Angiotensin II modulates CD40 expression in vascular smooth muscle cells

Abstract

The signalling pathway CD40/CD40L (CD40 ligand) plays an important role in atherosclerotic plaque formation and rupture. AngII (angiotensin II), which induces oxidative stress and inflammation, is also implicated in the progression of atherosclerosis. In the present study, we tested the hypothesis that AngII increases CD40/CD40L activity in vascular cells and that ROS (reactive oxygen species) are part of the signalling cascade that controls CD40/CD40L expression. Human CASMCs (coronary artery smooth muscle cells) in culture exposed to IL (interleukin)-1beta or TNF-alpha (tumour necrosis factor-alpha) had increased superoxide generation and enhanced CD40 expression, detected by EPR (electron paramagnetic resonance) and immunoblotting respectively. Both phenomena were abolished by previous incubation with membrane-permeant antioxidants or cell transfection with p22(phox)antisense. AngII (50-200 nmol/l) induced an early and sustained increase in CD40 mRNA and protein expression in CASMCs, which was blocked by treatment with antioxidants. Increased CD40 expression led to enhanced activity of the pathway, as AngII-treated cells stimulated with recombinant CD40L released higher amounts of IL-8 and had increased COX-2 (cyclo-oxygenase-2) expression. We conclude that AngII stimulation of vascular cells leads to a ROS-dependent increase in CD40/CD40L signalling pathway activity. This phenomenon may be an important mechanism modulating the arterial injury observed in atherosclerosis-related vasculopathy.

A critical role for both CD40 and VLA5 in angiotensin Il–mediated thrombosis and inflammation

“…Clinical reports describe blunted increases in plasma CD40L in patients who were treated with the Ang‐II receptor antagonist, losartan (26, 27), and experimental models have revealed that Ang‐II elicits an increased expression of CD40 and CD40L in different cell populations (25, 31). Furthermore, CD40L deficiency protects against endothelial dysfunction, platelet hyper‐reactivity, and hypercoagulability that accompanies chronic Ang‐II infusion (31).…”

Angiotensin II upregulates the expression of placental growth factor in human vascular endothelial cells and smooth muscle cells

“…Many studies have shown that inhibition of the RAS could reduce inflammation and oxidative stress [5]. Angiotensin II (Ang II), one of the major effectors of the RAS, is a cytokine that regulates cell growth, inflammation and fibrosis contributing to the progression of vascular damage [4,6,7]. Ang II participates in atherosclerosis pathogenesis by inducing inflammation and apoptosis, facilitating absorption of oxidative low density lipoprotein, generating oxygenic radicals and impacting fibrinolysis function [7].…”

CD40 Ligand: A neo-inflammatory molecule in vascular diseases

“…In addition to MMPs, CD40L was shown to stimulate SMCs to secrete cytokines such as MCP-1, IL-1␤, IL-6, and IL-8 (Lutgens and Daemen 2002;Mukundan et al 2004), contributing further to lesion progression and subsequent instability and rupture. It is worth noting at this point that an increased CD40 expression as well as activity has been reported in SMCs treated with the proatherogenic factors, Ang II and ET-1, via reactive oxygen specie (ROS) and NF-B pathways, respectively, emphasizing as such the important role of CD40L/CD40 dyad in atherosclerosis, as well as the synergy between various vasoactive factors and molecules in disease development (Browatzki et al 2007;Souza et al 2009). The atherogenic function of CD40L/CD40 dyad could even extend to the myofibroblast population in the atherosclerotic lesion.…”