HMG-CoA reductase inhibition by atorvastatin reduces neointimal inflammation in a rabbit model of atherosclerosis (original) (raw)
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Stroke, 2005
Background and Purpose-To investigate the effect of short-term high-dose atorvastatin on blood and plaque inflammation in patients with carotid stenosis. Methods-Twenty patients undergoing carotid endarterectomy without previous statin treatment were randomized to receive either atorvastatin 80 mg/d (nϭ11) or no statins (nϭ9) for 1 month. We studied inflammatory mediators in plasma (enzyme-linked immunosorbent assay), peripheral blood mononuclear cells (PBMCs; quantitative RT-PCR and EMSA) and plaques (immunohistochemistry and Southwestern histochemistry).
Bangladesh Journal of Physiology and Pharmacology, 2014
Background: Inhibitors of HMG-CoA-reductase reduce cardiovascular mortality through the mechanisms yet elucidated. Most ischemic events are secondary to disruption of atherosclerotic plaques highly infiltrated by macrophages.Objectives: To study the effect of the 3-hydroxy-3-methyl-glutaryl coenzyme A (HMG-CoA)-reductase inhibitor simvastatin on the potential mechanisms involved in the recruitment of monocytic cells into the vessel wall.Methodology: This experimental study was carried out in the Laboratory of the Department of Pharmacology & Therapeutics, BSMMU, Shahbag, Dhaka, during the period from 1st July 2008 to 30th June 2009. Fifty healthy Long-Evans Norwegian male rats aged between 3-4 months and weighing between 180-200gm were randomly selected and divided into 3 groups (A, B & C). Control group A (n=10) were fed on standard rat diet for 8 weeks, Vehicle fed group B (n=10) were fed soybean oil at a dose of 1ml once daily for 8 weeks and 2% cholesterol fed group C (n=30) wer...
Atherosclerosis, 2002
Inflammation is involved in the genesis and rupture of atherosclerotic plaques. We assessed the effect of atorvastatin (ATV) on the expression of cyclooxygenase-2 (COX-2) and other proinflammatory molecules in a rabbit model of atherosclerosis. Fourteen animals underwent injury of femoral arteries and 2 weeks of atherogenic diet. Afterwards, they were randomized to receive either 5 mg/kg per day of ATV (n=8) or no treatment (NT, n= 6) during 4 weeks, and were finally killed. ATV reduced lipid levels, neointimal size (0.13 (0.03-0.29) mm 2 vs 0.65 (0.14-1.81) mm 2 , P =0.005) and the percentage of neointimal area positive for macrophages (1% (0-3) vs 19% (5-32), P= 0.001), COX-2 (32% (23-39) vs 60% (37-81) P =0.019), interleukin-8 (IL-8) (23% (3-63) vs 63% (25-88) P =0.015), and metalloproteinase-3 (19% (12-34) vs 42% (27-93), P =0.010), without significant differences in COX-1 expression (immunohistochemistry). In situ hybridization confirmed a decreased expression of COX-2 mRNA (22% (5-40) vs 43% (34-59) P =0.038). The activity of nuclear factor-kB, which controls many proinflammatory genes including COX-2, was reduced in atherosclerotic lesions (3538 (2663-5094) vs 8696 (5429-11 312)) positive nuclei per mm 2 , P= 0.001) and circulating mononuclear cells (2966 vs 17 130 arbitrary units). In cultured vascular smooth muscle cells, ATV reduced the expression of COX-2 mRNA induced by IL-1b and TNF-a without affecting COX-1 expression. In conclusion, ATV, besides decreasing a number of inflammatory mediators in the atherosclerotic lesion, significantly downregulates COX-2 both in vivo and in vitro. These anti-inflammatory actions could partially account for the reduction of acute coronary events achieved by statins.
