Regulated complement deposition on the surface of human endothelial cells: Effect of tobacco smoke and shear stress

Abstract

Cigarette smoke and hemodynamic stress both contribute to vascular inflammation and associated atherosclerosis. We recently demonstrated direct activation of complement components C4 and C3 on human endothelial cells (EC). The present study was designed to explore complement activation on bone marrow microvascular endothelial cells (BMEC) and human umbilical vein endothelial cells (HUVEC) in response to endothelial cell injury by tobacco smoke extract, shear stress, or other known inflammatory and atherogenic mediators, lipopolysaccharide (LPS) and INF-γ. Following treatment, confluent EC monolayers were exposed to plasma (60 min, 37 °C), and cell surface deposition of stable complement derivatives C4d, iC3b and SC5b-9 was measured in situ using an ELISA approach. Consistent with previous results, moderate levels of C4d, iC3b and SC5b-9 deposition were observed on native EC monolayers exposed to human plasma. Tobacco smoke and shear stress enhanced EC C4d deposition. In contrast, LPS and INF-γ failed to affect EC mediated complement activation, despite evidence of EC activation illustrated by ICAM-1 expression. The combination of tobacco smoke and shear stress nearly doubled EC C4d expression. No increases in iC3b or SC5b-9 were noted, suggesting inhibition of classical and alternative pathway C3 convertase assembly or activity. Indeed, concomitantly increased surface expression of complement regulatory proteins CD35 (CR1) and CD55 was observed following EC exposure to tobacco smoke and shear stress. These results suggest that a balance between complement activation and regulation exists at the EC surface, and may impact vascular injury leading to thrombosis, arteriosclerosis, and atherogenesis.

The tag SNP rs10746463 in decay-accelerating factor is associated with the susceptibility to gastric cancer

“…Another study indicated that tobacco smoke enhanced classical pathway complement activation on human endothelial cells (Yin et al, 2008). As a key regulator of C3, DAF was induced by tobacco smoke on human endothelial cells (Yin et al, 2008).…”

“…In vitro, aqueous whole cigarette smoke solution can modify C3 and activate the alternative pathway of complement (Kew et al, 1985). Another study indicated that tobacco smoke enhanced classical pathway complement activation on human endothelial cells (Yin et al, 2008). As a key regulator of C3, DAF was induced by tobacco smoke on human endothelial cells (Yin et al, 2008).…”

Smoke Exposure Causes Endoplasmic Reticulum Stress and Lipid Accumulation in Retinal Pigment Epithelium through Oxidative Stress and Complement Activation

“…Self-cells are protected from complement activation by the expression of membrane-bound complement inhibitory molecules and soluble serum inhibitors that prevent self-cell complement-mediated injury. However, because the levels, as well as the cellular localization, of these inhibitors can be influenced by environmental factors such as oxidative stress (12) or cigarette smoke (13,14), self-cell surfaces can become targets of complement activation. For example, in AMD, changes in levels and localization of CFH and CD55 (15), CD46 (16), as well as CD59 (17) have been reported in RPE, BrM, and choroid, and have been associated with increased cellular deposition of complement C3 and membrane attack complex in tissue samples (4,18) of patients.…”

Mother and Child Reunion in “Hypertensive” End-Stage Renal Disease: Will They Complement Each Other?

“…The phenotype of patients with a single defect in CD46, however, is rather benign and often is localized to the kidneys, although relapses are common [11,12]. In our case, we therefore assume that ESRD developed on the background of smoldering disease activity as substantiated by his previous medical history and the presence of chronic rather than active TMA on kidney biopsy; hypertension, however, can aggravate complement activation [16] and TMA, leading to a vicious circle via ischemia and activation of the renin-angiotensin system. Furthermore, renin can enhance complement activation via cleavage of C3 [17].…”