Editorial Slides VP Watch – August 28, 2002 - Volume 2, Issue 34

CD40 Links Atherosclerosis to Thrombosis?

Inflammatory processes play a pivotal role in the pathogenesis of atherosclerosis and contributes to different stages of atheroma development from leukocyte recruitment to eventual rupture of the vulnerable plaque. 1

Inflammation links atherosclerosis to thrombosis.

CD40 receptor (CD40) and CD40 ligand (CD40L) are expressed on B and T lymphocytes and platelets.

CD40L is a transmembrane protein of the tumor necrosis factor family.

The role of CD40L in the immune response involves binding to its receptor on B cells, CD40, to induce B-cell proliferation, generate memory B cells, block B-cell apoptosis, and mediate antibody class switching.

Latest studies show that CD40/CD40L system plays an important role not only in cellular immunity and inflammation but also in the pathogenesis of atherosclerotic plaque. 2

CD40/CD40L interaction triggers a predominantly Th1 cytokine–driven inflammation which establishing the immune reaction characteristic for atherogenesis.

Libby et al shown that lipid lowering limits the expression of CD40L in experimental atheroma. 6

CD40/CD40L interactions mediate several of the processes for the progression of atherosclerotic plaques further fatty streak level, and for plaque rupture and its clinical consequences.

Libby, Schönbeck, and colleagues showed co-localization of both CD40 and CD40L on atheroma-associated endothelial cells, SMCs, and macrophages in vitro. 4

Ridker et al showed that high plasma concentrations of sCD40L may be associated with increased vascular risk in apparently healthy women. 7

More than 95% of the circulating CD40L exists in platelets.

André et al discussed three functions for CD40L which released from platelet-rich thrombi: 3

I. Inflammation - Inducing the production and release of cytokines from vascular cells and MMPs from cells in atheroma.

I. Thrombosis - Stabilizing platelet-rich thrombi

II. Restenosis - Inhibiting re-endothelialization of the injured vessel

As reported in VP Watch of this week, Urbich et al. showed that activation of the CD40 receptor by human recombinant CD40L inhibits basal and VEGF-induced endothelial

cell migration, leading to a reduction of re-endothelialization in vitro. 8

They also found that CD40L-induced inhibition of endothelial migration is achieved by generation of free radicals and inhibition of NO production. 8

The authors in this study showed that blockade of endothelial cell migration by CD40L may critically affect endothelial regeneration after injury induced by plaque erosion and thereby may contribute to the increased risk for development of acute coronary events in patients with high circulating levels of CD40L. 8

Conclusion CD40L plays multiple roles in inflammatory aspects of plaque progression, thrombosis, and restenosis.

Activation of CD40 inhibits both endothelial cell migration and angiogenesis.

Inhibitory effect of CD40L was not related to the induction of apoptosis or the blockade of cell cycle progression.

Questions:

• Can CD40L be a major factor in plaque vulnerability? If so which one would be a better marker of vulnerability ; serum CD40L or plaque CD40?

• Knowing elevated level of CD40L in inflammatory disorders like rheumatoid arthritis, can CD40L be a better predictor than CRP?

• Can CD40L predict prognosis after acute coronary syndrome? In other words is CD40L a powerful predictor in both healthy individuals and CAD patients?

Questions:

1) Ross, R. 1999. Atherosclerosis-an inflammatory disease. N. Engl. J. Med. 340:115–126.2) Phipps RP. Atherosclerosis: the emerging role of inflammation and the CD40-CD40 ligand system. Proc Natl Acad

Sci U S A. 2000; 97: 6930–6932 3) Patrick André, Lisa Nannizzi-Alaimo, Srinivasa K. Prasad, and David R. Phillips ; Platelet-Derived CD40L: The

Switch-Hitting Player of Cardiovascular Disease . Circulation 2002 106: 896 4) Schönbeck U, Libby P. The CD40/CD154 receptor/ligand dyad. Cell Mol Life Sci. 2001; 58: 4–43. 5) Henn V, Slupsky JR, Grafe M, Anagnostopoulos I, Forster R, Muller-Berghaus G, Kroczek RA. CD40 ligand on

activated platelets triggers an inflammatory reaction of endothelial cells. Nature 1998;391:591-594. 6) Aikawa M, Voglic SJ, Sugiyama S, Rabkin E, Taubman MB, Fallon JT, Libby P. Dietary lipid lowering reduces tissue

factor expression in rabbit atheroma. Circulation. 1999; 100: 1215–1222 7) Schonbeck U, Varo N, Libby P, Buring J, Ridker PM.Soluble CD40L and cardiovascular risk in women. Circulation.

2001 Nov 6;104(19):2266-8.8) Urbich C, Dernbach E, Aicher A, Zeiher AM, Dimmeler S.

CD40 Ligand Inhibits Endothelial Cell Migration by Increasing Production of Endothelial Reactive Oxygen Species.Circulation. 2002 Aug 20;106(8):981-6.

References