title: Inhibition of Thrombin With PPACK-Nanoparticles Restores Disrupted Endothelial Barriers and Attenuates Thrombotic Risk in Experimental Atherosclerosis.
abstract: OBJECTIVE
  A role for thrombin in the pathogenesis of atherosclerosis has been suggested through clinical and experimental studies revealing a critical link between the coagulation system and inflammation. Although approved drugs for inhibition of thrombin and thrombin-related signaling have demonstrated efficacy, their clinical application to this end may be limited because of significant potential for bleeding side effects. Thus, we sought to implement a plaque-localizing nanoparticle-based approach to interdict thrombin-induced inflammation and hypercoagulability in atherosclerosis.
  
  
  RESULTS
  We deployed a novel magnetic resonance spectroscopic method to quantify the severity of endothelial damage for correlation with traditional metrics of vessel procoagulant activity after dye-laser injury in fat-fed apolipoprotein E-null mice. We demonstrate that a 1-month course of treatment with antithrombin nanoparticles carrying the potent thrombin inhibitor PPACK (d-phenylalanyl-l-prolyl-l-arginyl chloromethylketone) nanoparticle (1) reduces the expression and secretion of proinflammatory and procoagulant molecules, (2) diminishes plaque procoagulant activity without the need for systemic anticoagulation, (3) rapidly restores disrupted vascular endothelial barriers, and (4) retards plaque progression in lesion-prone areas.
  
  
  CONCLUSIONS
  These observations illustrate the role of thrombin as a pleiotropic atherogenic molecule under conditions of hypercholesterolemia and suggest the utility of its inhibition with locally acting antithrombin nanoparticle therapeutics as a rapid-acting anti-inflammatory strategy in atherosclerosis to reduce thrombotic risk.
authors.affiliation: From the Department of Biomedical Engineering (R.U.P., S.A.W.), and Department of Medicine (A.P.J., H.P., S.A.W.), Washington University in St Louis, MO; and Department of Pharmacology, University of Pennsylvania, Philadelphia (J.W.M.).
authors.forename: Rohun U
authors.initials: RU
authors.lastname: Palekar
authors.affiliation: From the Department of Biomedical Engineering (R.U.P., S.A.W.), and Department of Medicine (A.P.J., H.P., S.A.W.), Washington University in St Louis, MO; and Department of Pharmacology, University of Pennsylvania, Philadelphia (J.W.M.).
authors.forename: Andrew P
authors.initials: AP
authors.lastname: Jallouk
authors.affiliation: From the Department of Biomedical Engineering (R.U.P., S.A.W.), and Department of Medicine (A.P.J., H.P., S.A.W.), Washington University in St Louis, MO; and Department of Pharmacology, University of Pennsylvania, Philadelphia (J.W.M.).
authors.forename: Jacob W
authors.initials: JW
authors.lastname: Myerson
authors.affiliation: From the Department of Biomedical Engineering (R.U.P., S.A.W.), and Department of Medicine (A.P.J., H.P., S.A.W.), Washington University in St Louis, MO; and Department of Pharmacology, University of Pennsylvania, Philadelphia (J.W.M.).
authors.forename: Hua
authors.initials: H
authors.lastname: Pan
authors.affiliation: From the Department of Biomedical Engineering (R.U.P., S.A.W.), and Department of Medicine (A.P.J., H.P., S.A.W.), Washington University in St Louis, MO; and Department of Pharmacology, University of Pennsylvania, Philadelphia (J.W.M.). wicklines@aol.com.
authors.forename: Samuel A
authors.initials: SA
authors.lastname: Wickline
mesh_terms: D000590:Amino Acid Chloromethyl Ketones / Q000493:pharmacokinetics / Q000494:pharmacology*; D000818:Animals; D000991:Antithrombins / Q000493:pharmacokinetics / Q000494:pharmacology*; D001057:Apolipoproteins E / Q000172:deficiency / Q000235:genetics; D050197:Atherosclerosis / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D001777:Blood Coagulation / Q000187:drug effects; D002199:Capillary Permeability / Q000187:drug effects*; D020212:Carotid Artery Injuries / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D002478:Cells, Cultured; D059305:Diet, High-Fat; D004195:Disease Models, Animal; D042783:Endothelial Cells / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D004730:Endothelium, Vascular / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D006801:Humans; D018836:Inflammation Mediators / Q000378:metabolism; D009682:Magnetic Resonance Spectroscopy; D008297:Male; D018345:Mice, Knockout; D053758:Nanoparticles; D058226:Plaque, Atherosclerotic; D015398:Signal Transduction / Q000187:drug effects; D013917:Thrombin / Q000037:antagonists & inhibitors* / Q000378:metabolism; D013927:Thrombosis / Q000235:genetics / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control*; D013997:Time Factors
chemical_list: D000590:Amino Acid Chloromethyl Ketones; D000991:Antithrombins; D001057:Apolipoproteins E; D018836:Inflammation Mediators; D013917:Thrombin; C040308:phenylalanyl-prolyl-arginine-chloromethyl ketone
keywords: atherosclerosis; endothelium; inflammation; nanoparticles; thrombin inhibitors