Cardiovascular Research, 2003
Objective: To study whether simvastatin reduces inflammation in atherosclerosis beyond its hypolipidemic effects. Methods: Twenty-four rabbits with induced femoral injury and on an atherogenic diet were randomized to normolipidemic diet (n59), or to continue the atherogenic diet while receiving simvastatin 5 mg / kg / day (n59) or no treatment (n56) for 4 weeks. Results: As compared with no treatment, the normolipidemic diet significantly reduced lipid levels, while simvastatin produced nonsignificant reductions. In spite of this, NF-kB binding activity in peripheral mononuclear cells was reduced in the simvastatin group [2,95865,123 arbitrary units (a.u.)] as compared with no treatment (49,267620,084 a.u.; P,0.05) and normolipidemic groups (41,492615,876 a.u.; P,0.05) (electrophoretic mobility shift assay). NF-kB activity in the atherosclerotic lesions was also reduced by simvastatin as compared to 2 nontreated animals (4,10863,264 vs. 8,69662,305 nuclei / mm ; P,0.05), while the normolipidemic diet induced only a nonsignificant diminution (P.0.05) (Southwestern histochemistry). Similarly, simvastatin decreased macrophage infiltration (4.6612 vs. 19612% of area staining positive; P,0.05) and the expression of interleukin-8 (24612 vs. 63621%; P,0.05) and metalloproteinase-3 (1663 vs. 42628%; P,0.05) (immunohistochemistry), while the reduction achieved by normolipidemic diet in all these parameters was again nonsignificant (P.0.05). Conclusions: These findings suggest that simvastatin reduces inflammation in atherosclerotic plaques and in blood mononuclear cells more than expected for the lipid reduction achieved.
Atherosclerosis, 2004
3-Hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors (statins) have been shown to reduce cardiovascular morbidity and mortality by their actions on atherogenic lipid profiles and by pleiotropic effects. In this study, we have investigated the effect of a new statin, rosuvastatin (Crestor ® ), on sterol synthesis and the expression of metalloproteinases (MMPs) in human monocyte-derived macrophages (HMDM). Rosuvastatin dose-dependently inhibited sterol synthesis from acetate with an IC 50 of 70 nM. In addition, MMP-7 levels were reduced in a dose-dependent manner with maximal inhibition of 50% (P < 0.01) at 1 M. Also, addition of isoprenoids such as farnesyl pyrophosphate (Fpp) or geranylgeranyl pyrophosphate (GGpp) fully overcame the inhibitory effect of rosuvastatin on MMP-7. Neither quantitative PCR nor transient transfection of HMDM with a luciferase reporter construct under the control of human MMP-7 promoter (2300 bp of the 5 region on MMP-7 gene) showed a decrease in MMP-7 mRNA following treatment with rosuvastatin (10 −6 M). However, the inhibitory effect of the statin occurred at the post-transcriptional level as determined by actinomycin D experiment. In conclusion, several studies have reported a high expression of active MMP-7 in human atherosclerotic plaques indicating a potential role in the weakening of the fibrous cap, predisposing it to rupture. The effect of rosuvastatin in reducing MMP-7 might protect fibrous caps from degradation and in turn stabilize atheromatous plaques.
Cardiovascular Research
To study whether simvastatin reduces inflammation in atherosclerosis beyond its hypolipidemic effects. Twenty-four rabbits with induced femoral injury and on an atherogenic diet were randomized to normolipidemic diet (n=9), or to continue the atherogenic diet while receiving simvastatin 5 mg/kg/day (n=9) or no treatment (n=6) for 4 weeks. As compared with no treatment, the normolipidemic diet significantly reduced lipid levels, while simvastatin produced nonsignificant reductions. In spite of this, NF-kappaB binding activity in peripheral mononuclear cells was reduced in the simvastatin group [2,958+/-5,123 arbitrary units (a.u.)] as compared with no treatment (49,267+/-20,084 a.u.; P<0.05) and normolipidemic groups (41,492+/-15,876 a.u.; P<0.05) (electrophoretic mobility shift assay). NF-kappaB activity in the atherosclerotic lesions was also reduced by simvastatin as compared to nontreated animals (4,108+/-3,264 vs. 8,696+/-2,305 nuclei/mm(2); P<0.05), while the normolipi...
