title: Reduced thrombosis in Klkb1-/- mice is mediated by increased Mas receptor, prostacyclin, Sirt1, and KLF4 and decreased tissue factor.
abstract: The precise mechanism for reduced thrombosis in prekallikrein null mice (Klkb1(-/-)) is unknown. Klkb1(-/-) mice have delayed carotid artery occlusion times on the rose bengal and ferric chloride thrombosis models. Klkb1(-/-) plasmas have long-activated partial thromboplastin times and defective contact activation-induced thrombin generation that partially corrects upon prolonged incubation. However, in contact activation-induced pulmonary thromboembolism by collagen/epinephrine or long-chain polyphosphate, Klkb1(-/-) mice, unlike F12(-/-) mice, do not have survival advantage. Klkb1(-/-) mice have reduced plasma BK levels and renal B2R mRNA. They also have increased expression of the renal receptor Mas and plasma prostacyclin. Increased prostacyclin is associated with elevated aortic vasculoprotective transcription factors Sirt1 and KLF4. Treatment of Klkb1(-/-) mice with the Mas antagonist A-779, COX-2 inhibitor nimesulide, or Sirt1 inhibitor splitomicin lowers plasma prostacyclin and normalizes arterial thrombosis times. Treatment of normal mice with the Mas agonist AVE0991 reduces thrombosis. Klkb1(-/-) mice have reduced aortic tissue factor (TF) mRNA, antigen, and activity. In sum, Klkb1(-/-) mice have a novel mechanism for thrombosis protection in addition to reduced contact activation. This pathway arises when bradykinin delivery to vasculature is compromised and mediated by increased receptor Mas, prostacyclin, Sirt1, and KLF4, leading to reduced vascular TF.
authors.affiliation: Divisions of Hematology and Oncology, Department of Medicine, Case Western Reserve University, Cleveland, OH; Department of Medicine, Louis Stokes Veterans Administration Hospital, Cleveland, OH;
authors.forename: Evi X
authors.initials: EX
authors.lastname: Stavrou
authors.affiliation: Divisions of Hematology and Oncology, Department of Medicine, Case Western Reserve University, Cleveland, OH; Department of Pathology, Case Western Reserve University, Cleveland, OH;
authors.forename: Chao
authors.initials: C
authors.lastname: Fang
authors.affiliation: Divisions of Hematology and Oncology, Department of Medicine, Case Western Reserve University, Cleveland, OH;
authors.forename: Alona
authors.initials: A
authors.lastname: Merkulova
authors.affiliation: Divisions of Hematology and Oncology, Department of Medicine, Case Western Reserve University, Cleveland, OH;
authors.forename: Omar
authors.initials: O
authors.lastname: Alhalabi
authors.affiliation: Department of Pharmacology and Toxicology, Wright State University Boonshoft School of Medicine, Dayton OH; and.
authors.forename: Nadja
authors.initials: N
authors.lastname: Grobe
authors.affiliation: Department of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, NC.
authors.forename: Silvio
authors.initials: S
authors.lastname: Antoniak
authors.affiliation: Department of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, NC.
authors.forename: Nigel
authors.initials: N
authors.lastname: Mackman
authors.affiliation: Divisions of Hematology and Oncology, Department of Medicine, Case Western Reserve University, Cleveland, OH; Department of Pathology, Case Western Reserve University, Cleveland, OH;
authors.forename: Alvin H
authors.initials: AH
authors.lastname: Schmaier
mesh_terms: D000804:Angiotensin II / Q000031:analogs & derivatives / Q000494:pharmacology; D000818:Animals; D002341:Carotid Artery Thrombosis / Q000139:chemically induced / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D011464:Epoprostenol / Q000096:biosynthesis / Q000235:genetics; D007093:Imidazoles / Q000494:pharmacology; D000090062:Kruppel-Like Factor 4; D051741:Kruppel-Like Transcription Factors / Q000037:antagonists & inhibitors / Q000096:biosynthesis / Q000235:genetics; D051379:Mice; D018345:Mice, Knockout; D009281:Naphthalenes / Q000494:pharmacology; D009419:Nerve Tissue Proteins / Q000096:biosynthesis / Q000235:genetics; D010314:Partial Thromboplastin Time; D010446:Peptide Fragments / Q000494:pharmacology; D011288:Prekallikrein; D000090063:Proto-Oncogene Mas; D011518:Proto-Oncogene Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D011753:Pyrones / Q000494:pharmacology; D012333:RNA, Messenger; D043782:Receptor, Bradykinin B2 / Q000096:biosynthesis / Q000235:genetics; D043562:Receptors, G-Protein-Coupled / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D056564:Sirtuin 1 / Q000037:antagonists & inhibitors / Q000096:biosynthesis / Q000235:genetics; D013449:Sulfonamides / Q000494:pharmacology; D050857:Synaptotagmins / Q000096:biosynthesis / Q000235:genetics; D013925:Thromboplastin / Q000037:antagonists & inhibitors / Q000096:biosynthesis / Q000235:genetics
chemical_list: C092006:7-Ala-angiotensin (1-7); C469726:AVE 0991; D007093:Imidazoles; C000715468:Klf4 protein, mouse; D000090062:Kruppel-Like Factor 4; D051741:Kruppel-Like Transcription Factors; D009281:Naphthalenes; D009419:Nerve Tissue Proteins; D010446:Peptide Fragments; D000090063:Proto-Oncogene Mas; D011518:Proto-Oncogene Proteins; D011753:Pyrones; D012333:RNA, Messenger; D043782:Receptor, Bradykinin B2; D043562:Receptors, G-Protein-Coupled; D013449:Sulfonamides; C498723:Syt17 protein, mouse; D000804:Angiotensin II; D050857:Synaptotagmins; C444426:splitomicin; D013925:Thromboplastin; D011288:Prekallikrein; D011464:Epoprostenol; C470545:Sirt1 protein, mouse; D056564:Sirtuin 1; C012655:nimesulide