SHAPE Society

1. Editorial Slides
VP Watch – August 28, 2002 - Volume 2, Issue 34
CD40 Links Atherosclerosis to
Thrombosis?

2.  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.

3.  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.

4.  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

5.  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

6.  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.

7.  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

8.  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

9.  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

10. 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.

11. 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?

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

13. 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