Matrix metalloproteinases (MMPs), also designated matrixins, hydrolyze components of the extracellular matrix. These proteinases play a central role in many biological processes, such as embryogenesis, normal tissue remodeling, wound healing, and angiogenesis, and in diseases such as atheroma, arthritis, cancer, and tissue ulceration. Currently 23 MMP genes have been identified in humans, and most are multidomain proteins. This review describes the members of the matrixin family and discusses substrate specificity, domain structure and function, the activation of proMMPs, the regulation of matrixin activity by tissue inhibitors of metalloproteinases, and their pathophysiological implication.

Matrix metalloproteinases and tissue inhibitors of metalloproteinases: structure, function, and biochemistry.

The thrombolysis in myocardial infarction (TIMI) trial. Phase I findings

Publisher Summary This chapter discusses the role of plasminogen activators in various biological processes. In specific, it describes two types of plasminogen activators—namely, the urokinase-type plasminogen activator (u-PA) and the tissue-type plasminogen activator (t-PA), which are essentially different gene products. The amino acid sequences of these activators and nucleotide sequences of the corresponding cDNAs have largely been determined, and the cDNAs have been cloned using recombinant techniques. A variety of enzymatic as well as immunological assay and detection methods have also been developed that allows a precise quantification of the activators, a distinction between u-PA and t-PA, determination of whether an activator is present in its active or zymogen form, analysis of the kinetics of different steps of the cascade reaction, and immunocytochemical identification of u-PA and t-PA in tissue sections. Much of the studies on plasminogen activators and cancer has been guided by the hypothesis that proteolysis of the components of extracellular matrix, initiated by the release of plasminogen activator from the cancer cells, plays a decisive role for the degradation of normal tissue, and thereby for invasive growth and metastases.

Plasminogen activators, tissue degradation, and cancer.

Intravenous administration of 80 mg of recombinant tissue plasminogen activator (rt-PA, 40, 20, and 20 mg in successive hours) and streptokinase (SK, 1.5 million units over 1 hr) was compared in a double-blind, randomized trial in 290 patients with evolving acute myocardial infarction. These patients entered the trial within 7 hr of the onset of symptoms and underwent baseline coronary arteriography before thrombolytic therapy was instituted. Ninety minutes after the start of thrombolytic therapy, occluded infarct-related arteries had opened in 62% of 113 patients in the rt-PA and 31% of 119 patients in the SK group (p less than .001). Twice as many occluded infarct-related arteries opened after rt-PA compared with SK at the time of each of seven angiograms obtained during the first 90 min after commencing thrombolytic therapy. Regardless of the time from onset of symptoms to treatment, more arteries were opened after rt-PA than SK. The reduction in circulating fibrinogen and plasminogen and the increase in circulating fibrin split products at 3 and 24 hr were significantly less in patients treated with rt-PA than in those treated with SK (p less than .001). The occurrence of bleeding events, administration of blood transfusions, and reocclusion of the infarct-related artery was comparable in the two groups. Thus, in patients with acute myocardial infarction, rt-PA elicited reperfusion in twice as many occluded infarct-related arteries as compared with SK at each of seven serial observations during the first 90 min after onset of treatment.

Thrombolysis in Myocardial Infarction (TIMI) Trial, Phase I: A comparison between intravenous tissue plasminogen activator and intravenous streptokinase. Clinical findings through hospital discharge.

Utilization of polymers as biomaterials has greatly impacted the advancement of modern medicine. Specifically, polymeric biomaterials that are biodegradable provide the significant advantage of being able to be broken down and removed after they have served their function. Applications are wide ranging with degradable polymers being used clinically as surgical sutures and implants. In order to fit functional demand, materials with desired physical, chemical, biological, biomechanical and degradation properties must be selected. Fortunately, a wide range of natural and synthetic degradable polymers has been investigated for biomedical applications with novel materials constantly being developed to meet new challenges. This review summarizes the most recent advances in the field over the past 4 years, specifically highlighting new and interesting discoveries in tissue engineering and drug delivery applications.

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Biomedical Applications of Biodegradable Polymers

Kinetics of the activation of plasminogen by human tissue plasminogen activator. Role of fibrin.

Basic and clinical aspects of fibrinolysis and thrombolysis.

Vascular remodeling, defined as lasting structural changes in the vessel wall in response to hemodynamic stimuli, plays a role in many (patho)physiological processes requiring cell migration and degradation of extracellular matrix (ECM). Two proteolytic systems, the fibrinolytic (plasminogen/plasmin) and matrix metalloproteinase (MMP) systems can degrade most ECM components. The availability of mice models with deficiency of main components of both systems has allowed to study their contribution to vascular remodeling in several biological processes. In mouse models of atherosclerosis, urokinase-mediated plasmin generation plays a role in activation of several macrophage-derived MMPs (MMP-3, -9, -12 and -13), triggering elastolysis and collagenolysis, resulting in media destruction and aneurysm formation. Neointima formation after vascular injury, a process that depends on smooth muscle cell migration, is reduced in mice with plasminogen or urokinase deficiency and enhanced in mice with deficiency of TIMP-1 (type 1 tissue inhibitor of MMPs). Also in allograft transplant arteriosclerosis and in abdominal aortic aneurysm both proteolytic systems contribute to matrix degradation. In a mouse model of myocardial infarction, urokinase deficiency protects totally and MMP-9 deficiency partially against cardiac rupture, but these animals suffer cardiac failure. Thus, the plasminogen/plasmin and MMP systems, in concert, contribute to vascular remodeling in the setting of cardiovascular disease.

Plasmin and Matrix Metalloproteinases in Vascular Remodeling

https://onlinelibrary.wiley.com/doi/pdf/10.1111/j.1538-7836.2008.03220.x

H.R. Lijnen

Papers

Kinetics of the activation of plasminogen by human tissue plasminogen activator. Role of fibrin.

Basic and clinical aspects of fibrinolysis and thrombolysis.

Plasmin and Matrix Metalloproteinases in Vascular Remodeling

New insights into the molecular mechanisms of the fibrinolytic system.

Pleiotropic functions of plasminogen activator inhibitor-1.