TY - JOUR
T1 - CD40L deficiency protects against aneurysm formation
AU - Kusters, Pascal J.H.
AU - Seijkens, Tom T.P.
AU - Beckers, Linda
AU - Lievens, Dirk
AU - Winkels, Holger
AU - De Waard, Vivian
AU - Duijvestijn, Adriaan
AU - Liljeqvist, Moritz Lindquist
AU - Roy, Joy
AU - Daugherty, Alan
AU - Newby, Andrew
AU - Gerdes, Norbert
AU - Lutgens, Esther
N1 - Publisher Copyright:
© 2018 American Heart Association, Inc.
PY - 2018
Y1 - 2018
N2 - 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.
AB - 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.
KW - Aneurysms
KW - Angiotensin II
KW - Cytokines
KW - Inflammation
KW - Matrix metalloproteinase 9
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U2 - 10.1161/ATVBAHA.117.310640
DO - 10.1161/ATVBAHA.117.310640
M3 - Article
C2 - 29519940
AN - SCOPUS:85060467423
SN - 1079-5642
VL - 38
SP - 1076
EP - 1085
JO - Arteriosclerosis, thrombosis, and vascular biology
JF - Arteriosclerosis, thrombosis, and vascular biology
IS - 5
ER -