Fibrinogen is a multifunctional plasma protein that after conversion into fibrin promotes hemostasis and contributes to other physiological and pathological processes including inflammation, which plays a pivotal role in the pathophysiology of cardiovascular diseases. Recruitment of leukocytes from the circulation to sites of inflammation is an integral part of the inflammatory response and transendothelial migration of leukocytes is a key step in such recruitment. Our previous study revealed that fibrin interacts with the VLDL receptor (VLDLR) on endothelial cells and this interaction promotes leukocyte transmigration and thereby inflammation. Further, we clarified the molecular mechanism of fibrin-VLDLR interaction and identified two anti-VLDLR monoclonal antibodies that inhibit this interaction, and exhibit significant anti-inflammatory properties and cardioprotective effects in animal models. Thus, fibrin-VLDLR interaction triggers a novel fibrin-VLDLR-dependent pathway of leukocyte transmigration, which may contribute to the pathophysiology of myocardial ischemia-reperfusion injury. However, the molecular mechanism underlying this pathway is still unclear. We have generated numerous preliminary data that indicate the feasibility of studying this interaction by NMR and suggest that there is a link between this pathway and VE-cadherin. Based on these data we propose to solve NMR solution of a complex between fibrin- and VLDLR-derived fragments and establish the structural basis for fibrin-VLDLR interaction (Specific Aim 1). Next, we will test our hypothesis that fibrin promotes leukocyte transmigration by increasing endothelial permeability via a VLDLR-dependent internalization of VE-cadherin (Specific Aim 2). Finally, we will test our new concept related to the anti-inflammatory mechanism of fibrin-derived ?15-42 peptide and will develop more efficient anti-inflammatory agents (Specific Aim 3). Thus, the major goals of the proposed project are to establish the molecular mechanisms underlying fibrin-dependent inflammation and, based on the results obtained, to design more efficient anti-inflammatory agents that can be developed as novel therapeutics for treatment of fibrin-dependent inflammatory disorders including myocardial ischemia-reperfusion injury.
Inflammatory mechanisms play a pivotal role in the pathophysiology of cardiovascular diseases. They involve various factors including fibrin, which promotes transendothelial migration of leukocytes and thereby inflammation. Our previous study discovered a novel fibrin-VLDL receptor-dependent pathway of leukocyte transmigration, which is involved in fibrin-dependent inflammation and may contribute to the pathophysiology of myocardial ischemia-reperfusion injury. The major goals of the proposed study are to establish the molecular mechanism underlying this pathway and to identify novel more efficient anti- inflammatory agents that may be developed as potent therapeutics for treatment of inflammation-related cardiovascular disorders.
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