Local Overexpression of Thrombomodulin for In Vivo Prevention of Arterial Thrombosis in a Rabbit Model

Waugh, Jacob M.; Yüksel, Eser; Li, J.; Kuo, Michael; Kattash, Maan; Saxena, Romil; Geske, Robert S.; Thung, Swan N.; Shenaq, Saleh M.; Woo, Savio L. C.

doi:10.1161/01.res.84.1.84

Cited by 89 publications

(59 citation statements)

References 40 publications

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“…46 Given that plasminogen activator inhibitor-1 and thrombospondin-1 both involved thrombus formation, and thrombomodulin overexpression may reduce thrombosis, 97 this pattern of effects of 1,25(OH) 2 D is consistent with an antithrombotic role. Results from a KO model confirmed initial in vitro studies, with VDR null mice exhibiting a prothrombotic state because of downregulation of both antithrombin and thrombomodulin and upregulation of tissue factor gene expression.…”

Section: Thrombosismentioning

confidence: 90%

Vitamin D and Cardiovascular Disease

Norman¹,

Powell

2014

Circulation Research

450

353

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Vitamin D (nutritional term for compounds with biological activity of 1α,25-dihydroxyvitamin D; also used to indicate summation of Vitamin D 2 and D 3 ) is a fat-soluble vitamin that functions as a steroid hormone. It plays a crucial role in mineral homeostasis and skeletal health and its deficiency classically leads to rickets in children and osteomalacia in adults. 1 Its primary action on the skeletal system is to regulate calcium and phosphorus metabolism by influencing intestinal absorption, bone resorption, and renal retention (Figure 1). Vitamin D metabolites also play an integral physiological role in nonskeletal tissues and have been implicated in a wide range of chronic pathology, including skin and autoimmune disease, cancer, diabetes mellitus, hypertension, and cardiovascular disease (CVD).2 Interest in the role of vitamin D in CVD arose from evidence of adverse cardiovascular effects of vitamin D deficiency in animal models, 3 and epidemiological studies reporting the increase in cardiovascular events in winter and at increasing distance from the equator. Various extrarenal tissues, including many cell types involved in CVD, also express CYP27B1 and are therefore able to produce 1,25(OH) 2 D. This local production and breakdown is not subject to the same feedback controls as renal production. Vitamin D Deficiency and ExcessThere is controversy about the definition of vitamin D deficiency (or hypovitaminosis D), the optimum serum level of 25(OH)D, and the dietary requirements of vitamin D.

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Section: Thrombosismentioning

confidence: 90%

Vitamin D and Cardiovascular Disease

Norman¹,

Powell

2014

Circulation Research

450

353

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“…Models that are based on vascular trauma or injection of endotoxin to initiate intravascular fibrin formation are useful (10,11,18,47,56,57) but difficult to control in terms of clot size, prevalence, and destination. Injection of preformed clots overcomes some of these limitations (3,6,29).…”

