Fluvastatin Inhibits Matrix Metalloproteinase-1 Expression in Human Vascular Endothelial Cells

Abstract

Abstract-Matrix metalloproteinase-1 (MMP-1), also called interstitial collagenase, may play an important role in the pathogenesis of atherosclerosis and atherosclerotic plaque rupture. We investigated the effects of fluvastatin on MMP-1 expression in human vascular endothelial cells (ECs). The addition of fluvastatin decreased the basal MMP-1 levels in the culture media of ECs in a time-dependent (0 to 48 hours) and dose-dependent (10 Ϫ8 to 10 Ϫ5 mol/L) manner. On the other hand, fluvastatin did not affect tissue inhibitor of metalloproteinase-1 levels. Collagenolytic activity in conditioned media of ECs was also dose-dependently reduced by fluvastatin. The effect of fluvastatin on MMP-1 expression was completely reversed in the presence of mevalonate or geranylgeranyl-pyrophosphate, but not in the presence of squalene. Key Words: atherosclerosis Ⅲ nitric oxide Ⅲ extracellular matrix Ⅲ collagen U nstable atherosclerotic plaque rupture is an important event that triggers acute coronary syndrome. Plaque rupture is frequently correlated with loss of the extracellular matrix at certain locations, often in the shoulder areas of the plaque. Focal destruction of the extracellular matrix renders the plaques less resistant to the mechanical stresses imposed during systole and therefore vulnerable to rupture. 1-3 Recent studies have suggested that matrix metalloproteinases (MMPs) may contribute to the vulnerability of atherosclerotic plaques by degrading the components of the fibrous cup: collagens, elastin, fibronectin, and proteoglycans. 4 Immunocytochemistry studies have demonstrated that MMP-1, MMP-9, and MMP-3 are expressed by cells present in atheromas, including luminal and neovascular endothelial cells, macrophages, and smooth muscle cells, but not by cells present in the walls of normal arteries. 5 Studies including in situ zymography and enzymatic activity assays showed a significantly enhanced collagenase activity in atherosclerotic plaques. 6 -8 The expression of MMP-1, also called interstitial collagenase, in atherosclerotic lesions warrants special attention because this enzyme is involved in the initial cleavage of collagens, mainly type I collagen. Type I collagen is the predominant protein in atherosclerotic plaques that confers strength to the fibrous cap. MMP-1 is also the only enzyme able to initiate the degradation of collagen at neutral pH.Hydroxymethylglutaryl coenzyme A (HMG-CoA) reductase inhibitors (statins) have been widely used for treatment of hyperlipidemia. They may also directly interfere with the major processes of atherogenesis occurring in the arterial wall. 9 Smooth muscle cell migration and proliferation are inhibited by HMG-CoA reductase inhibitors, 10,11 and cholesterol accumulation is prevented in macrophages by reducing modified-LDL endocytosis. 12 All of these cellular effects are mediated by inhibition of the isoprenoid pathway. If HMGCoA reductase inhibitors affect MMP activity, they could influence plaque stability and disease progression of coronary artery diseases. Recently,...

Statins Inhibit Secretion of Metalloproteinases-1, -2, -3, and -9 From Vascular Smooth Muscle Cells and Macrophages

“…Previous studies demonstrated that the inhibition of geranylgeranyl transferase with L-839,867 and the inhibition of Rho by C3 exoenzyme significantly decreased production of MMPs. 39,40 Rho are small GTP-binding proteins that cycle between the inactive GDP-bound state and active GTP-bound state; they play crucial roles in diverse cellular events such as cytoskeleton organization, membrane trafficking, secretion, transcriptional regulation, cell growth control, and development. 35 In summary, we demonstrate for the first time that statins inhibit the secretion of a broad spectrum of MMPs from both SMC and foam cell macrophages.…”

Statins, Nitric Oxide and Neovascularization

“…The anti-angiogenic effects of statins may include inhibition of the expression or activity of inflammatory factors such as monocyte chemoattractant protein-1, metalloproteinase and angiotensin-2 (33,60,69). In addition, statins might interfere with angiogenic signaling mediated by inflammatory cells.…”

Lack of isoprenoid products raises ex vivo interleukin‐1β secretion in hyperimmunoglobulinemia D and periodic fever syndrome

“…In vitro, inhibitors of HMG-CoA reductase, also known as statins, may either suppress or enhance inflammatory responses, depending on the cell type studied and the way in which these cells were stimulated. Many antiinflammatory effects of statins have been reported, including the reduction of lymphocyte proliferation, and the expression of major histocompatibility complex class II molecules, matrix metalloproteinases, cytokines, and chemokines (11)(12)(13)(14)(15). Also, these compounds do have proinflammatory properties.…”