Matrix Metalloproteinases In Atherosclerosis Research Articles

Short-Term Atorvastatin Therapy in Healthy Individuals Results in Unaltered Plasma MMP Levels and Disrupted MMP-7 Correlation with Blood Lipids and Blood Count-Derived Inflammatory Markers.

Background: Matrix metalloproteinases (MMPs) play an important role in the pathophysiology of atherosclerosis. Reportedly, statins can decrease MMP activity in patients with atherosclerotic cardiovascular disease, but this effect has not been studied in healthy individuals. Methods: MMPs 2, 7, and 9 and several other parameters were measured before and after a four-week course of moderate-dose atorvastatin (20 mg/day) in 21 healthy individuals. Results: Atorvastatin treatment resulted in lower total cholesterol, LDL-cholesterol, non-HDL-cholesterol, and triglycerides (p < 0.001 for all), but higher levels of plasma enzymes AST, ALT, CK, and LDH (p < 0.05 for all). No effect of atorvastatin on plasma MMP median concentrations was recorded. Before treatment, moderate positive significant correlations were found between MMP-7 and age, blood lipids, and blood count-derived inflammatory markers. Pre-treatment MMP-7 was best predicted by the total cholesterol-to-HDL cholesterol ratio in a remnant cholesterol-weighted least squares regression model. After atorvastatin treatment, MMP-7 no longer correlated with these markers. Conclusions: While the effect of statins on plasma MMPs in atherosclerosis is controversial, short-term moderate-dose atorvastatin treatment does not seem to affect levels of MMPs 2, 7, and 9 in healthy individuals. However, an intriguing correlation between MMP-7 and atherosclerosis-related blood lipids and neutrophil-associated inflammatory biomarkers seems to be disrupted by atorvastatin independently of hsCRP, possibly via pleiotropic effects.

Study of Diagnostic Value of Cyclooxygenase-2 and Matrix Metalloproteinases in Atherosclerosis

Background and Aim: Atherosclerosis is a chronic systematic disease where lesion (plaque) develops results in activation of inflammatory reaction that leads to arterial obstruction. Atherosclerosis is the underlying cause for many cardiovascular diseases (CVD) which were estimated with 42 percent of total death in Saudi Arabia while Coronary artery diseases (CAD) accounted for 35 percent of total chronic diseases death in Saudi Arabia by 2008. Risk factors that attribute in progression of atherosclerotic lesion and subsequent complications are smoking, high Low Density Lipoprotein –Cholesterol (LDL-C), high blood pressure, obesity and alcohol.&#x0D; Materials and Methods: This study was carried on 20 healthy individuals as a control group, 15 patients with stable angina, 15 patients with recent myocardial infraction (MI) and 15 patient 24-hours post MI. All subjects were males with age 45±65 years and underwent exclusion/inclusion criteria. COX-2, MMPs levels were quantitatively measured by enzyme-linked immunosorbent assay (ELISA).&#x0D; Results: There is insignificant differences in both COX-2 and MMP-2 levels among studied groups (P = 0.450 and 0.246 respectively) .On other hand, MMP-9 demonstrate a significant elevation in its level in studied groups (P = 0.014): its level significantly increase in stable angina (31.474 ± 12.188 ng/ml) compared to both control (9.920 ± 0.075 ng/ml) and Post MI groups (16.012 ± 13.852 ng/ml) (P = 0.001 and 0.004 respectively) and significantly increase in MI group (26.020 ± 14.792 ng/ml) when compared to both control (P = 0.006) and post MI (P = 0.038) groups.&#x0D; Conclusion: We can conclude that both COX-2 and MMP-2 cannot be used as markers for diagnosis of stable angina or MI. While MMP-9 as it showed significant elevation in its level in MI and then decrease in post MI, it can be considered as a good marker for confirming the diagnosis of MI and post MI stage.