Section: Discussionmentioning

confidence: 99%

Platelets inhibit the lysis of pulmonary microemboli

Murciano

Harshaw

Neschis

et al. 2002

American Journal of Physiology-Lung Cellular and Molecular Phys

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Using tracings of 125 I-labeled fibrin(ogen) in rodents, we examined the hypothesis that platelets impede the lysis of pulmonary emboli.125 I-Microemboli (ME, 3-10 micron diameter) lodged homogeneously throughout the lungs after intravenous injection in both rats and mice (60% of injected dose), caused no lethality, and underwent spontaneous dissolution (50 and 100% within 1 and 5 h, respectively). Although lung homogenates displayed the most intense fibrinolytic activity of all the major organs, dissolution of ME was much slower in isolated perfused lungs (IPL) than was observed in vivo. Addition of rat plasma to the perfusate facilitated ME dissolution in IPL to a greater extent than did addition of tissue-type plasminogen activator alone, suggesting that permeation of the clot by plasminogen is the rate-limited step in lysis. Platelet-containing ME injected in rats lysed much more slowly than did ME formed from fibrin alone.125 I-Thrombi, formed in the pulmonary vasculature of mice in response to intravascular activation of platelets by injection of collagen and epinephrine, were essentially resistant to spontaneous dissolution. Moreover, injection of the antiplatelet glycoprotein IIb/IIIa antibody 7E3 F(abЈ) 2 facilitated spontaneous dissolution of pulmonary ME and augmented fibrinolysis by a marginally effective dose of Retavase (10 g/kg) in rats. These studies show that platelets suppress pulmonary fibrinolysis. The mechanism(s) by which platelets stabilize ME and utility of platelet inhibitors to facilitate their dissolution deserves further study. pulmonary embolism; plasminogen activators; platelets; fibrinolysis; animal model; glycoprotein IIb/IIIa THE LUNG SERVES as a natural filter for thromboemboli of diverse sizes (12). Thrombotic occlusion of the main or lobar pulmonary arteries by large clots (massive pulmonary embolism, PE) is a common cause of morbidity and mortality (15,20). In contrast, pulmonary deposition of microemboli (ME) often does not cause acute symptoms (silent ME). Nevertheless, pulmonary ME is a relatively common accompaniment to acute lung injury (adult respiratory distress syndrome), hyperoxia, bleomycin toxicity, sepsis, trauma, surgery on the lower extremities, and angioplasty (2,21,30,33,36,39,40,44,52,53). Microembolism may lead to inflammation and edema acutely and contribute to the development of pulmonary fibrosis and hypertension over time (4,9,22,27,31).The treatment of PE, as with other venous thromboembolic conditions, is typically restricted to agents such as heparin that retard fibrin clot formation, with a relatively limited use of agents that promote fibrinolysis. Despite the effectiveness of such therapy, PE remains a common cause of mortality and morbidity. Thus there is a continuing need for more effective means to prevent and treat both PE and ME, based on a more thorough understanding of the mechanisms that regulate clot dissolution in the lung.For example, the role of platelets in PE and ME has received relatively little study. Recently, it has been shown tha...

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“…We thus postulated that replenishing TM by anchoring it to endothelial luminal surfaces might circumvent these limitations (Video E1). The antithrombotic effect of TM transfected into rabbit artery supports this concept (21), but this approach cannot be applied in acute settings. In theory, it may be possible to achieve the AT A GLANCE COMMENTARY Scientific Knowledge on the Subject Thrombomodulin (TM) is a pivotal endothelial molecule that helps maintain tissue homeostasis and prevents tissue injury.…”

mentioning

confidence: 94%

Anchoring Fusion Thrombomodulin to the Endothelial Lumen Protects against Injury-induced Lung Thrombosis and Inflammation

Ding¹,

Hong²,

Christofidou‐Solomidou³

et al. 2009

Am J Respir Crit Care Med

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Rationale: Endothelial thrombomodulin (TM) regulates thrombosis and inflammation. Diverse forms of pulmonary and vascular injury are accompanied by down-regulation of TM, which aggravates tissue injury. We postulated that anchoring TM to the endothelial surface would restore its protective functions. Objectives: To design an effective and safe strategy to treat pulmonary thrombotic and inflammatory injury. Methods: We synthesized a fusion protein, designated scFv/TM, by linking the extracellular domain of mouse TM to a single-chain variable fragment of an antibody to platelet endothelial cell adhesion molecule-1 (PECAM-1). The targeting and protective functions of scFv/TM were tested in mouse models of lung ischemia-reperfusion and acute lung injury (ALI) caused by intratracheal endotoxin and hyperoxia, both of which caused approximately 50% reduction in the endogenous expression of TM. Measurements and Main Results: Biochemical assays showed that scFv/ TM accelerated protein C activation by thrombin and bound mouse PECAM-1 and cytokine high mobility group-B1. After intravenous injection, scFv/TM preferentially accumulated in the mouse pulmonary vasculature. In a lung model of ischemia-reperfusion injury, scFv/TM attenuated elevation of early growth response-1, inhibited pulmonary deposition of fibrin and leukocyte infiltration, and preserved blood oxygenation more effectively than soluble TM. In an ALI model, scFv/TM, but not soluble TM, suppressed activation of nuclear factor-kB, inflammation and edema in the lung and reduced mortality without causing hemorrhage. Conclusions: Targeting TM to the endothelium using an scFv anchor enhances its antithrombotic and antiinflammatory effectiveness in models of ALI.

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Local Overexpression of Thrombomodulin for In Vivo Prevention of Arterial Thrombosis in a Rabbit Model

Cited by 89 publications

References 40 publications

Vitamin D and Cardiovascular Disease

Vitamin D and Cardiovascular Disease

Platelets inhibit the lysis of pulmonary microemboli

Anchoring Fusion Thrombomodulin to the Endothelial Lumen Protects against Injury-induced Lung Thrombosis and Inflammation

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