NF-kappaB is required for cytokine upregulation of MMP-1, -3 and -9 in VSMCs, which suggests that NF-kappaB inhibition may promote plaque stabilisation.

Objective-Production of several metalloproteinases (MMPs) from smooth muscle cells (SMCs) and macrophages causes matrix destruction and atherosclerotic plaque instability. Statins, which inhibit HMG-CoA reductase and hence cholesterol and isoprenoid synthesis, stabilize plaques. We investigated whether statins inhibit MMP secretion from SMCs and macrophages. Methods and Results-We used human saphenous vein and rabbit aortic SMC and foamy macrophages from cholesterol-fed rabbits. Cerivastatin (50 nmol/L) inhibited inducible MMP-1, -3, and -9 secretion from human SMC by 52Ϯ19%, 71Ϯ18%, and 73Ϯ17%, respectively (PϽ0.01, nϭ3). Similar dose-related effects of cerivastatin (50 to 500 nmol/L), simvastatin (1 to 20 mol/L), and lovastatin (5 to 20 mol/L) were consistent with their relative potencies against HMG-CoA reductase. Statins also inhibited inducible MMP-1, -3, and -9 and constitutive MMP-2 secretion but not TIMP-1 or -2 secretion from rabbit SMC. Statins also dose-dependently inhibited MMP-1, -3, and -9 secretion from rabbit foam cells; cerivastatin (50 nmol/L) inhibited by 68Ϯ18%, 74Ϯ14%, and 74Ϯ14%, respectively (PϽ0.01, nϭ4 [3][4][5][6] Overexpression of MMPs, including MMP-1, MMP-3, and MMP-9, has been demonstrated in human and animal atherosclerotic plaques, [7][8][9][10][11][12][13][14][15][16] where it is colocalized with morphological and mechanical determinants of plaque rupture. MMPs together can catalyze the complete destruction of interstitial collagen, 17 which is the main component of fibrous caps responsible for their tensile strength. Loss of collagen leads to structural weakness and less resistance to the mechanical stresses imposed during systole. 18 This results ultimately in plaque rupture, the key event in triggering coronary thrombosis and hence acute coronary syndromes such as unstable angina and myocardial infarction. 19 Expression of MMPs-1, -3, and -9 is upregulated in cells present in atheromas, including endothelial cells, 20 VSMCs, 21-25 and macrophages. 26 -29 Inflammatory mediators, including interleukin-1 (IL-1), CD-40 ligand, and tumor necrosis factor-␣, upregulate MMP activity in vascular cells, especially in combination with platelet-derived growth factor (PDGF) or basic fibroblast growth factor. 23,25 Tissue inhibitors of metalloproteinases (TIMPs) are a family of naturally occurring specific inhibitors of MMPs whose activity in atherosclerotic plaques seems to correlate with decreased MMP activity 30,31 and hence reduced matrix remodelling.Statins are a structurally related group of hydroxymethylglutaryl coenzyme A (HMG-CoA) reductase inhibitors that are widely used to treat hyperlipidemia. Their use is associated with significant reduction of adverse coronary events, including myocardial infarction, and a marginal regression of plaque size. 32,33 Furthermore, recent studies, both in vitro and in vivo, have suggested that the beneficial effects of statins may extend to mechanisms beyond cholesterol reduction. [33][34][35][36] These pleiotropic effects of statins are mediate...

AimsAcute coronary syndromes (ACSs) are driven by inflammation within coronary plaque. Interleukin-1 (IL-1) has an established role in atherogenesis and the vessel-response to injury. ACS patients have raised serum markers of inflammation. We hypothesized that if IL-1 is a driving influence of inflammation in non-ST elevation ACS (NSTE-ACS), IL-1 inhibition would reduce the inflammatory response at the time of ACS.Methods and resultsA phase II, double-blinded, randomized, placebo-controlled, study recruited 182 patients with NSTE-ACS, presenting <48 h from onset of chest pain. Treatment was 1:1 allocation to daily, subcutaneous IL-1receptor antagonist (IL-1ra) or placebo for 14 days. Baseline characteristics were well matched. Treatment compliance was 85% at 7 days. The primary endpoint (area-under-the-curve for C-reactive protein over the first 7 days) was: IL-1ra group, 21.98 mg day/L (95%CI 16.31–29.64); placebo group, 43.5 mg day/L (31.15–60.75) (geometric mean ratio = 0.51 mg/L; 95%CI 0.32–0.79; P = 0.0028). In the IL-1ra group, 14-day achieved high-sensitive C-reactive protein (P < 0.0001) and IL-6 levels (P = 0.02) were lower than Day 1. Sixteen days after discontinuation of treatment (Day 30) high-sensitive C-reactive protein levels had risen again in the IL-1ra group [IL-1ra; 3.50 mg/L (2.65–4.62): placebo; 2.21 mg/L (1.67–2.92), P = 0.022]. MACE at Day 30 and 3 months was similar but at 1 year there was a significant excess of events in the IL-1ra group.ConclusionIL-1 drives C-reactive protein elevation at the time of NSTE-ACS. Following 14 days IL-1ra treatment inflammatory markers were reduced. These results show the importance of IL-1 as a target in ACS, but also indicate the need for additional studies with anti-IL-1 therapy in ACS to assess duration and safety.Clinical Trial RegistrationEUCTR: 2006-001767-31-GB: .