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Gene Therapy for Cardiovascular Diseases
Published in Yashwant Pathak, Gene Delivery, 2022
Dhwani Thakkar, Vandit Shah, Jigna Shah
A thrombosis can be caused by a ruptured plaque in an atherosclerotic artery, resulting in an acute ischemic episode, such as unstable angina and myocardial infarction. Transfer of the tissue inhibitor of metalloproteinase (TIMP) gene can aid in the stabilization of unstable plaques.25 Many studies have shown that transferring genes for biological indicators, including hirudin, thrombodulin, tissue plasminogen activator, cyclooxygenase, and tissue factor pathway inhibitor, lowers thrombotic events.15
Haemostasis and Thrombosis
Published in Karl H. Pang, Nadir I. Osman, James W.F. Catto, Christopher R. Chapple, Basic Urological Sciences, 2021
Anticoagulant factors:Tissue factor pathway inhibitor (TFPI)Present in plasma and released by platelets, but the majority is on the surface of EC. It binds FXa and then TF-FVIIa and thus acts to dampen any procoagulant stimulus.AntithrombinBinds and inhibits the coagulation proteases, particularly thrombin (FIIa) and FXa. Its action is greatly potentiated by the heparans on the surface of EC and by heparin administered therapeutically.Protein C-Protein SThrombin escaping from the haemostatic event is captured by thrombomodulin on the surface or normal endothelium. This drastically changes its specificity so that it now activates protein C (APC). APC in concert with Protein S degrades FVa and FVIIIa, thus limiting further thrombin generation.
Studies of the Primate Inflammatory Hemostatic Axis and Its Response to Inflammatory Mediators
Published in Helmut Brade, Steven M. Opal, Stefanie N. Vogel, David C. Morrison, Endotoxin in Health and Disease, 2020
We believe that modulators may “tilt” the four-quadrant hemostatic playing field to favor one or another of its functional domains either by altering the balance between mediator or regulator components or the sensitivity of target tissues to the action of these components. Figure 2D shows the effect of IL-6 (40 |jig) injected i.m. daily for 6–10 days on the response to XaPCPS (20). The controlled response shown in Figure 2A is converted into a microvascular thrombotic coagulopathic (MVT) response shown in Figure 2D. Although IL-6 has other effects, this change is presumably due to increases in the concentrations of both fibrinogen and platelets, shifting the balance in favor of the coagulant (↑fibrinogen) and antifibrinolytic (↑platelet PAI-1) domains. IL-6 may exert other effects on this system. These include effects on the vascular endothelium (dysfunctional) and elements of the anticoagulant and fibrinolytic domains, which operate from the endothelium such as tissue plasminogen activator (21), components of the protein C system (protein S) (22–24), tissue factor pathway inhibitor (TFPI) (25,26) antithrombin (AT-III) (27) and thrombin-activated fibrinolytic inhibitor (TAFI) (28).
Promoting plaque stability by gene silencing of monocyte chemotactic protein-3 or overexpression of tissue factor pathway inhibitor in ApoE-/- mice
Published in Journal of Drug Targeting, 2021
Yong Zhao, Wenjia Chen, Yue Liu, Hui Li, Jinyu Chi, Qing Chang, Li Shen, Runan Yan, Jiashu Li, Xinhua Yin, Yu Fu
Tissue factor pathway inhibitor (TFPI), which is a protease inhibitor consisting of three Kunitz-type domains , is a serum anticoagulant factor which is critical for inhibiting the process of blood coagulation mediated by tissue factor (TF) [10]. TFPI can form the compoud of TFPI/FXa/FVIIa/TF and suppress TF activity, eventually resulting in anticoagulant and antithrombotic function. Our group and other groups have indicated that TFPI obtained from gene transfer or recombinant method can exert many effects such as inhibiting restenosis, thrombosis and neointimal hyperplasia [11–13]. Moreover, we also found that TFPI could provoke apoptosis of vascular smooth muscle cell (VSMC) apoptosis, and thus inhibit neointima formation, which was mediated by surpressing JAK2/STAT3 signalling pathway [14,15]. We reported that TFPI could inhibit proliferation of TNF-α-induced VSMCs, probably through the MCP-3/CCR2 signal pathway [16]. However, effect of TFPI on the development, and especially the stability and the mechaniam, of atherosclerotic plaques remains unclear. Therefore, the mechanisms underlying the efficacy of TFPI on plaque stability are also unknown and require further elucidation.
Lipoplex-based therapeutics for effective oligonucleotide delivery: a compendious review
Published in Journal of Liposome Research, 2020
Pirthi Pal Singh, Veena Vithalapuram, Sunita Metre, Ravinder Kodipyaka
On April 2016, the FDA approved Defibrotide (Defitelio®) treatment of severe hepatic veno-occlusive disease [VOD, known as sinusoidal obstruction syndrome] occurring after high-dose chemotherapy and autologous bone marrow transplantation (Stein et al.2016b). The natural process of controlled depolymerization of porcine intestinal mucosal DNA is used for defibrotide generation. Defibrotide has a very complicated non-specific mechanism of action, most certainly based on the charge–charge interactions of its phosphodiester constituents with proteins. Although the mechanism of action of defibrotide is reported as too complex, Pescador et al. (2013) described the anti-coagulating ability of defibrotide in the hepatic sinusoidal endothelium. It increases plasma tissue plasminogen activator activity and decreases the activity of its inhibitor. It is also reported to release tissue-factor pathway inhibitor from endothelial cells and inhibit platelet aggregation by plasma prostaglandin E2 elevation (Coccheri et al.1988, Cella et al.2001).
Hemostatic effect of acylated ghrelin in control and sleeve gastrectomy-induced rats: mechanisms of action
Published in Archives of Physiology and Biochemistry, 2020
Tissue factor (TF) is a membrane-bound glycoprotein secreted by the active vascular ECs to initiate the extrinsic pathway of blood coagulation (Hinsbergh 2012). On the cell surface, TF can activate circulatory factor VII leading to the formation of TF/VIIa complex which eventually induces the activation of circulating factors X and IX and deposition of insoluble fibrin (Nemerson 1988, Mackman 2009). On the opposite, vascular ECs also secrete an opposing anti-thrombotic protein named tissue factor pathway inhibitor (TFPI), which acts to inhibit TF directly (Hinsbergh 2012, Wood et al.2014). Similarly, tissue plasminogen activator (tPA) is the major fibrinolytic anti-coagulant protein released by the vascular ECs to degrade fibrin clots by increasing active plasmin levels in blood and body cavities (Rijken et al.2009). Plasminogen activator inhibitor-1 (PAI-1) is the most potent inhibitor of tPA activator and is also released by the vascular ECs (Hinsbergh 2012, Yau et al.2015).