Targeting Matrix Metalloproteinases in Atherosclerosis and Cardiovascular Dysfunction

Matrix metalloproteinases (MMPs) are the primary mediators of extracellular remodeling and their properties are useful in diagnostic evaluation and treatment. They are zinc-dependent proteases. MMPs have been involved in the mechanisms of atherosclerosis in various arterial areas, ischemic heart disease and myocardial infarction, atrial fibrillation and aortic aneurysms. Recently, MMP9 has been implicated in dyslipidemia and cholesterol synthesis by the liver. Increased MMP expression and activity has been associated with neointimal arterial lesions and migration of smooth muscle cells after arterial balloon dilation, while MMP inhibition decreases smooth muscle cell migration in vivo and in vitro.

Matrix Gelatinases in Atherosclerosis and Diabetic Nephropathy: Progress and Challenges.

Matrix metalloproteinases (MMPs) are zinc-dependent proteases that degrade components of the extracellular matrix (ECM). In glomerular disease, MMPs are major regulators of ECM degradation as well as structural and functional integrity in the glomerulus. In altered matrix composition diseases, glomerular damage is due to increased degradation of kidney and vessel basement membranes (BMs) by MMPs. MMP -2 and -9 are both considered as the main enzymes that degrade collagen type-IV (coll-IV), which represents the key collagenous component of ECM and constitutes the architectural structure of vessels and glomerular BM. There is growing evidence implicating MMPs in atherosclerosis as well as in cardiovascular disease (CVD) and chronic kidney disease (CKD). Specific endogenous tissue inhibitors of MMPs (TIMPs) are also implicated in CKD, CVD and diabetic nephropathy (DN). The present review discusses the role of MMPs -2 and -9 in DN, as a leading cause of endstage renal disease and as a model of the link between progressive glomerulosclerosis and MMP expression.

Matrix metalloproteinases in atherosclerosis: role of nitric oxide, hydrogen sulfide, homocysteine, and polymorphisms.

Atherosclerosis is an inflammatory process that involves activation of matrix metalloproteinases (MMPs); MMPs degrade collagen and allow for smooth-muscle cell migration within a vessel. Moreover, this begets an accumulation of other cellular material, resulting in occlusion of the vessel and ischemic events to tissues in need of nutrients. Homocysteine has been shown to activate MMPs via an increase in oxidative stress and acting as a signaling molecule on receptors like the peroxisome proliferator activated receptor-γ and N-methyl-D-aspartate receptor. Nitric oxide has been shown to be beneficial in some cases of deactivating MMPs. However, in other cases, it has been shown to be harmful. Further studies are warranted on the scenarios that are beneficial versus destructive. Hydrogen sulfide (H2S) has been shown to decrease MMP activities in all cases in the literature by acting as an antioxidant and vasodilator. Various MMP-knockout and gene-silencing models have been used to determine the function of the many different MMPs. This has allowed us to discern the role that each MMP has in promoting or alleviating pathological conditions. Furthermore, there has been some study into the MMP polymorphisms that exist in the population. The purpose of this review is to examine the role of MMPs and their polymorphisms on the development of atherosclerosis, with emphasis placed on pathways that involve nitric oxide, hydrogen sulfide, and homocysteine.

Matrix Metalloproteinase-8 and the Regulation of Blood Pressure, Vascular Inflammation, and Atherosclerotic Lesion Growth

See related articles, pages 921–929 The description in the early 1990s of intriguing associations between the expression/activity of specific matrix metalloproteinases (MMPs) and signs of plaque inflammation and matrix degradation1–3 spurred an impressive effort of research to precisely define the roles of MMPs in both the development and complications of atherosclerosis. After two decades of research in this area, mechanistic studies using genetically manipulated mice with deletion or overexpression of specific MMPs, complemented with genetic epidemiological studies, have revealed more complex and, sometimes divergent, roles of MMPs in the modulation of lesion development, progression and complications.4 There are many potential explanations for these findings. Ambivalent effects of specific MMPs have been reported in different models of atherosclerosis,5 emphasizing the urgent need for clinically relevant animal models of disease complications. For example, even the use of the brachiocephalic artery of apolipoprotein (Apo)E knockout mice as a model of site-specific plaque rupture did not allow to differentiate between the roles of MMPs in plaque development versus plaque complications. A close look at this model reveals that the number of buried fibrous caps is highly proportional to lesion size, independently of mouse genetic background and MMP expression.6 The complex role of MMPs in atherosclerosis could be attributed to the diversity of biological processes relevant to this disease, which are subject to tight control by MMPs and the modulation of which could have divergent consequences for lesion development and fibrous cap stability. The MMP-controlled processes include those classically related to matrix remodeling, vascular …

