Thromb Haemost 2022; 122(05): 777-788
DOI: 10.1055/s-0041-1735191
Endothelium and Angiogenesis

KLF11 Protects against Venous Thrombosis via Suppressing Tissue Factor Expression

1   Department of Internal Medicine, Frankel Cardiovascular Center, University of Michigan Medical Center, Ann Arbor, Michigan, United States
2   Department of Molecular and Integrative Physiology, University of Michigan, Ann Arbor, Michigan, United States
,
Haocheng Lu
1   Department of Internal Medicine, Frankel Cardiovascular Center, University of Michigan Medical Center, Ann Arbor, Michigan, United States
,
Jinjian Sun
1   Department of Internal Medicine, Frankel Cardiovascular Center, University of Michigan Medical Center, Ann Arbor, Michigan, United States
,
Guizhen Zhao
1   Department of Internal Medicine, Frankel Cardiovascular Center, University of Michigan Medical Center, Ann Arbor, Michigan, United States
,
Huilun Wang
1   Department of Internal Medicine, Frankel Cardiovascular Center, University of Michigan Medical Center, Ann Arbor, Michigan, United States
2   Department of Molecular and Integrative Physiology, University of Michigan, Ann Arbor, Michigan, United States
,
Yanhong Guo
1   Department of Internal Medicine, Frankel Cardiovascular Center, University of Michigan Medical Center, Ann Arbor, Michigan, United States
,
Daniel Eitzman
1   Department of Internal Medicine, Frankel Cardiovascular Center, University of Michigan Medical Center, Ann Arbor, Michigan, United States
,
Y Eugene Chen
1   Department of Internal Medicine, Frankel Cardiovascular Center, University of Michigan Medical Center, Ann Arbor, Michigan, United States
,
Yanbo Fan
3   Department of Cancer Biology, University of Cincinnati College of Medicine, Cincinnati, Ohio, United States
4   Division of Cardiovascular Health and Disease, Department of Internal Medicine, University of Cincinnati College of Medicine, Cincinnati, Ohio, United States
,
Jifeng Zhang
1   Department of Internal Medicine, Frankel Cardiovascular Center, University of Michigan Medical Center, Ann Arbor, Michigan, United States
› Author Affiliations
Funding This work was partially supported by National Institutes of Health grants HL138139 (J.Z.), HL138094 and HL145176 (Y.F.), HL137214 and HL134569 (Y.E.C.), American Heart Association grants 18PRE34000005 (W.L) and 17PRE33400179 (H.L.).

Abstract

Krüppel-like factors (KLFs) play essential roles in multiple biological functions, including maintaining vascular homeostasis. KLF11, a causative gene for maturity-onset diabetes of the young type 7, inhibits endothelial activation and protects against stroke. However, the role of KLF11 in venous thrombosis remains to be explored. Utilizing stasis-induced murine deep vein thrombosis (DVT) model and cultured endothelial cells (ECs), we identified an increase of KLF11 expression under prothrombotic conditions both in vivo and in vitro. The expression change of thrombosis-related genes was determined by utilizing gain- and loss-of-function approaches to alter KLF11 expression in ECs. Among these genes, KLF11 significantly downregulated tumor necrosis factor-α (TNF-α)-induced tissue factor (TF) gene transcription. Using reporter gene assay, chromatin immunoprecipitation assay, and co-immunoprecipitation, we revealed that KLF11 could reduce TNF-α-induced binding of early growth response 1 (EGR1) to TF gene promoter in ECs. In addition, we demonstrated that conventional Klf11 knockout mice were more susceptible to developing stasis-induced DVT. These results suggest that under prothrombotic conditions, KLF11 downregulates TF gene transcription via inhibition of EGR1 in ECs. In conclusion, KLF11 protects against venous thrombosis, constituting a potential molecular target for treating thrombosis.

Supplementary Material



Publication History

Received: 03 April 2021

Accepted: 20 July 2021

Article published online:
24 August 2021

© 2021. Thieme. All rights reserved.

