Enhanced Levels of Soluble and Membrane-Bound CD40 Ligand in Patients With Unstable Angina

Abstract

Background-The CD40 ligand (CD40L) on activated T cells and platelets may be activating matrix metalloproteinases, inducing procoagulant activity, and be involved in the pathogenesis of acute coronary syndromes by promoting plaque rupture in atheroma. Methods and Results-To study the role of CD40L-CD40 interaction in coronary disease, we analyzed levels of soluble (s) and membrane-bound CD40L in the peripheral blood from 29 patients with stable angina, 26 with unstable angina, and 19 controls. Our main findings follow.(1) Patients with unstable angina had significantly raised serum levels of sCD40L when compared with patients with stable angina and controls. (2) Platelets could release large amounts of sCD40L when stimulated ex vivo with the thrombin receptor-agonist peptide SFLLRN in both patients and controls. (3) Platelets in patients with unstable angina were characterized ex vivo by decreased intracellular levels and decreased SFLLRN-stimulated release of sCD40L, which may possibly represent a higher percentage of degranulated platelets in these patients. (4) T cells in patients with unstable angina had enhanced surface expression of CD40L and increased release of sCD40L on anti-CD3/anti-CD28 stimulation in vitro when compared with patients with stable angina and controls. (5) Recombinant CD40L and serum from patients with unstable angina who had high sCD40L levels induced enhanced release of monocyte chemoattractant peptide-1 from mononuclear cells, a CC-chemokine involved in the pathogenesis of atherosclerosis. Conclusions-This first demonstration of enhanced levels of soluble and membrane-bound forms of CD40L in angina patients, with particularly high levels in patients with unstable angina, suggests that CD40L-CD40 interaction may play a pathogenic role in both the long-term atherosclerotic process and in the triggering and propagation of acute coronary syndromes. (Circulation. 1999;100:614-620.)

CD40 Ligand–Dependent Tyrosine Nitration of Prostacyclin Synthase In Vivo

“…4,5 In addition to the cell-associated form, CD40L also exists in a soluble, biologically active form (sCD40L), which has similar proinflammatory effects on vascular cells. Interestingly, sCD40L is associated with acute coronary syndromes, 6,7 as well as hypercholesterolemia, 8 and elevated sCD40L levels predict an increased cardiovascular risk in healthy subjects. 9 Therefore, CD40L has been suggested as a potential therapeutic target to modulate vascular inflammation and possibly influence cardiovascular risks.…”

The inflammatory receptor CD40 is expressed on human adipocytes: contribution to crosstalk between lymphocytes and adipocytes

“…While extensive research is dedicated to the effect of an inflammatory reaction on obesity-related insulin resistance, little is known about the triggering pathway of inflammation during obesity. Considerable evidence implicates the proinflammatory CD40 molecule, TNF receptor superfamily member 5 (CD40) ligand (CD40L or CD154) in atherosclerosis [2][3][4], and some recent data identify CD40/CD40L as a potential contributor to inflammation associated with obesity and its metabolic complications. Soluble CD40L (sCD40L) levels are increased in obese [5,6] and type 2 diabetic [7][8][9] individuals, as well as in individuals with the metabolic (insulin resistance) syndrome [10].…”

Plaque, Platelets, and Plug – The Pathogenesis of Acute Coronary Syndrome

“…Upon platelet activation, the cytosolic CD40L protein is exocytosed to the platelet plasma membrane from where it is also shed and release into circulation in soluble form, sCD40L (Andre et al, 2002). These transmembran and soluble forms are detected to be elevated in patients with acute coronary syndrome (Aukrust et al, 1999;Garlichs et al, 2001;Setianto et al, 2010). Both transmembrane and soluble CD40L can form a cluster with platelet IIb 3 and lead to more platelet activation and enhance thrombus formation and stabilization (Andre et al, 2002).…”