ATHEROSCLEROSIS, CANCER AND WOUND HEALING; THE SYSTEMS BIOLOGY CONNECTION



Alexandra R. Lucas, M.D., Department Medicine, Division Cardiology, University of Florida, USA

Serpins have critical regulatory roles in coagulation, inflammatory, and apoptosis, representing a large percentage of circulating proteins. Genetic serpin mutations cause severe disorders such as deficiency in alpha1 antitrypsin and neuroserpin or in sepsis with disseminated intravascular coagulation. Modified serpin activity is used in treating clinical disorders, i.e. heparin decreases clotting through activation of anti-thrombin (SERPINC1) and alpha anti-trypsin replacement (SERPINA1) is given to patients with genetic deficiency and emphysema. Prior studies report the use of serpin peptides for treatment in sepsis and HIV. Our research group is examining virus-derived serpins as potential therapeutics. Prior work demonstrated significant reductions in vascular disease with the Myxomaviral serpin, Serp-1, in models of arterial balloon angioplasty and aortic, renal and cardiac transplants. Serp-1 treatment also improved mortality in lethal Mouse gamma herpes virus (MHV68) infection where we detected marked reductions in pulmonary hemorrhage and congestion Serp-1 has also been tested in a phase 2A clinical trial after coronary stent implant for patients with unstable coronary syndromes (NSTEMI) with a demonstrated significant reduction in markers for myocardial damage. Another Myxomavirus derived serpin, Serp-2, that targets the infammasome and apoptotic pathways markedly reduced anti-inflammatory activity in animal models of vascular surgery, ischemia reperfusion injury and transplant, whereas CrmA from Cowpox was inactive. Related work using mammalian serpins such as neuroserpin (SERPINI1) also demonstrated anti-inflammatory activity and reduced tumor growth in animal models. In recent work we assessed the capacity of serpin reactive center loop (RCL) peptides to expand serpin functions and reduce inflammatory responses detecting reductions in plaque growth in an aortic transplant models and improved survival in lethal MHV68 infection model. In conclusion, viral serpins have evolved over many millions of years to form highly efficient regulators of central inflammatory pathways, identifying shared pathogenic pathways driving disease and new therapeutic horizons.