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 - Funding Information:
This work was supported by the following grants. We acknowledge the support from the Netherlands CardioVascular Research Initiative: the Dutch Heart Foundation, Dutch Federation of University Medical Centres, the Netherlands Organisation for Health Research and Development, and the Royal Netherlands Academy of Sciences for the GENIUS project Generating the best evidence-based pharmaceutical targets for atherosclerosis (CVON2011-19). This study was supported by the Deutsche Forschungs Gemeinschaft (SFB 1123 to E. Lutgens, N. Gerdes), the Netherlands Organization for Scientific Research (NWO [Netherlands Scientific Organization]; VICI grant to E. Lutgens 016.130.676), the Dutch Heart Foundation (Dr E. Dekker MD grant to T. Seijkens), the European Union (H2020-PHC-2015–667673, REPROGRAM to E. Lutgens, T. Seijkens), and the European Research Council (ERC consolidator grant to E.L CD40-INN 681492).
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
VL - 38
SP - 1076
EP - 1085
JO - Arteriosclerosis, Thrombosis, and Vascular Biology
JF - Arteriosclerosis, Thrombosis, and Vascular Biology
SN - 1079-5642
IS - 5
ER -