Published online before print March 3, 2005, doi: 10.1161/01.ATV.0000161420.55482.ef
© 2005 American Heart Association, Inc.
Atherosclerosis and Lipoproteins |
Atherogenesis in Mice Does Not Require CD40 Ligand From Bone Marrow–Derived Cells
From Donald W. Reynolds Cardiovascular Clinical Research Center (U.B., A.Z., S.L., L.M., P.L., U.S.), Department of Medicine, Brigham and Women’s Hospital, Harvard Medical School, Boston, Mass; and Cardiology & Angiology (U.B.), Hannover Medical School, Germany. Current affiliation for Uwe Schönbeck: Boehringer Ingelheim Pharmaceutical Inc, Ridgefield, Conn.
Correspondence to Peter Libby, MD, Brigham and Women’s Hospital, 77 Avenue Louis Pasteur, NRB 741, Boston, MA 02115. E-mail plibby{at}rics.bwh.harvard.edu
Objective— Recent research suggests a central role for CD40 ligand (CD40L) in atherogenesis. However, the relevant cellular source of this proinflammatory cytokine remains unknown. To test the hypothesis that CD40L expressed on hematopoietic cell types (eg, macrophages, lymphocytes, platelets) is crucial to atherogenesis, we performed bone marrow reconstitution experiments using low-density receptor-deficient (ldlr–/–) and ldlr–/–/cd40l–/– compound-mutant mice.
Methods and Results— As expected, systemic lack of CD40L in hypercholesterolemic ldlr–/– mice significantly reduced the development of atherosclerotic lesions in the aortic arch, aortic root, and abdominal aorta compared with ldlr–/– mice. Furthermore, atheromata in ldlr–/–/cd40l–/– mice showed reduced accumulation of macrophages and lipids and increased content in smooth muscle cells and collagen compared with ldlr–/– mice. Surprisingly, reconstitution of irradiated ldlr–/– mice with ldlr–/–/cd40l–/– bone marrow did not affect the size or composition of atherosclerotic lesions in the root or arch of hypercholesterolemic ldlr–/– mice. Moreover, lipid deposition in the abdominal aorta diminished only marginally compared with mouse aortas reconstituted with ldlr–/– bone marrow.
Conclusions— These experiments demonstrate that CD40L modulates atherogenesis, at least in mice, primarily by its expression on nonhematopoietic cell types rather than monocytes, T lymphocytes, or platelets, a surprising finding with important pathophysiologic and therapeutic implications.
Although previous studies established CD40L as a mediator of atherogenesis, its relevant cellular source remains unknown. The present study demonstrates that CD40L modulates atherogenesis in mice, primarily by its expression on nonhematopoietic cell types in bone marrow chimeras. This surprising finding has important pathophysiologic and therapeutic implications.
Key Words: atherosclerosis • bone-marrow reconstitution • CD40 ligand • low-density lipoprotein receptor–deficient mice
Related Article:
Arterioscler. Thromb. Vasc. Biol. 2005 25: 1088-1090.
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