Related Experiment Video
Updated: Aug 16, 2026
Induction of Atherosclerotic Plaques Through Activation of Mineralocorticoid Receptors in Apolipoprotein E-deficient Mice
Published on: September 26, 2018
Inhibition of CD40 signaling limits evolution of established atherosclerosis in mice
U Schönbeck1, G K Sukhova, K Shimizu
1Cardiovascular Division, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, 221 Longwood Avenue, LMRC 309, Boston, MA 02115, USA.
Insights
Blocking the CD40/CD40L pathway with anti-CD40L antibodies significantly slowed the progression of established atherosclerosis in mice. This immune intervention also improved plaque stability by altering its cellular and lipid composition.
Area of Science:
- Cardiovascular Research
- Immunology
- Atherosclerosis Pathogenesis
Background:
- Atherosclerosis involves inflammatory pathways, with the CD40/CD40L dyad implicated in its development.
- Previous studies showed CD40 signaling interruption reduced early atheroma formation.
- The effect of CD40 signaling blockade on established atherosclerotic lesions was previously unknown.
Purpose of the Study:
- To investigate whether interrupting CD40 signaling can retard the progression or induce regression of established atherosclerotic lesions.
- To evaluate the impact of anti-CD40L antibody treatment on established atheroma composition.
Main Methods:
- Low-density lipoprotein receptor-deficient mice were fed a high-cholesterol diet for 26 weeks.
- Anti-CD40L antibody treatment was administered during the second half of the diet regimen.
- Lesion progression and composition in the aorta were compared to control groups (rat-IgG or saline).
Main Results:
- Anti-CD40L treatment did not cause regression but significantly reduced the further evolution of established atherosclerotic lesions.
- Lesion progression was notably reduced in the aortic arch, thoracic aorta, and abdominal aorta.
- Treatment favorably altered atheroma composition, decreasing macrophages and lipids while increasing smooth muscle cells and collagen, suggesting enhanced plaque stability.
Conclusions:
- CD40/CD40L signaling is crucial not only in initiating atherogenesis but also in the progression of established atherosclerotic lesions.
- Interruption of CD40/CD40L signaling represents a potential therapeutic strategy for atherosclerosis.
- Targeting this inflammatory pathway may help stabilize atherosclerotic plaques and prevent complications.
Abstract:
Interruption of inflammatory pathways may provide a novel approach to the therapy of atherosclerosis. Recently, we and others have implicated the immune mediator dyad CD40/CD40L (CD40 ligand), which is expressed on endothelial and smooth muscle cells, macrophages, and T lymphocytes within human atherosclerotic lesions, in aspects of atherogenesis and the acute coronary syndromes, including regulation of matrix metalloproteinases, procoagulant activity, cytokines, etc. In vivo, interruption of CD40 signaling reduced the initiation and early phases of atheroma formation in hypercholesterolemic mice. However, whether interruption of CD40 signaling can retard the progression or even regress established lesions remains unknown. We report here that anti-CD40L antibody treatment of randomly assigned low-density lipoprotein receptor-deficient mice during the second half of a 26-week regimen of high-cholesterol diet did not regress, but did significantly reduce further evolution of established atherosclerotic lesions within the aortic arch and particularly the thoracic and abdominal aorta, as compared with control treatment (application of rat-IgG or saline; 13 weeks, continued high-cholesterol diet). In addition to limiting lesion progression, anti-CD40L treatment changed the composition of atheroma in manners thought to favor plaque stability, e.g., reduced relative content of macrophages and lipid, as well as increased relative content of smooth muscle cells and collagen. These data implicate CD40/CD40L as crucial mediators not only in the initial events of atherogenesis but also during the evolution of established atheroma. This study lends further support to the importance of this specific inflammatory signaling pathway in atherosclerosis and its complications.
