Laminar shear stress is known to confer potent anti-inflammatory, antithrombotic, and antiadhesive effects by differentially regulating endothelial gene expression. The identification of Krüppel-like factor 2 as a flow-responsive molecule has greatly advanced our understanding of molecular mechanisms governing vascular homeostasis. This review summarizes the current understanding of Krüppel-like factor 2 action in endothelial gene expression and function. Antioxid. Redox Signal. 15, 1449–1461.
Get full access to this article
View all access options for this article.
References
1.
AdamPJ, ReganCP, HautmannMB, OwensGK. Positive- and negative-acting Krüppel-like transcription factors bind a transforming growth factor beta control element required for expression of the smooth muscle cell differentiation marker SM22alpha in vivo. J Biol Chem, 275:37798–37806. 2000.
2.
AliF, ZakkarM, KaruK, LidingtonEA, HamdulaySS, BoyleJJ, ZlohM, BauerA, HaskardDO, EvansPC, MasonJC. Induction of the cytoprotective enzyme heme oxygenase-1 by statins is enhanced in vascular endothelium exposed to laminar shear stress and impaired by disturbed flow. J Biol Chem, 284:18882–18892. 2009.
3.
AndersonKP, KernCB, CrableSC, LingrelJB. Isolation of a gene encoding a functional zinc finger protein homologous to erythroid Krüppel-like factor: identification of a new multigene family. Mol Cell Biol, 15:5957–5965. 1995.
4.
AoiT, YaeK, NakagawaM, IchisakaT, OkitaKet al.Generation of pluripotent stem cells from adult mouse liver and stomach cells. Science, 321:699–702. 2008.
5.
AtkinsGB, JainMK. Role of Krüppel-like transcription factors in endothelial biology. Circ Res, 100:1686–1695. 2007.
BasuP, MorrisPE, HaarJL, WaniMA, LingrelJB, GaenslerKM, LloydJA. KLF2 is essential for primitive erythropoiesis and regulates the human and murine embryonic beta-like globin genes in vivo. Blood, 106:2566–2571. 2005.
9.
BhattacharyaR, SenbanerjeeS, LinZ, MirS, HamikA, WangP, MukherjeeP, MukhopadhyayD, JainMK. Inhibition of vascular permeability factor/vascular endothelial growth factor-mediated angiogenesis by the Krüppel-like factor KLF2. J Biol Chem, 280:28848–28851. 2005.
10.
BiekerJJ. Isolation, genomic structure, and expression of human erythroid Krüppel-like factor (EKLF)DNA Cell Biol, 15:347–352. 1996.
11.
BiekerJJ. Krüppel-like factors: three fingers in many pies. J Biol Chem, 276:34355–34358. 2001.
12.
BielenbergDR, HidaY, ShimizuA, KaipainenA, KreuterM, KimCC, KlagsbrunM. Semaphorin 3F, a chemorepulsant for endothelial cells, induces a poorly vascularized, encapsulated, nonmetastatic tumor phenotype. J Clin Invest, 114:1260–1271. 2004.
13.
BlackAR, BlackJD, Azizkhan-CliffordJ. Sp1 and Krüppel-like factor family of transcription factors in cell growth regulation and cancer. J Cell Physiol, 188:143–160. 2001.
14.
BoonRA, FledderusJO, VolgerOL, van WanrooijEJ, PardaliE, WeesieF, KuiperJ, PannekoekH, ten DijkeP, HorrevoetsAJ. KLF2 suppresses TGF-beta signaling in endothelium through induction of Smad7 and inhibition of AP-1. Arterioscler Thromb Vasc Biol, 27:532–539. 2007.
15.
BoonRA, LeyenTA, FontijnRD, FledderusJO, BaggenJM, VolgerOL, van Nieuw AmerongenGP, HorrevoetsAJ. KLF2-induced actin shear fibers control both alignment to flow and JNK signaling in vascular endothelium. Blood, 115:2533–2542. 2010.
CarmelietP. Angiogenesis in life, disease and medicine. Nature, 438:932–936. 2005.
18.
ChauhanSD, NilssonH, AhluwaliaA, HobbsAJ. Release of C-type natriuretic peptide accounts for the biological activity of endothelium-derived hyperpolarizing factor. Proc Natl Acad Sci U S A, 100:1426–1431. 2003.
19.
ChenXL, VarnerSE, RaoAS, GreyJY, ThomasS, CookCK, WassermanMA, MedfordRM, JaiswalAK, KunschC. Laminar flow induction of antioxidant response element-mediated genes in endothelial cells. A novel anti-inflammatory mechanism. J Biol Chem, 278:703–711. 2003.
20.
ConkrightMD, WaniMA, LingrelJB. Lung Krüppel-like factor contains an autoinhibitory domain that regulates its transcriptional activation by binding WWP1, an E3 ubiquitin ligase. J Biol Chem, 276:29299–29306. 2001.
21.
DangDT, PevsnerJ, YangVW. The biology of the mammalian Krüppel-like family of transcription factors. Int J Biochem Cell Biol, 32:1103–1121. 2000.
