Carbon monoxide and nitric oxide modulate α₂-antiplasmin and plasmin activity: role of heme.
Cigarette smoke and carbon monoxide (CO) released from tricarbonyldichlororuthenium (II) dimer (CORM-2) attenuate fibrinolysis. The purpose of the present study was to determine whether CO diminished fibrinolysis by enhancement of α₂-antiplasmin via a putative heme group. Plasma, isolated α₂-antiplasmin and isolated plasmin were exposed to CO released from CORM-2 and nitric oxide (NO) via a NO donor to induce carboxyheme and metheme states, respectively. Exposed, isolated enzymes were placed in either α₂-antiplasmin-deficient or normal plasma. Effects of CO and NO on tissue-type plasminogen activator initiated fibrinolysis were determined by thrombelastography. Liquid chromatography-mass spectrometry (LC-MS/MS) was used to identify heme released from α₂-antiplasmin and plasmin. CO significantly enhanced α₂-antiplasmin activity, but decreased plasmin activity. NO decreased both α₂-antiplasmin and plasmin activity. Although inadequate LC-MS/MS data were obtained with α₂-antiplasmin (secondary to glycosylation), a putative plasmin-associated heme was identified. CO elicits hypofibrinolysis by enhancing α₂-antiplasmin activity and decreasing plasmin activity. On the basis of the responses to NO and LC-MS/MS data, it is highly likely that both enzymes are modulated by attached heme groups. Efforts to develop methods to detect CO-mediated hypercoagulability are ongoing, with the goal of identifying populations at risk of thrombotic morbidity secondary to cigarette smoking.
Department of Anesthesiology, Drexel University College of Medicine, Philadelphia, Pennsylvania, USA.
Matthew R
MR
Arkebauer
Sri S
SS
Kanaparthy
Saninuj N
SN
Malayaman
Keith
K
Vosseller
Vance G
VG
Nielsen
D000933:Antifibrinolytic Agents / Q000494:pharmacology; D002248:Carbon Monoxide / Q000378:metabolism*; D002853:Chromatography, Liquid; D004305:Dose-Response Relationship, Drug; D005341:Fibrinolysin / Q000494:pharmacology*; D005342:Fibrinolysis / Q000187:drug effects*; D006418:Heme / Q000378:metabolism*; D006801:Humans; D006834:Hydrazines / Q000494:pharmacology; D006898:Hydroxylamines / Q000494:pharmacology; D009569:Nitric Oxide / Q000378:metabolism*; D009942:Organometallic Compounds / Q000494:pharmacology; D010949:Plasma / Q000737:chemistry / Q000378:metabolism; D011485:Protein Binding; D012907:Smoking / Q000009:adverse effects / Q000097:blood*; D053719:Tandem Mass Spectrometry; D013916:Thrombelastography / Q000379:methods*; D013927:Thrombosis / Q000097:blood / Q000473:pathology; D010959:Tissue Plasminogen Activator / Q000097:blood; D000979:alpha-2-Antiplasmin / Q000494:pharmacology*
C105785:1-hexanamine-6-(2-hydroxy-1-methyl-2-nitrosohydrazine)-N-methyl; D000933:Antifibrinolytic Agents; D006834:Hydrazines; D006898:Hydroxylamines; D009942:Organometallic Compounds; D000979:alpha-2-Antiplasmin; C447082:tricarbonyldichlororuthenium (II) dimer; C012484:phenylhydroxylamine; D009569:Nitric Oxide; D006418:Heme; D002248:Carbon Monoxide; D010959:Tissue Plasminogen Activator; D005341:Fibrinolysin