Evaluation of Matrix Metalloproteinases in Atherosclerosis Using a Novel Noninvasive Imaging Approach

Despite great advances in our knowledge, atherosclerosis continues to kill more people than any other disease in the Western world. This is because our means of identifying truly vulnerable patients is limited. Prediction of atherosclerotic plaque rupture may be addressed by MRI of activated matrix metalloproteinases (MMPs), a family of enzymes that have been implicated in the vulnerability of plaques prone to rupture. This study evaluated the ability of the novel gadolinium-based MRI contrast agent P947 to target MMPs in atherosclerotic plaques. The affinity of P947 toward activated MMPs was demonstrated in vitro. The affinity and specificity of P947 toward matrix metalloproteinase (MMP)-rich plaques was evaluated both in vivo using ApoE-/- mice and ex vivo in hyperlipidemic rabbits. Gadolinium content quantification and MRI showed a preferential accumulation of P947 in atherosclerotic lesions compared with the nontargeted reference compound, Gd-DOTA. The ex vivo assay on rabbit plaques revealed a higher uptake of P947. Moreover, using human carotid artery endarterectomy specimens, P947 facilitated discrimination between histologically defined MMP-rich and MMP-poor plaques. An in vivo MRI investigation in mice revealed that P947 greatly improved the ability to visualize and delineate atherosclerotic plaques. P947 may be a useful tool for the detection and characterization of the MMP-rich atherosclerotic plaques.

Induction of mucosal tolerance to E-selectin targets immunomodulation to activating vessel segments and prevents ischemic and hemorrhagic stroke.

Inflammatory and immune reactions at blood vessel segments that lead to local release of proinflammatory cytokines and local activation of luminal endothelium can initiate stroke (Hallenbeck et al. 1988; Libby et al. 1995). These multipotent autocrine or paracrine mediators can regulate expression of leukocyte adhesion molecules, production of other cytokines, growth factors, and chemokines, and production of matrix metalloproteinases in atherosclerosis. Local endothelium integrates extracellular signals and cellular responses in different regions of the vascular tree (Rosenberg and Aird 1999). Scattered perivascular ring patterns of immunoreactive tumor necrosis factor-alpha (TNF-α), heme oxygenase-1 (HO-1), and manganese superoxide dismutase (MnSOD) within the brain parenchyma of normal rats reflect cyclic activation and inactivation of brain vessel segments (Ruetzler et al. 2001). These cycles appear to be more frequent and intense in stroke-prone animals.

Matrix metalloproteinases and atherosclerotic plaque instability.

There is growing interest in the role of matrix metalloproteinases in atherosclerosis. Excessive tissue remodelling and increased matrix metalloproteinase activity have been demonstrated during atherosclerotic plaque disruption, a frequent predeterminant of ischaemic cardiac events and stroke. These enzymes represent a potential target for therapeutic intervention to modify vascular pathology. The core of this review is derived from a Medline database literature search. There is convincing evidence of increased matrix metalloproteinase activity during acute plaque disruption. Evidence for an imbalance promoting increased matrix degradation is less well documented. However, studies of matrix metalloproteinase inhibition in models of vascular disease suggest a potential therapeutic benefit. In vivo studies of matrix metalloproteinase inhibition are required to study the potential for reversal or deceleration of the excessive tissue remodelling that accompanies acute plaque disruption.