Matrix metalloproteinases (MMPs) are a family of zinc-dependent endopeptidases that primarily degrade components of the extracellular matrix (ECM). Remodeling of the ECM by MMPs is important in both physiological and pathological processes, including organ generation/regeneration, angiogenesis, wound healing, inflammation and tumor growth. In the vasculature, MMPs play a role in beneficial processes such as angiogenesis, collateral artery formation and thrombus resolution. However, MMP expression is also implicated in the pathogenesis of vascular diseases such as atherosclerosis, aortic aneurysms, plaque rupture and neointimal hyperplasia after balloon angioplasty. Here, we review the structure, functions and roles of MMPs in both neovascularization and vascular pathology and discuss the potential of, and challenges that face, adapting MMPs as therapeutic targets in vascular disease.

Breast cancer metastasis suppressor 1 (BRMS1) is a metastasis suppressor gene in several solid tumors. The role of BRMS1 in non-small cell lung cancer (NSCLC) is not well established. To assess in vitro and in vivo metastatic behavior H1299 NSCLC cells stably expressing BRMS1 or a vector control were created. BRMS1 expression significantly decreases both migration and invasion of NSCLC cells in vitro. Importantly, in flank xenografts, BRMS1 suppresses the formation of pulmonary and hepatic metastases but does not significantly affect primary tumor growth. To evaluate whether BRMS1 is related to the progression of NSCLC, we examined BRMS1 expression in human NSCLC. Both BRMS1 mRNA and protein levels are diminished in NSCLC compared to adjacent non-cancerous lung. BRMS1 expression is also lower in squamous cell carcinoma compared to adenocarcinoma. Moreover, preservation of tumor BRMS1 expression is associated with improved patient survival. Thus, BRMS1 functions as a metastasis suppressor and may be a prognostic indicator for human NSCLC.

Background Patients undergoing tricuspid valve surgery have a mortality of 9.8%, which is higher than expected given the complexity of the procedure. Despite liver dysfunction seen in many patients with tricuspid disease, no existing risk model accounts for this. The Model for End-Stage Liver Disease (MELD) score accurately predicts mortality for abdominal surgery. The objective of this study was to determine if MELD could accurately predict mortality after tricuspid valve surgery and compare it to existing risk models. Methods From 1994 to 2008, 168 patients (mean age, 61 ± 14 years; male = 72, female = 96) underwent tricuspid repair (n = 156) or replacement (n = 12). Concomitant operations were performed in 87% (146 of 168). Patients with history of cirrhosis or MELD score 15 or greater (MELD = 3.8*LN [total bilirubin] + 11.2*log normal [international normalized ratio] + 9.6*log normal [creatinine] + 6.4) were compared with patients without liver disease or MELD score less than 15. Preoperative risk, intraoperative findings, and complications including operative mortality were evaluated. Statistical analyses were performed using χ2, Fisher’s exact test, and area under the curve (AUC) analyses. Results Patients with a history of liver disease or MELD score of 15 or greater had significantly higher mortality (18.9% [7 of 37] versus 6.1% [8 of 131], p = 0.024). To further characterize the effect of MELD, patients were stratified by MELD alone. No major differences in demographics or operation were identified between groups. Mortality increased as MELD score increased, especially when MELD score of 15 or greater (p = 0.0015). A MELD score less than 10, 10 to 14.9, 15 to 19.9, and more than 20 was associated with operative mortality of 1.9%, 6.8%, 27.3%, and 30.8%, respectively. By multivariate analysis, MELD score of 15 or greater remained strongly associated with mortality (p = 0.0021). The MELD score predicted mortality (AUC = 0.78) as well as the European System for Cardiac Operative Risk Evaluation logistic risk calculator (AUC = 0.78, p = 0.96). Conclusions The MELD score predicts mortality in patients undergoing tricuspid valve surgery and offers a simple and effective method of risk stratification in these patients.

Background The resolution of deep vein thrombosis (DVT) requires an inflammatory response and mobilization of proteases, such as urokinase-type plasminogen activator (uPA) and matrix metalloproteinases (MMPs), to degrade the thrombus and remodel the injured vein wall. PAI-2 is a serine protease inhibitor (serpin) with unique immunosuppressive and cell survival properties that was originally identified as an inhibitor of uPA. Objective To investigate the role of PAI-2 in venous thrombus formation and resolution. Methods Venous thrombus resolution was compared in wild type C57BL/6, PAI-2 -/- and PAI-1 -/- mice using the stasis model of DVT. Formed thrombi were harvested, thrombus weights were recorded, and tissue was analyzed for uPA, and MMP activities, PAI-1 expression, and the nature of inflammatory cell infiltration. Results We found that absence of PAI-2 enhanced venous thrombus resolution, while thrombus formation was unaffected. Enhanced venous thrombus resolution in PAI-2 -/- mice was associated with increased uPA activity and reduced levels of PAI-1, with no significant effect on MMP-2 and -9 activities. PAI-1 deficiency resulted in an increase in thrombus resolution similar to PAI-2 deficiency, but additionally reduced venous thrombus formation and altered MMP activity. PAI-2 deficient thrombi had increased levels of the neutrophil chemoattractant, CXCL2, which was associated with early enhanced neutrophil recruitment. Conclusions These data identify PAI-2 as a novel regulator of venous thrombus resolution, which modulates several pathways involving both inflammatory and uPA activity mechanisms, distinct from PAI-1. Further examination of these pathways may lead to potential therapeutic prospects in accelerating thrombus resolution.

Summary Background: Thrombus resolution is a complex process that involves thrombosis, leukocyte-mediated thrombolysis, and the final resolution of inflammation. Activated Protein C (APC) is an anticoagulant that also possesses immunoregulatory activities. Objective: In this study, we sought to examine the effects of APC administration on thrombus resolution using a mouse model of deep vein thrombosis by ligating the inferior vena cava (IVC). Methods: The IVCs of C57BL/6 mice were ligated. Beginning on Day 4 post-IVC ligation, mice were injected i.p. daily with APC, APC plus a heme oxygenase-1 (HO-1) inhibitor Sn-protoporphyrin IX (SnPP), SnPP alone, or vehicle control. At different time points following surgery, the thrombus-containing IVCs were weighed and then analyzed by biochemical assays and histology. Results: Venous thrombi reached maximum size on Day 4 post ligation. The APC-treated group exhibited a significant reduction in thrombus weights on Day 12 but not on Day 7 as compared to control mice. The enhanced thrombus resolution in APC-treated mice correlated with an increased HO-1 expression and a reduced interleukin-6 production. No significant difference was found in urokinase-type plasminogen activator, plasminogen activator inhibitor-1, matrix metalloproteinase-2 and -9 between APC-treated and control mice. Co-injection of an HO-1 inhibitor SnPP abolished the ability of APC to enhance thrombus resolution. Conclusions: Our data show that APC enhances the resolution of existing venous thrombi via a mechanism that is in part dependent on HO-1, suggesting that APC could be used as a potential treatment for patients with deep vein thrombosis to accelerate thrombus resolution.