C5a: a promising therapeutic target
Thursday, March 24, 2016
Short summary related to C5a from Wezel, A; Innate immune modulation in atherosclerosis and vascular remodeling, dissertation University Leiden 2014
High numbers of activated mast cells are detected in the rupture-prone shoulder regions of human atherosclerotic plaques. An increased amount of mast cells in the plaque of patients suffering from carotid artery stenosis is even found to correlate with intraplaque hemorrhage and the occurrence of future cardiovascular events. Moreover, a causal role is established linking mast cell activation to both atherosclerotic plaque growth and destabilization.
Mast cell activation in the context of atherosclerosis may be induced by various ligands. For instance, the bioactive lysophospholipid acid (LPA) is present in atherosclerotic plaques, and local administration of LPA in apoE-/- mice results in increased mast cell activation and plaque destabilization. Other mast cell ligands present in the atherosclerotic plaque include C5a, substance P, neuropeptide Y, and oxidized LDL, which may all contribute to mast cell activation, with subsequent aggravation of atherosclerosis.
Instead of complete mast cell stabilization, a different approach may also be used, for instance via the inhibition of a specific ligand responsible for one route of mast cell activation in the setting of atherosclerosis. One of these ligands which may be advantageous for drug targeting is complement factor C5a. Research has demonstrated adverse effects for C5a mediated mast cell activation on vein graft lesion development. Moreover, we have demonstrated that C5a itself has direct effects on late stage lesional disruptions, indeed making C5a a promising therapeutic target. Previous studies have reported increased serum levels of C5a in patients with CVD; also, high C5a serum levels directly before stent placement have been correlated with increased in-stent restenosis. The therapeutic potential in cardiovascular disease of a C5 inhibitor, the monoclonal antibody Pexelizumab, has already been tested in phase III trials. For instance, patients undergoing coronary artery bypass surgery and reperfusion therapy for myocardial infarction have received treatment with Pexelizumab. Interestingly, a systemic meta-analysis pointed out that Pexelizumab was associated with a 26% reduction in risk of death after coronary artery bypass surgery.
Taken together, these data indicate that C5a may be a promising therapeutic target in the treatment of cardiovascular disease.