PMID- 29167396 OWN - NLM STAT- MEDLINE DCOM- 20180827 LR - 20240314 IS - 1946-6242 (Electronic) IS - 1946-6234 (Print) IS - 1946-6234 (Linking) VI - 9 IP - 417 DP - 2017 Nov 22 TI - Targeting STUB1-tissue factor axis normalizes hyperthrombotic uremic phenotype without increasing bleeding risk. LID - 10.1126/scitranslmed.aam8475 [doi] LID - eaam8475 AB - Chronic kidney disease (CKD/uremia) remains vexing because it increases the risk of atherothrombosis and is also associated with bleeding complications on standard antithrombotic/antiplatelet therapies. Although the associations of indolic uremic solutes and vascular wall proteins [such as tissue factor (TF) and aryl hydrocarbon receptor (AHR)] are being defined, the specific mechanisms that drive the thrombotic and bleeding risks are not fully understood. We now present an indolic solute-specific animal model, which focuses on solute-protein interactions and shows that indolic solutes mediate the hyperthrombotic phenotype across all CKD stages in an AHR- and TF-dependent manner. We further demonstrate that AHR regulates TF through STIP1 homology and U-box-containing protein 1 (STUB1). As a ubiquitin ligase, STUB1 dynamically interacts with and degrades TF through ubiquitination in the uremic milieu. TF regulation by STUB1 is supported in humans by an inverse relationship of STUB1 and TF expression and reduced STUB1-TF interaction in uremic vessels. Genetic or pharmacological manipulation of STUB1 in vascular smooth muscle cells inhibited thrombosis in flow loops. STUB1 perturbations reverted the uremic hyperthrombotic phenotype without prolonging the bleeding time, in contrast to heparin, the standard-of-care antithrombotic in CKD patients. Our work refines the thrombosis axis (STUB1 is a mediator of indolic solute-AHR-TF axis) and expands the understanding of the interconnected relationships driving the fragile thrombotic state in CKD. It also establishes a means of minimizing the uremic hyperthrombotic phenotype without altering the hemostatic balance, a long-sought-after combination in CKD patients. CI - Copyright (c) 2017 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works. FAU - Shashar, Moshe AU - Shashar M AUID- ORCID: 0000-0002-9744-856X AD - Renal Section, Department of Medicine, Boston University School of Medicine, Boston, MA 02118, USA. FAU - Belghasem, Mostafa E AU - Belghasem ME AUID- ORCID: 0000-0002-2097-6882 AD - Department of Pathology and Laboratory Medicine, Boston University School of Medicine, Boston, MA 02118, USA. FAU - Matsuura, Shinobu AU - Matsuura S AUID- ORCID: 0000-0002-3914-5376 AD - Department of Medicine and Whitaker Cardiovascular Institute, Boston University School of Medicine, Boston, MA 02118, USA. FAU - Walker, Joshua AU - Walker J AUID- ORCID: 0000-0002-4197-9978 AD - Renal Section, Department of Medicine, Boston University School of Medicine, Boston, MA 02118, USA. FAU - Richards, Sean AU - Richards S AD - Renal Section, Department of Medicine, Boston University School of Medicine, Boston, MA 02118, USA. FAU - Alousi, Faisal AU - Alousi F AUID- ORCID: 0000-0002-6523-0494 AD - Renal Section, Department of Medicine, Boston University School of Medicine, Boston, MA 02118, USA. FAU - Rijal, Keshab AU - Rijal K AUID- ORCID: 0000-0001-6980-4128 AD - Renal Section, Department of Medicine, Boston University School of Medicine, Boston, MA 02118, USA. FAU - Kolachalama, Vijaya B AU - Kolachalama VB AUID- ORCID: 0000-0002-5312-8644 AD - Department of Medicine and Whitaker Cardiovascular Institute, Boston University School of Medicine, Boston, MA 02118, USA. FAU - Balcells, Mercedes AU - Balcells M AD - Institute of Medical Engineering and Science, Massachusetts Institute of Technology, Cambridge, MA 02139, USA. AD - Biological Engineering Department, Institut Quimic de Sarria, Universitat Ramon Llull, Barcelona 08017, Spain. FAU - Odagi, Minami AU - Odagi M AUID- ORCID: 0000-0002-0334-3565 AD - Tokyo University of Agriculture and Technology, 2-24-16 Naka-cho, Koganei, Tokyo 184-8588, Japan. FAU - Nagasawa, Kazuo AU - Nagasawa K AD - Tokyo University of Agriculture and Technology, 2-24-16 Naka-cho, Koganei, Tokyo 184-8588, Japan. FAU - Henderson, Joel M AU - Henderson JM AUID- ORCID: 0000-0002-9178-1708 AD - Department of Pathology and Laboratory Medicine, Boston University School of Medicine, Boston, MA 02118, USA. FAU - Gautam, Amitabh AU - Gautam A AUID- ORCID: 0000-0002-0969-7866 AD - Department of Surgery, Boston University School of Medicine, Boston, MA 02118, USA. FAU - Rushmore, Richard AU - Rushmore R AD - Department of Anatomy and Neurobiology, Boston University School of Medicine, Boston, MA 02118, USA. FAU - Francis, Jean AU - Francis J AD - Renal Section, Department of Medicine, Boston University School of Medicine, Boston, MA 02118, USA. FAU - Kirchhofer, Daniel AU - Kirchhofer D AD - Department of Early Discovery and Biochemistry, Genentech Inc., South San Francisco, CA 94080, USA. FAU - Kolandaivelu, Kumaran AU - Kolandaivelu K AD - Institute of Medical Engineering and Science, Massachusetts Institute of Technology, Cambridge, MA 02139, USA. AD - Cardiovascular Division, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA. FAU - Sherr, David H AU - Sherr DH AUID- ORCID: 0000-0003-3353-0553 AD - Department of Environmental Health, School of Public Health, Boston University School of Medicine, Boston, MA 02118, USA. FAU - Edelman, Elazer R AU - Edelman ER AUID- ORCID: 0000-0002-7832-7156 AD - Institute of Medical Engineering and Science, Massachusetts Institute of Technology, Cambridge, MA 02139, USA. AD - Cardiovascular Division, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA. FAU - Ravid, Katya AU - Ravid K AD - Department of Medicine and Whitaker Cardiovascular Institute, Boston University School of Medicine, Boston, MA 02118, USA. FAU - Chitalia, Vipul C AU - Chitalia VC AUID- ORCID: 0000-0002-6663-6058 AD - Renal Section, Department of Medicine, Boston University School of Medicine, Boston, MA 02118, USA. vichital@bu.edu. AD - Department of Pathology and Laboratory Medicine, Boston University School of Medicine, Boston, MA 02118, USA. AD - Department of Medicine and Whitaker Cardiovascular Institute, Boston University School of Medicine, Boston, MA 02118, USA. LA - eng GR - P42 ES007381/ES/NIEHS NIH HHS/United States GR - T32 DK007053/DK/NIDDK NIH HHS/United States GR - T32 HL007224/HL/NHLBI NIH HHS/United States GR - R01 GM049039/GM/NIGMS NIH HHS/United States GR - R01 CA175382/CA/NCI NIH HHS/United States GR - R01 HL080442/HL/NHLBI NIH HHS/United States GR - R01 HL132325/HL/NHLBI NIH HHS/United States PT - Journal Article PL - United States TA - Sci Transl Med JT - Science translational medicine JID - 101505086 RN - EC 2.3.2.27 (Stub1 protein, mouse) RN - EC 2.3.2.27 (Ubiquitin-Protein Ligases) SB - IM CIN - Nat Rev Nephrol. 2018 Feb;14(2):72. PMID: 29225344 CIN - Ann Transl Med. 2018 Jun;6(11):225. PMID: 30023388 MH - Analysis of Variance MH - Animals MH - Female MH - Hemorrhage/enzymology/*metabolism/pathology MH - Male MH - Mice MH - Renal Insufficiency, Chronic/enzymology/metabolism/pathology MH - Thrombosis/enzymology/*metabolism/pathology MH - Ubiquitin-Protein Ligases/genetics/*metabolism MH - Uremia/enzymology/*metabolism/pathology PMC - PMC5854487 MID - NIHMS949214 COIS- Competing interests: The authors declare that they have no competing interests. EDAT- 2017/11/24 06:00 MHDA- 2018/08/28 06:00 PMCR- 2018/03/15 CRDT- 2017/11/24 06:00 PHST- 2017/01/24 00:00 [received] PHST- 2017/07/31 00:00 [revised] PHST- 2017/10/04 00:00 [accepted] PHST- 2017/11/24 06:00 [entrez] PHST- 2017/11/24 06:00 [pubmed] PHST- 2018/08/28 06:00 [medline] PHST- 2018/03/15 00:00 [pmc-release] AID - 9/417/eaam8475 [pii] AID - 10.1126/scitranslmed.aam8475 [doi] PST - ppublish SO - Sci Transl Med. 2017 Nov 22;9(417):eaam8475. doi: 10.1126/scitranslmed.aam8475.