Abstract
Venous grafts are often used to bypass occlusive atherosclerotic lesions; however, poor patency leads to vein graft disease. Deficiency of TLR4, an inflammatory regulator, reduces vein graft disease. Here, we investigate the effects of the accessory molecule and TLR4 analogue RadioProtective 105 (RP105) on vein graft disease. RP105 deficiency resulted in a 90% increase in vein graft lesion area compared to controls. In a hypercholesterolemic setting (LDLr−/−/RP105−/− versus LDLr−/− mice), which is of importance as vein graft disease is usually characterized by excessive atherosclerosis, total lesion area was not affected. However we did observe an increased number of unstable lesions and intraplaque hemorrhage upon RP105 deficiency. In both setups, lesional macrophage content, and lesional CCL2 was increased. In vitro, RP105−/− smooth muscle cells and mast cells secreted higher levels of CCL2. In conclusion, aggravated vein graft disease caused by RP105 deficiency results from an increased local inflammatory response.
Highlights
Rupture of an atherosclerotic lesion with subsequent thrombus formation may lead to distal embolization of the blood vessel, resulting in adverse cardiovascular events[1]
In the current study we demonstrate that lack of the regulatory molecule RadioProtective 105 (RP105) results in a marked increase in vein graft lesion area
RP105 deficiency resulted in an increase in vein graft disease mainly due to an increase in macrophage content, while lesion growth was similar between control and RP105 deficient mice under hypercholesterolemic conditions
Summary
Rupture of an atherosclerotic lesion with subsequent thrombus formation may lead to distal embolization of the blood vessel, resulting in adverse cardiovascular events[1]. Excessive and uncontrolled smooth muscle cell (SMC) accumulation and proliferation result in the formation of intimal hyperplasia[9]. This process is accompanied by leukocyte influx into the vessel wall, which aggravates the inflammatory process and leads to superimposed atherosclerosis. Excessive SMC proliferation, lipid accumulation and an enhanced inflammatory response seem to be causing vein graft disease. Highlighting the importance of vascular inflammation in vein graft disease, we have previously shown that local silencing of Toll like receptor 4 (TLR4) significantly reduces vessel wall thickening in these murine venous grafts[13], rendering this pathway of interest for future therapeutic interventions. In contrast to its role on the B cell, RP105 inhibits TLR4 mediated responses in DCs and macrophages, leading for instance to an aggravated inflammatory response after lipopolysaccharide (LPS) injection in RP105 deficient mice[16]
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