| First Author | Kusters PJH | Year | 2018 |
| Journal | Arterioscler Thromb Vasc Biol | Volume | 38 |
| Issue | 5 | Pages | 1076-1085 |
| PubMed ID | 29519940 | Mgi Jnum | J:285173 |
| Mgi Id | MGI:6385492 | Doi | 10.1161/ATVBAHA.117.310640 |
| Citation | Kusters PJH, et al. (2018) CD40L Deficiency Protects Against Aneurysm Formation. Arterioscler Thromb Vasc Biol 38(5):1076-1085 |
| abstractText | OBJECTIVE: The mechanisms underlying formation of arterial aneurysms remain incompletely understood. Because inflammation is a common feature during the progressive degeneration of the aortic wall, we studied the role of the costimulatory molecule CD40L, a major driver of inflammation, in aneurysm formation. APPROACH AND RESULTS: Transcriptomics data obtained from human abdominal aortic aneurysms and normal aortas revealed increased abundance of both CD40L and CD40 in media of thrombus-free and thrombus-covered human abdominal aortic aneurysms samples. To further unravel the role of CD40L in aneurysm formation, apolipoprotein E-deficient (Apoe(-/-)) and Cd40l(-/-)Apoe(-/-) mice were infused with angiotensin II for 7 and 28 days. Only a minority of Cd40l(-/-)Apoe(-/-) mice (33% and 17%) developed (dissecting) aneurysms compared with 75% and 67% of Apoe(-/-) littermates after 7 and 28 days of infusion, respectively. Total vessel area of the aorta at the suprarenal level was 52% smaller in angiotensin II-infused Cd40l(-/-)Apoe(-/-) mice compared with that in angiotensin II-infused Apoe(-/-) mice. Chimeric Apoe(-/-) mice repopulated with Cd40l(-/-)Apoe(-/-) bone marrow afforded a similar protection against dissecting aneurysm formation. Moreover, lack of CD40L protected mice from fatal aneurysm rupture. T helper cell and macrophage accumulation in aneurysmal tissue was reduced in Cd40l(-/-)Apoe(-/-) mice with a concomitant decrease in expression of proinflammatory chemo- and cytokines. In addition, aneurysms of Cd40l(-/-)Apoe(-/-) mice displayed reduced abundance of matrix metalloproteinase-13 and an increase in tissue inhibitor of metalloproteinase-3 while activity of matrix metalloproteinase-2 and matrix metalloproteinase-9 was diminished. CONCLUSIONS: Deficiency of (hematopoietic) CD40L protects against dissecting aneurysm formation and reduces the incidence of fatal rupture. This is associated with a decreased accumulation and activation of inflammatory cells and a dampened protease activity in the arterial wall. |
