Complement Blocking Therapeutic Strategies: A Prospective Approach for the Treatment of Cardiovascular Diseases

Despite huge improvements in clinical diagnosis as well as numerous options in patient care and treatment, the incidence of cardiovascular disease (CVD) has been on the rise in the last decade potentially due to hitherto deteriorating lifestyle. As a chronic inflammatory response of the arterial vessel wall, atherosclerosis and its clinical sequelae such as coronary heart disease, cerebrovascular disease and peripheral artery disease continue to be the leading causes of morbidity and mortality worldwide. This makes it necessary to explore novel therapeutic strategies to control and manipulate the mediators of atherosclerosis and cardiac repair processes in order to help combat cardiovascular events. The complement system, an important part of the innate immune response, constitutes a complex network of plasma proteins and membrane cofactors which act in concert with other immunological systems of the body for a rapid defense against foreign intrusions and infections. Activation of the complement cascade in CVD is well established. Numerous well-conducted studies on targeting specific components of the complement cascade in CVD have opened avenues for targeted pharmacological inhibition of the complement system at different levels of complement activation. The use of gene targeting and neutralizing antibodies as well as small molecule inhibitors in animal models of human CVD has provided a clear beneficial role for blocking complement C5, C5a, C5a receptor (C5aR1, CD88) and the soluble complement receptor 1 (sCR1) and different regulators at C3 convertase level. Moreover, the discovery of the second receptor for C5a, the C5aR2 (C5L2, C5a receptor-like 2) and recent studies on the functional role in atherosclerosis has raised the intriguing possibility of the use of this receptor as a novel antiinflammatory strategy. Though work is still in progress to determine whether there is a global effect of this receptor in pathogenesis of cardiovascular disease, there is no doubt that complement blocking strategies is an emerging field in medical pharmacology.

Keywords: Atherosclerosis, Cardiac and vascular remodelling, Cardiovascular disease, Complement inhibitors, Complement system and activation, Myocardial infarction.