Abstract 1742: Cell-Type Specific CD40(L) Signaling in Atherosclerosis: Role of Platelet and Leukocyte CD40(L) on Plaque Development
Although absence of CD40(L) signaling reduces atherosclerosis and induces a stable plaque phenotype, the CD40(L) expressing plaque cell-type(s) responsible for these phenomena are unknown. Here we investigated the role of platelet and leukocyte CD40(L) in atherosclerosis. Platelets were obtained from ApoE−/− or CD40L−/−/ApoE mice, activated with thrombin, and injected intravenously into 5 wk old ApoE−/− mice (3x107 platelets), every 5 days for 14 wks. Injection of activated platelets did not cause differences in platelet, red and white blood cell counts, Hb or Ht levels or in the number of blood granulocytes, monocytes, T- and B-cells of mice receiving a vehicle (n=5), ApoE−/ − (n=10) or CD40L−/ −ApoE−/ − (n=10) platelets. ApoE−/ −mice receiving activated CD40L−/ − platelets developed less atherosclerosisin the aortic arch and its major branchpoints (ApoE−/ − 201,212 ±37443μm2 vs CD40L−/ −ApoE−/ −100,507±15,674μm2; p<0.05) to levels that were comparable to the controls (116,825±16,134μm2). This decrease was due to a reduced number of plaques (ApoE−/ −2.55±0.32 vs CD40L−/ −ApoE−/ − 1.68±0.24), while the relative amount of initial and advanced plaques was not affected (ApoE: 71.2±13.0% ini; 28.8±13% adv; CD40L−/ −ApoE−/ −: 92.4±5.2% ini; 7.6±5.2% adv), indicating an important role for platelet CD40L in plaque initiation. To investigate the effect of leukocyte CD40(L) on atherosclerosis, CD40L−/ −, CD40−/ −or wt bone marrow was transplanted into irradiated LDLR−/ − mice, that were fed a 1.25% cholesterol diet for 26 wks. No effect was observed after transplantation of CD40L−/ − bone marrow. Transplantation of CD40−/ − bone marrow resulted in a 35.1% decrease in aortic arch plaque area (wt 907,593±49,785μm2 n=8 vs CD40−/ − 589,135±108,651μm2 n=8). This was not only caused by a decreased number of plaques (wt 6.4±0.3 vs CD40−/ − 5.1±0.5; p<0.05), but also by an impaired progression of advanced plaques (advanced plaque area: wt 187,336±20194μm2 vs CD40−/ − 91,235±19024μm2; p<0.05). Hematology and FACS analysis of blood, spleen and lymph nodes showed no major differences between both groups. Here we show that platelet CD40L plays an important role in the initiation of atherosclerosis, while leukocyte CD40 is more important in atherosclerosis progression.