The Construction Of Soluble CD40-IgG Fc Fusion Gene Recombinant Adenovirus Vector And The In Vitro Study About Inhibition Of Atherosclerotic Plaque Remodeling

Vulnearble plaque of atherosclerosis rupture followed by thrombosis is the main pathologic basis resulting in acute cardiovascular events (ie, acute myocardial infarction, unstable angina, sudden cardiac death and ischemic stroke). Inflammation/immune reaction mediated by nflammatory cells, mainly referred as macrophages and T lymphocytes, and inflammation mediators exist in atheroma plays key role in acute coronary syndromes following plaque repture and prothrombotic response.In recent years, researchers pay more attention to the role of CD40 and CD40L in atherogenic and plaque stablization. CD40 is a membrane receptor expressed in almost all kinds of cell types associated with atherosclerotic lesion (ie macrophages, endothelium, and vascular smooth muscle cells. CD40L mainly located in T lymphocytes and activated platelet. Serum sCD40L level, membrane type CD40 on T Lymphocytes and platelet are significantly higher in patierns with unstable angina than those in controls and patients with stable angina. sCD40L is associated with cardiovascular risk in women. Participants with elevated baseline mean sCD40 developed myocardial infarction, stroke, and cardiac death in the following 4 years. Hoever there is no evidence for cardiovascular disease in control. Pathologic study confirmed that CD40/CD40L dyad expressed in both early and complex atherosclerotic lesion, especially at the vulnerable shoulder region of a plaque or reptured plaque. An in vivo study with high-resolution MRI revealed that soluble CD40 ligand levels indicate lipid accumulation in carotid atheroma. Many in vitro studies showed that CD40L may enhance secretion of Chemotactic Factors, adhencive molecular, cytokines, matrix metalproteinases and prothrombotic factors by AS associated cells (ie, macrophages, endothelium, and smooth muscle cells). Plaque associated cells may express matrix metalproteinasesand TF and trigger acute coronary events induced by CD40 signal. CD40 participated in the expression of TF, and accelerated the prothrombotic role of atheroraa in atherosclerogenic and vascular lesional inflammation. sCD40L may represent the molecular link between hypercholesterolemia and the prothrombotic state. Statin therapy may significantly reduce sCD40L and the prothrombotic state. In addition, serum sCD40L was positively associated with in vivo platelet activation and with procoagulant state. CD40 signal probably promote thrombosis. CD40L may induce the expression and secretion of TF by endothelium to form stable thrombus. Activated T lymphocytes and platelet CD40L may activate MMPs, thereby enhance the atheroma repture. All these evidences support the inflammation trigered by CD40-CD40L interaction may induce plaque repture and thrombosis. CD40 ligand inhibits endothelial cell migration by increasing production of endothelial reactive oxygen species. The blockade of EC migration by CD40L may critically affect endothelial regeneration after plaque erosion and thereby may contribute to the increased risk for development of acute coronary events in patients with high circulating levels of CD40L.Statins and GPIIb/IIIa antagonist inhibit the expression of CD40 and CD40L separately. Inhibition of CD40 signaling not only limits evolution of established atherosclerosis in mice, but also changes the composition of atheroma in manners thought to favor plaque stability, e. g., reduced relative content of macrophages and lipid, as well as increased relative content of smooth muscle cells and collagen. Both early and delayed anti-CD40L antibody treatment induces a stable plaque phenotype. CD40 may become a nove therapeutic strategy in preventing unstable atheroma from repture.Bloking CD40-CD40L interaction with CD40-IgGl Fc fusion protein benefits the therapy of GVHD in mice. Adenovirus mediated CD40-IgG gene therapy induced donor-specific tolerance in rat liver transplantation. However there is no research in stablizing atherosclerotic plaque using CD40-Ig fusion protein. We are planning to block CD40 signal so as to seek for an effe...