Arteriosclerosis, Thrombosis, and Vascular Biology, 2002
The expression of tissue factor (TF), mainly by infiltrated inflammatory cells, has been shown to be responsible for the thrombogenicity associated with atheroma. The contribution of the nonlipid-related effects of statins to the clinical benefits of statin therapy is currently under intense investigation. In this study, we evaluated the ability of fluvastatin to modulate TF expression and macrophage accumulation in rabbit carotid intimal lesions independently of cholesterol lowering. Male rabbits were fed for 30 days a 1% cholesterol-rich diet with or without fluvastatin at 5 mg/kg per day. Two weeks from the start of treatment, a silastic collar was placed around the carotid artery. Fifteen days later, the animals were killed, and carotid segments were excised and processed. The atherogenic diet caused a consistent increase in plasma cholesterol levels (610Ϯ231 mg/dL versus 50Ϯ9 mg/dL at baseline), which were not affected by fluvastatin (603Ϯ248 mg/dL). In the rabbits fed a high cholesterol diet without fluvastatin, an intimal lesion with macrophage accumulation and TF expression was detected. Fluvastatin significantly reduced TF and macrophage content of the lesion (Ϫ50% for both). Results indicate that fluvastatin may attenuate the inflammatory and thrombogenic potential of atherosclerotic lesions through a mechanism(s) other than cholesterol reduction, providing new insight regarding the complex mode of action of statins. (Arterioscler Thromb Vasc Biol. 2002;22:692-698.)
Journal of Cardiovascular Pharmacology, 2006
Prostaglandin E 2 (PGE 2), the product of cyclooxygenase-2 (COX-2) and prostaglandin E synthase-1 (mPGES-1), acts through its receptors (EPs) and induces matrix metalloproteinase (MMP) expression, which may favor the instability of atherosclerotic plaques. The effect of statins on EPs expression has not been previously studied. The aim of this study was to investigate the effect of atorvastatin (ATV, 80 mg/d, for one month) on EP expression in plaques and peripheral blood mononuclear cells (PBMC) of patients with carotid atherosclerosis. In addition, we studied the mechanisms by which statins could modulate EPs expression on cultured monocytic cells (THP-1) stimulated with proinflammatory cytokines (IL-1b and TNF-a). Patients treated with atorvastatin showed reduced EP-1 (14 6 1.8% versus 26 6 2%; P , 0.01), EP-3 (10 6 1.5% versus 26 6 1.5%; P , 0.05), and EP-4 expression (10 6 4.1% versus 26.6 6 4.9%; P , 0.05) in atherosclerotic plaques (immunohistochemistry), and EP-3 and EP-4 mRNA expression in PBMC (real time PCR) in relation to non-treated patients. In cultured monocytic cells, atorvastatin (10 mmol/L) reduced EP-1/-3/-4 expression, along with COX-2, mPGES-1, MMP-9, and PGE 2 levels elicited by IL-1b and TNF-a. Similar results were noted with aspirin (100 mmol/L), dexamethasone (1 mmol/L), and the Rho kinase inhibitors Y-27632 and fasudil (10 mmol/L both). The effect of atorvastatin was reversed by mevalonate, farnesyl pyrophosphate, and geranylgeranyl pyrophosphate. On the whole, we have shown that atorvastatin reduces EPs expression in atherosclerotic plaques and blood mononuclear cells of patients with carotid stenosis and in cultured monocytic cells. The inhibition of EP receptors could explain, at least in part, some of the mechanisms by which statins could modulate the COX-2/mPGES-1 proinflammatory pathway and favor plaque stabilization in humans.