PMID- 29891592 OWN - NLM STAT- MEDLINE DCOM- 20190305 LR - 20190305 IS - 2473-9537 (Electronic) IS - 2473-9529 (Print) IS - 2473-9529 (Linking) VI - 2 IP - 11 DP - 2018 Jun 12 TI - The endothelial tumor suppressor p53 is essential for venous thrombus formation in aged mice. PG - 1300-1314 LID - 10.1182/bloodadvances.2017014050 [doi] AB - Venous thromboembolism (VTE) is a leading cause of morbidity and mortality in elderly people. Increased expression of tumor suppressor protein 53 (p53) has been implicated in vascular senescence. Here, we examined the importance of endothelial p53 for venous thrombosis and whether endothelial senescence and p53 overexpression are involved in the exponential increase of VTE with age. Mice with conditional, endothelial-specific deletion of p53 (End.p53-KO) and their wild-type littermates (End.p53-WT) underwent subtotal inferior vena cava (IVC) ligation to induce venous thrombosis. IVC ligation in aged (12-month-old) End.p53-WT mice resulted in higher rates of thrombus formation and greater mean thrombus size vs adult (12-week-old) End.p53-WT mice, whereas aged End.p53-KO mice were protected from vein thrombosis. Analysis of primary endothelial cells from aged mice or human vein endothelial cells after induction of replicative senescence revealed significantly increased early growth response gene-1 (Egr1) and heparanase expression, and plasma factor Xa levels were elevated in aged End.p53-WT, but not in End.p53-KO mice. Increased endothelial Egr1 and heparanase expression also was observed after doxorubicin-induced p53 overexpression, whereas p53 inhibition using pifithrin-alpha reduced tissue factor (TF) expression. Importantly, inhibition of heparanase activity using TF pathway inhibitor-2 (TFPI2) peptides prevented the enhanced venous thrombus formation in aged mice and restored it to the thrombotic phenotype of adult mice. Our findings suggest that p53 accumulation and heparanase overexpression in senescent endothelial cells are critically involved in mediating the increased risk of venous thrombosis with age and that heparanase antagonization may be explored as strategy to ameliorate the prothrombotic endothelial phenotype with age. CI - (c) 2018 by The American Society of Hematology. FAU - Bochenek, Magdalena L AU - Bochenek ML AD - Center for Cardiology, Cardiology I, and. AD - Center for Thrombosis and Hemostasis, University Medical Center Mainz, Mainz, Germany. AD - Deutsches Zentrum fur Herz-Kreislauf-Forschung e.V., partner site RheinMain, Mainz, Germany. FAU - Bauer, Tobias AU - Bauer T AD - Center for Cardiology, Cardiology I, and. AD - Deutsches Zentrum fur Herz-Kreislauf-Forschung e.V., partner site RheinMain, Mainz, Germany. FAU - Gogiraju, Rajinikanth AU - Gogiraju R AD - Center for Cardiology, Cardiology I, and. FAU - Nadir, Yona AU - Nadir Y AD - Department of Haematology and Bone Marrow Transplantation, Rambam Health Care Campus, Haifa, Israel; and. AD - Technion-Israel Institute of Technology, Haifa, Israel. FAU - Mann, Amrit AU - Mann A AD - Center for Cardiology, Cardiology I, and. AD - Center for Thrombosis and Hemostasis, University Medical Center Mainz, Mainz, Germany. FAU - Schonfelder, Tanja AU - Schonfelder T AD - Center for Thrombosis and Hemostasis, University Medical Center Mainz, Mainz, Germany. FAU - Hunig, Leonie AU - Hunig L AD - Center for Cardiology, Cardiology I, and. AD - Center for Thrombosis and Hemostasis, University Medical Center Mainz, Mainz, Germany. FAU - Brenner, Benjamin AU - Brenner B AD - Department of Haematology and Bone Marrow Transplantation, Rambam Health Care Campus, Haifa, Israel; and. AD - Technion-Israel Institute of Technology, Haifa, Israel. FAU - Munzel, Thomas AU - Munzel T AD - Center for Cardiology, Cardiology I, and. AD - Deutsches Zentrum fur Herz-Kreislauf-Forschung e.V., partner site RheinMain, Mainz, Germany. FAU - Wenzel, Philip AU - Wenzel P AD - Center for Cardiology, Cardiology I, and. AD - Center for Thrombosis and Hemostasis, University Medical Center Mainz, Mainz, Germany. AD - Deutsches Zentrum fur Herz-Kreislauf-Forschung e.V., partner site RheinMain, Mainz, Germany. FAU - Konstantinides, Stavros AU - Konstantinides S AD - Center for Thrombosis and Hemostasis, University Medical Center Mainz, Mainz, Germany. FAU - Schafer, Katrin AU - Schafer K AD - Center for Cardiology, Cardiology I, and. AD - Deutsches Zentrum fur Herz-Kreislauf-Forschung e.V., partner site RheinMain, Mainz, Germany. LA - eng PT - Journal Article PT - Research Support, Non-U.S. Gov't PL - United States TA - Blood Adv JT - Blood advances JID - 101698425 RN - 0 (Early Growth Response Protein 1) RN - 0 (Egr1 protein, mouse) RN - 0 (Glycoproteins) RN - 0 (Trp53 protein, mouse) RN - 0 (Tumor Suppressor Protein p53) RN - 0 (tissue-factor-pathway inhibitor 2) RN - EC 3.4.21.6 (Factor Xa) RN - EC 4.2.2.7 (Heparin Lyase) SB - IM MH - Aging/genetics/*metabolism/pathology MH - Animals MH - Early Growth Response Protein 1/biosynthesis/genetics MH - Endothelial Cells/*metabolism/pathology MH - Factor Xa/biosynthesis/genetics MH - Glycoproteins/genetics/metabolism MH - Heparin Lyase/genetics MH - Mice MH - Mice, Knockout MH - Tumor Suppressor Protein p53/*biosynthesis/genetics MH - Venous Thrombosis/genetics/*metabolism PMC - PMC5998933 COIS- Conflict-of-interest disclosure: The authors declare no competing financial interests. EDAT- 2018/06/13 06:00 MHDA- 2019/03/06 06:00 PMCR- 2018/06/11 CRDT- 2018/06/13 06:00 PHST- 2017/11/09 00:00 [received] PHST- 2018/05/11 00:00 [accepted] PHST- 2018/06/13 06:00 [entrez] PHST- 2018/06/13 06:00 [pubmed] PHST- 2019/03/06 06:00 [medline] PHST- 2018/06/11 00:00 [pmc-release] AID - bloodadvances.2017014050 [pii] AID - 2017/014050 [pii] AID - 10.1182/bloodadvances.2017014050 [doi] PST - ppublish SO - Blood Adv. 2018 Jun 12;2(11):1300-1314. doi: 10.1182/bloodadvances.2017014050.