title: Recombinant soluble apyrase APT102 inhibits thrombosis and intimal hyperplasia in vein grafts without adversely affecting hemostasis or re-endothelialization.
abstract: Essentials New strategies are needed to inhibit thrombosis and intimal hyperplasia (IH) in vein grafts (VG). We studied effects of apyrase (APT102) on VGs and smooth muscle and endothelial cells (SMC/EC). APT102 inhibited thrombosis, SMC migration, and IH without impairing hemostasis or EC recovery. Apyrase APT102 is a single-drug approach to inhibit multiple processes that cause VG failure.
  
  
  
  Background Occlusion of vein grafts (VGs) after bypass surgery, owing to thrombosis and intimal hyperplasia (IH), is a major clinical problem. Apyrases are enzymes that scavenge extracellular ATP and ADP, and promote adenosine formation at sites of vascular injury, and hence have the potential to inhibit VG pathology. Objectives To examine the effects of recombinant soluble human apyrase, APT102, on platelets, smooth muscle cells (SMCs) and endothelial cells (ECs) in vitro, and on thrombosis and IH in murine VGs. Methods SMC and EC proliferation and migration were studied in vitro. Inferior vena cava segments from donor mice were grafted into carotid arteries of recipient mice. Results APT102 potently inhibited ADP-induced platelet aggregation and VG thrombosis, but it did not impair surgical hemostasis. APT102 did not directly inhibit SMC or EC proliferation, but significantly attenuated the effects of ATP on SMC and EC proliferation. APT102 significantly inhibited SMC migration, but did not inhibit EC migration, which may be mediated, at least in part, by inhibition of SMC, but not EC, migration by adenosine. At 4 weeks after surgery, there was significantly less IH in VGs of APT102-treated mice than in control VGs. APT102 significantly inhibited cell proliferation in VGs, but did not inhibit re-endothelialization. Conclusions Systemic administration of a recombinant human apyrase inhibits thrombosis and IH in VGs without increasing bleeding or compromising re-endothelialization. These results suggest that APT102 has the potential to become a novel, single-drug treatment strategy to prevent multiple pathologic processes that drive early adverse remodeling and occlusion of VGs.
authors.affiliation: Departments of Medicine and Medical Pharmacology and Physiology, University of Missouri School of Medicine and the Research Service, Harry S. Truman Memorial Veterans Hospital, Columbia, MO, USA.
authors.forename: Y
authors.initials: Y
authors.lastname: Ji
authors.affiliation: Departments of Medicine and Medical Pharmacology and Physiology, University of Missouri School of Medicine and the Research Service, Harry S. Truman Memorial Veterans Hospital, Columbia, MO, USA.
authors.forename: O
authors.initials: O
authors.lastname: Adeola
authors.affiliation: Departments of Medicine and Medical Pharmacology and Physiology, University of Missouri School of Medicine and the Research Service, Harry S. Truman Memorial Veterans Hospital, Columbia, MO, USA.
authors.forename: T L
authors.initials: TL
authors.lastname: Strawn
authors.affiliation: APT Therapeutics, St Louis, MO, USA.
authors.forename: S S
authors.initials: SS
authors.lastname: Jeong
authors.affiliation: APT Therapeutics, St Louis, MO, USA.
authors.forename: R
authors.initials: R
authors.lastname: Chen
authors.affiliation: Departments of Medicine and Medical Pharmacology and Physiology, University of Missouri School of Medicine and the Research Service, Harry S. Truman Memorial Veterans Hospital, Columbia, MO, USA.
authors.forename: W P
authors.initials: WP
authors.lastname: Fay
mesh_terms: D000241:Adenosine / Q000737:chemistry; D000251:Adenosine Triphosphatases / Q000737:chemistry; D000818:Animals; D001081:Apyrase / Q000494:pharmacology*; D001792:Blood Platelets / Q000166:cytology; D001808:Blood Vessels / Q000637:transplantation*; D002339:Carotid Arteries / Q000473:pathology; D002465:Cell Movement; D049109:Cell Proliferation; D003331:Coronary Vessels / Q000473:pathology; D042783:Endothelial Cells / Q000473:pathology; D004730:Endothelium, Vascular / Q000473:pathology; D006487:Hemostasis; D006801:Humans; D006965:Hyperplasia; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009131:Muscle, Smooth, Vascular / Q000473:pathology; D032389:Myocytes, Smooth Muscle / Q000166:cytology; D010974:Platelet Aggregation; D011517:Prothrombin Time; D011994:Recombinant Proteins / Q000494:pharmacology*; D012995:Solubility; D013927:Thrombosis / Q000188:drug therapy*; D017539:Tunica Intima / Q000187:drug effects* / Q000473:pathology
chemical_list: D011994:Recombinant Proteins; D000251:Adenosine Triphosphatases; C027201:ectoATPase; D001081:Apyrase; D000241:Adenosine
keywords: adenine nucleotides; apyrase; coronary artery bypass; neointima; venous thrombosis