2, TNF-α, IFN-β, IL-1b, IL-2, IL-4, IL-8, and IL-10, both in the thoracic and abdominal aorta. Fluvastatin also downregulated MYD88, CCR2, IFN-β, IFN-γ, IL-1b, IL-2, IL-4, and IL-10 in both aortic segments. Rosuvastatin curtailed the expression of CCL4, IFN-β, IL-2, IL-4, and IL-10 more effectively than fluvastatin in both types of tissue. MYD88, TNF-α, IL-1b, and IL-8 showed a stronger downregulation with rosuvastatin compared to fluvastatin only in the thoracic aorta. The CCL20 and CCR2 levels reduced more extensively with rosuvastatin treatment only in abdominal aortic tissue. In conclusion, statin therapy can halt proatherogenic inflammation in hyperlipidemic animals. Rosuvastatin may be more effective in downregulating MYD88 in atherosclerotic thoracic aortas.

Topics: Animals; Aorta, Abdominal; Aortic Diseases; Atherosclerosis; Chemokines; Fluvastatin; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Inflammation; Interleukin-10; Interleukin-2; Interleukin-4; Interleukin-8; Male; Myeloid Differentiation Factor 88; Rabbits; Rosuvastatin Calcium; Tumor Necrosis Factor-alpha

Atherosclerosis is the major cause of cardiovascular disease; hypercholesterolemia is a major risk factor. We hypothesized that specific TLR members (TLR2, TLR3, TLR4, TLR8) may play a role in atherosclerosis progression and its accompanying inflammatory response. We determined the association of atherosclerotic lesions and TLR mRNA expression in different aortic sites. We also assessed the effects of fluvastatin (Flu) treatment on TLR expression and plaque characteristics.. Male rabbits, fed with an atherogenic diet for a duration of 3 months, were screened for advanced atherosclerotic lesions in the aorta. Additional animals received normal diet or normal diet plus Flu for 1 additional month. TLR mRNA expression in various thoracic and abdominal aortic segments was assessed, together with atherosclerotic changes.. After high lipid diet, the atherosclerotic burden increased more in the abdominal than in the thoracic aorta; TLR2, 3, 4, and 8 also increased significantly. Flu decreased atherosclerotic plaque, calcium deposition, lipid cores, intraplaque hemorrhage, erythrocyte membranes, endothelial cells, and macrophage infiltration, while increasing smooth muscle cells in plaques of both aortic segments; it also lowered TLR2, 3, 4, and 8 expression in all aortic segments to a stronger degree than resumption of normal diet. There was a strong association between blood and tissue parameters during experimental period and finally a strong correlation found between these parameters with mRNA of TLR2, 3, 4, and 8 in various stages.. For the first time TLR2, 3, 4, and 8 mRNA expression is prospectively explored after hypercholesterolemic diet in the rabbit model. TLR2, 3, 4, and 8 mRNA expression is strongly upregulated and correlates with the progression of atherosclerosis in the aorta. Flu significantly inhibited this progress and reduced inflammation via TLR downregulation which was strongly associated with regression of plaque morphology and atherosclerosis promoting factors.

Topics: Animals; Aorta, Abdominal; Aorta, Thoracic; Aortic Diseases; Atherosclerosis; Diet, Atherogenic; Disease Models, Animal; Disease Progression; Fatty Acids, Monounsaturated; Fluvastatin; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Hyperlipidemias; Indoles; Male; Plaque, Atherosclerotic; Rabbits; Toll-Like Receptor 2; Toll-Like Receptor 3; Toll-Like Receptor 4; Toll-Like Receptor 8; Up-Regulation

To compare the effects of atorvastatin, fluvastatin, pravastatin, and simvastatin on endothelial function, aortic atherosclerosis, and the content of malondialdehyde (MDA) in native and oxidized LDL and in the arterial wall of hypercholesterolemic rabbits after adjusting the dosages of those statins to reduce total serum cholesterol levels to similar values.. Male rabbits were divided into the following 6 groups of 10 animals (n=10): 1) GH (control)--hypercholesterolemic animals; 2) GA--atorvastatin; 3) GF--fluvastatin; 4) GP--pravastatin; 5) GS--simvastatin; and 6) GN--normal. The animals were fed a standard food preparation enriched with 0.5% cholesterol and 2% coconut oil for 45 days. Fifteen days after beginning the experiment, atorvastatin, fluvastatin, pravastatin and simvastatin were administered for 15 days through gavage, and the dosages were adjusted to obtain similar cholesterol values in each group. At the end of the experiment, a blood sample was withdrawn for determining total cholesterol and separating the lipoproteins, and a segment of the thoracic aorta was removed to be used for studying endothelial function and lipid peroxidation, and for measuring aortic atherosclerosis in histological sections.. The statins significantly reduced total serum cholesterol levels, LDL-cholesterol levels, and aortic atherosclerosis. The MDA content was also significantly reduced in native and oxidized LDL, as well as in the arterial wall. Endothelium-dependent relaxation was significantly greater in the treated group compared with that in the hypercholesterolemic group.. The statins, at dosages adjusted, had a significant and similar effect in reducing lipid peroxidation in native and oxidized LDL-C and in arterial walls, in decreasing aortic atherosclerosis, and in reverting endothelial dysfunction.

Topics: Animals; Anticholesteremic Agents; Aortic Diseases; Arteriosclerosis; Atorvastatin; Cholesterol; Cholesterol, LDL; Endothelium, Vascular; Fatty Acids, Monounsaturated; Fluvastatin; Heptanoic Acids; Hypercholesterolemia; Indoles; Lipid Peroxidation; Male; Malondialdehyde; Pravastatin; Pyrroles; Rabbits; Simvastatin