Fibrinogen interaction with complement C3: a potential therapeutic target to reduce thrombosis risk.

Complement C3 binds fibrinogen and compromises fibrin clot lysis thereby enhancing thrombosis risk. We investigated the role of fibrinogen-C3 interaction as a novel therapeutic target to reduce thrombosis risk by analysing: i) consistency in the fibrinolytic properties of C3, ii) binding sites between fibrinogen and C3 and iii) modulation of fibrin clot lysis by manipulating fibrinogen-C3 interactions. Purified fibrinogen and C3 from the same individuals (n=24) were used to assess inter-individual variability in the anti-fibrinolytic effects of C3. Microarray screening and molecular modelling evaluated C3 and fibrinogen interaction sites. Novel synthetic conformational proteins, termed Affimers, were used to modulate C3-fibrinogen interaction and fibrinolysis. C3 purified from patients with type 1 diabetes showed enhanced prolongation of fibrinolysis compared with healthy control protein [195±105 and 522±166 seconds, respectively (p=0.04)], with consistent effects but a wider range (5-51% and 5-18% lysis prolongation, respectively). Peptide microarray screening identified 2 potential C3-fibrinogen interactions sites within fibrinogen ß chain (residues 424-433, 435-445). One fibrinogen-binding Affimer was isolated that displayed sequence identity with C3 in an exposed area of the protein. This Affimer abolished C3-induced prolongation of fibrinolysis (728±25.1 seconds to 632±23.7 seconds, p=0.005) and showed binding to fibrinogen in the same region that is involved in C3-fibrinogen interactions. Moreover, it shortened plasma clot lysis of patients with diabetes, cardiovascular disease or controls by 7-11%. C3 binds fibrinogen ß-chain and disruption of fibrinogen-C3 interaction using Affimer proteins enhances fibrinolysis, which represents a potential novel target tool to reduce thrombosis in high risk individuals.

Vascular risk in obesity: Facts, misconceptions and the unknown.

Obesity is a major burden on healthcare systems worldwide due to the association with numerous complications, arguably the most important of which are the development of type 2 diabetes and cardiovascular disease. Both are thought to develop from similar origins and occur at variable rates in obese individuals, including those with similar body mass indices. This phenomenon is likely a result of an increased susceptibility for the storage of excess fat in the wrong place, namely, ectopic fat surrounding the liver, pancreas and muscles. This triggers a concatenation of events leading to insulin resistance and inflammation which culminate in an increased atherothrombotic potential due to the dysfunction of vascular endothelial cells causing accelerated atherosclerotic plaque formation and a pro-thrombotic phenotype. The degree of weight loss following different interventions is well documented but it is less widely known what effect weight loss by various means has on the deleterious process mentioned above, in particular their effects on cardiovascular events. This review summarises the processes leading to increased vascular risk in obesity and examines the effects of currently available weight loss strategies on reversing these processes and how this translates to cardiovascular disease.