C5a Receptor Targeting in Neointima Formation After Arterial Injury in Atherosclerosis-Prone Mice

Abstract

Background-Receptor binding of complement C5a leads to proinflammatory activation of many cell types, but the role of receptor-mediated action during arterial remodeling after injury has not been studied. In the present study, we examined the contribution of the C5a receptor (C5aR) to neointima formation in apolipoprotein E-deficient mice employing a C5aR antagonist (C5aRA) and a C5aR-blocking monoclonal antibody. Methods and Results-Mice fed an atherogenic diet were subjected to wire-induced endothelial denudation of the carotid artery and treated with C5aRA and anti-C5aR-blocking monoclonal antibody or vehicle control. Compared with controls, neointima formation was significantly reduced in mice receiving C5aRA or anti-C5aR-blocking monoclonal antibody for 1 week but not for 3 weeks, attributable to an increased content of vascular smooth muscle cells, whereas a marked decrease in monocyte and neutrophil content was associated with reduced vascular cell adhesion molecule-1. As assessed by immunohistochemistry, reverse transcription polymerase chain reaction, and flow cytometry, C5aR was expressed in lesional and cultured vascular smooth muscle cells, upregulated by injury or tumor necrosis factor-␣, and reduced by C5aRA. Plasma levels and neointimal plasminogen activator inhibitor-1 peaked 1 week after injury and were downregulated in C5aRA-treated mice. In vitro, C5a induced plasminogen activator inhibitor-1 expression in endothelial cells and vascular smooth muscle cells in a C5aRA-dependent manner, possibly accounting for higher vascular smooth muscle cell immigration. Conclusions-One-week treatment with C5aRA or anti-C5aR-blocking monoclonal antibody limited neointimal hyperplasia and inflammatory cell content and was associated with reduced vascular cell adhesion molecule-1 expression. 3 and adverse cardiovascular events have been correlated with C5a plasma levels. 4 C5a is a potent soluble anaphylotoxic and chemotactic inflammatory mediator promoting the recruitment and activation of neutrophils and monocytes. 5 C5a specifically binds to its receptor C5aR (also named CD88), a rhodopsin-type receptor expressed in various cell types. In addition to immune cells (neutrophils, eosinophils, basophils, monocytes/macrophages, mast cells, dendritic cells, and T cells), C5aR has also been detected in nonimmune cells, including neuronal and endothelial cells (ECs), and in different tissues (lung, kidney, liver, spleen, intestine, skin, and heart). 6 Binding of C5a to C5aR leads to cellular activation, including adhesion and chemotaxis. 7 Enhanced surface and messenger RNA (mRNA) expression of C5aR was found in microvascular ECs after exposure to lipopolysaccharide, interferon-␥, and interleukin-6, concomitant with an upregulation of macrophage-inflammatory protein-2/ CXCL2 and macrophage chemoattractant protein-1/CCL2. 8 Stimulation of ECs with C5a increases the gene expression of adhesion molecules, 9,10 cytokines, chemokines, and related receptors. 9,11 Clinical Perspective on p 1036In C5aR-deficient mice, IgG...

Complement 5a Receptor Mediates Angiotensin II–Induced Cardiac Inflammation and Remodeling

“…12,13 Although our data showed macrophages to be the dominant C5aR-expressing cells in Ang II-infused mouse hearts, they do not exclude the possibility of a low-level C5aR expression on cardiomyocytes and myofibroblasts that nevertheless could have played a critical role in the cardiac inflammation and injury. To assess the role of C5aR expression on leukocytes in this model, we created C5aR-chimeric mice using bone marrow (BM) transplantation.…”

International Union of Basic and Clinical Pharmacology. LXXXVII. Complement Peptide C5a, C4a, and C3a Receptors

“…The potency of JPE-1375 is comparable with PMX53, but the former has increased stability in liver microsome preparations. JPE-1375 has been discontinued (Qu et al, 2009) despite showing some promise in AMD (Ricklin and Lambris, 2007), renal allograft survival (Gueler et al, 2008), experimental tubulointerstitial fibrosis (Boor et al, 2007), and atherosclerotic plaque stabilization (Shagdarsuren et al, 2010). The hexadepsipeptide L156,602 (Fig.…”

Endogenous cannabinoid receptor CB1 activation promotes vascular smooth-muscle cell proliferation and neointima formation

“…Interestingly, the reduction of 2-AG levels was found in both apoE Ϫ / Ϫ and apoE and 28 days after injury (data not shown). We may speculate that neutrophils are rarely recruited to neointimal lesions, although their presence in neointimal lesions and their pathophysiological role has been previously evidenced ( 26,27 ). In particular, neutrophil-derived granule proteins were shown to play a protective role by promoting reendothelialization ( 27 ).…”