Georg Thieme Verlag KG
Rüdigerstraße 14, 70469 Stuttgart, Germany

 
  • References

  • 1 Raskob GE, Angchaisuksiri P, Blanco AN. et al; ISTH Steering Committee for World Thrombosis Day. Thrombosis: a major contributor to global disease burden. Arterioscler Thromb Vasc Biol 2014; 34 (11) 2363-2371
  • 2 Di Nisio M, van Es N, Büller HR. Deep vein thrombosis and pulmonary embolism. Lancet 2016; 388 (10063): 3060-3073
  • 3 Virani SS, Alonso A, Benjamin EJ. et al; American Heart Association Council on Epidemiology and Prevention Statistics Committee and Stroke Statistics Subcommittee. Heart Disease and Stroke Statistics-2020 Update: a report from the American Heart Association. Circulation 2020; 141 (09) e139-e596
  • 4 McConnell BB, Yang VW. Mammalian Krüppel-like factors in health and diseases. Physiol Rev 2010; 90 (04) 1337-1381
  • 5 Alaiti MA, Orasanu G, Tugal D, Lu Y, Jain MK. Kruppel-like factors and vascular inflammation: implications for atherosclerosis. Curr Atheroscler Rep 2012; 14 (05) 438-449
  • 6 Fan Y, Lu H, Liang W, Hu W, Zhang J, Chen YE. Krüppel-like factors and vascular wall homeostasis. J Mol Cell Biol 2017; 9 (05) 352-363
  • 7 Neve B, Fernandez-Zapico ME, Ashkenazi-Katalan V. et al. Role of transcription factor KLF11 and its diabetes-associated gene variants in pancreatic beta cell function. Proc Natl Acad Sci U S A 2005; 102 (13) 4807-4812
  • 8 Vazzana N, Ranalli P, Cuccurullo C, Davì G. Diabetes mellitus and thrombosis. Thromb Res 2012; 129 (03) 371-377
  • 9 Fan Y, Guo Y, Zhang J. et al. Krüppel-like factor-11, a transcription factor involved in diabetes mellitus, suppresses endothelial cell activation via the nuclear factor-κB signaling pathway. Arterioscler Thromb Vasc Biol 2012; 32 (12) 2981-2988
  • 10 Yin KJ, Fan Y, Hamblin M. et al. KLF11 mediates PPARγ cerebrovascular protection in ischaemic stroke. Brain 2013; 136 (Pt 4): 1274-1287
  • 11 Zhang X, Tang X, Ma F. et al. Endothelium-targeted overexpression of Krüppel-like factor 11 protects the blood-brain barrier function after ischemic brain injury. Brain Pathol 2020; 30 (04) 746-765
  • 12 Glineur C, Gross B, Neve B. et al. Fenofibrate inhibits endothelin-1 expression by peroxisome proliferator-activated receptor α-dependent and independent mechanisms in human endothelial cells. Arterioscler Thromb Vasc Biol 2013; 33 (03) 621-628
  • 13 Zhao G, Chang Z, Zhao Y. et al. KLF11 protects against abdominal aortic aneurysm through inhibition of endothelial cell dysfunction. JCI Insight 2021; 6 (05) 141673
  • 14 Liang W, Fan Y, Lu H. et al. KLF11 (Krüppel-like factor 11) inhibits arterial thrombosis via suppression of tissue factor in the vascular wall. Arterioscler Thromb Vasc Biol 2019; 39 (03) 402-412
  • 15 Song CZ, Gavriilidis G, Asano H, Stamatoyannopoulos G. Functional study of transcription factor KLF11 by targeted gene inactivation. Blood Cells Mol Dis 2005; 34 (01) 53-59
  • 16 Wrobleski SK, Farris DM, Diaz JA, Myers Jr DD, Wakefield TW. Mouse complete stasis model of inferior vena cava thrombosis. J Vis Exp 2011; (52) 2738
  • 17 Chang Z, Zhao G, Zhao Y. et al. BAF60a deficiency in vascular smooth muscle cells prevents abdominal aortic aneurysm by reducing inflammation and extracellular matrix degradation. Arterioscler Thromb Vasc Biol 2020; 40 (10) 2494-2507
  • 18 Rom O, Xu G, Guo Y. et al. Nitro-fatty acids protect against steatosis and fibrosis during development of nonalcoholic fatty liver disease in mice. EBioMedicine 2019; 41: 62-72
  • 19 Hu W, Lu H, Zhang J. et al. Krüppel-like factor 14, a coronary artery disease associated transcription factor, inhibits endothelial inflammation via NF-κB signaling pathway. Atherosclerosis 2018; 278: 39-48
  • 20 Kobayashi M, Inoue K, Warabi E, Minami T, Kodama T. A simple method of isolating mouse aortic endothelial cells. J Atheroscler Thromb 2005; 12 (03) 138-142
  • 21 Day SM, Reeve JL, Pedersen B. et al. Macrovascular thrombosis is driven by tissue factor derived primarily from the blood vessel wall. Blood 2005; 105 (01) 192-198
  • 22 Yau JW, Teoh H, Verma S. Endothelial cell control of thrombosis. BMC Cardiovasc Disord 2015; 15: 130
  • 23 Wang M, Hao H, Leeper NJ, Zhu L. Early Career Committee. Thrombotic regulation from the endothelial cell perspectives. Arterioscler Thromb Vasc Biol 2018; 38 (06) e90-e95
  • 24 Moll T, Czyz M, Holzmüller H. et al. Regulation of the tissue factor promoter in endothelial cells. Binding of NF kappa B-, AP-1-, and Sp1-like transcription factors. J Biol Chem 1995; 270 (08) 3849-3857
  • 25 Mackman N. Regulation of the tissue factor gene. Thromb Haemost 1997; 78 (01) 747-754
  • 26 Shin IS, Kim JM, Kim KL. et al. Early growth response factor-1 is associated with intraluminal thrombus formation in human abdominal aortic aneurysm. J Am Coll Cardiol 2009; 53 (09) 792-799
  • 27 Houston P, Campbell CJ, Svaren J, Milbrandt J, Braddock M. The transcriptional corepressor NAB2 blocks Egr-1-mediated growth factor activation and angiogenesis. Biochem Biophys Res Commun 2001; 283 (02) 480-486
  • 28 Fernandez-Zapico ME, van Velkinburgh JC, Gutiérrez-Aguilar R. et al. MODY7 gene, KLF11, is a novel p300-dependent regulator of Pdx-1 (MODY4) transcription in pancreatic islet beta cells. J Biol Chem 2009; 284 (52) 36482-36490
  • 29 Bonnefond A, Lomberk G, Buttar N. et al. Disruption of a novel Kruppel-like transcription factor p300-regulated pathway for insulin biosynthesis revealed by studies of the c.-331 INS mutation found in neonatal diabetes mellitus. J Biol Chem 2011; 286 (32) 28414-28424
  • 30 Mechtcheriakova D, Wlachos A, Holzmüller H, Binder BR, Hofer E. Vascular endothelial cell growth factor-induced tissue factor expression in endothelial cells is mediated by EGR-1. Blood 1999; 93 (11) 3811-3823
  • 31 Bode M, Mackman N. Regulation of tissue factor gene expression in monocytes and endothelial cells: thromboxane A2 as a new player. Vascul Pharmacol 2014; 62 (02) 57-62
  • 32 Swystun LL, Liaw PC. The role of leukocytes in thrombosis. Blood 2016; 128 (06) 753-762