22.
DangDT, ZhaoW, MahatanCS, GeimanDE, YangVW. Opposing effects of Krüppel-like factor 4 (gut-enriched Krüppel-like factor) and Krüppel-like factor 5 (intestinal-enriched Krüppel-like factor) on the promoter of the Krüppel-like factor 4 gene. Nucleic Acids Res, 30:2736–2741. 2002.
23.
DasH, KumarA, LinZ, PatinoWD, HwangPM, FeinbergMW, MajumderPK, JainMK. Krüppel-like factor 2 (KLF2) regulates proinflammatory activation of monocytes. Proc Natl Acad Sci U S A, 103:6653–6658. 2006.
24.
DavidsN. Finite element methods of studying mechanical factors in blood flow. Neurol Res, 3:83–105. 1981.
25.
DekkerRJ, BoonRA, RondaijMG, KragtA, VolgerOL, ElderkampYW, MeijersJC, VoorbergJ, PannekoekH, HorrevoetsAJ. KLF2 provokes a gene expression pattern that establishes functional quiescent differentiation of the endothelium. Blood, 107:4354–4363. 2006.
26.
DekkerRJ, van SoestS, FontijnRD, SalamancaS, de GrootPG, VanBavelE, PannekoekH, HorrevoetsAJ. Prolonged fluid shear stress induces a distinct set of endothelial cell genes, most specifically lung Krüppel-like factor (KLF2)Blood, 100:1689–1698. 2002.
27.
DekkerRJ, van ThienenJV, RohlenaJ, de JagerSC, ElderkampYW, SeppenJ, de VriesCJ, BiessenEA, van BerkelTJ, PannekoekH, HorrevoetsAJ. Endothelial KLF2 links local arterial shear stress levels to the expression of vascular tone-regulating genes. Am J Pathol, 167:609–618. 2005.
28.
FarbA, TangAL, BurkeAP, SessumsL, LiangY, VirmaniR. Sudden coronary death. Frequency of active coronary lesions, inactive coronary lesions, and myocardial infarction. Circulation, 92:1701–1790. 1995.
29.
FeinbergMW, CaoZ, WaraAK, LebedevaMA, SenbanerjeeS, JainMK. Krüppel-like factor 4 is a mediator of proinflammatory signaling in macrophages. J Biol Chem, 280:38247–38258. 2005.
30.
FeinbergMW, WaraAK, CaoZ, LebedevaMA, RosenbauerF, IwasakiH, HiraiH, KatzJP, HaspelRL, GrayS, AkashiK, SegreJ, KaestnerKH, TenenDG, JainMK. The Krüppel-like factor KLF4 is a critical regulator of monocyte differentiation. EMBO J, 26:4138–4148. 2007.
31.
FiedlerU, AugustinHG. Angiopoietins: a link between angiogenesis and inflammation. Trends Immunol, 27:552–558. 2006.
32.
FiedlerU, ReissY, ScharpfeneckerM, GrunowV, KoidlS, ThurstonG, GaleNW, WitzenrathM, RosseauS, SuttorpN, SobkeA, HerrmannM, PreissnerKT, VajkoczyP, AugustinHG. Angiopoietin-2 sensitizes endothelial cells to TNF-alpha and has a crucial role in the induction of inflammation. Nat Med, 12:235–239. 2006.
33.
FledderusJO, BoonRA, VolgerOL, HurttilaH, Yla-HerttualaS, PannekoekH, LevonenAL, HorrevoetsAJ. KLF2 primes the antioxidant transcription factor Nrf2 for activation in endothelial cells. Arterioscler Thromb Vasc Biol, 28:1339–1346. 2008.
34.
FledderusJO, van ThienenJV, BoonRA, DekkerRJ, RohlenaJ, VolgerOL, BijnensAP, DaemenMJ, KuiperJ, van BerkelTJ, PannekoekH, HorrevoetsAJ. Prolonged shear stress and KLF2 suppress constitutive proinflammatory transcription through inhibition of ATF2. Blood, 109:4249–4257. 2007.
Garrett-SinhaLA, EberspaecherH, SeldinMF, de CrombruggheB. A gene for a novel zinc-finger protein expressed in differentiated epithelial cells and transiently in certain mesenchymal cells. J Biol Chem, 271:31384–31390. 1996.
37.
GimbroneMAJr.Endothelial dysfunction, hemodynamic forces, and atherosclerosis. Thromb Haemost, 82:722–726. 1999.
38.
GoodwinBL, SolomonsonLP, EichlerDC. Argininosuccinate synthase expression is required to maintain nitric oxide production and cell viability in aortic endothelial cells. J Biol Chem, 279:18353–18360. 2004.
HuddlesonJP, AhmadN, LingrelJB. Up-regulation of the KLF2 transcription factor by fluid shear stress requires nucleolin. J Biol Chem, 281:15121–15128. 2006.
43.
HuddlesonJP, AhmadN, SrinivasanS, LingrelJB. Induction of KLF2 by fluid shear stress requires a novel promoter element activated by a phosphatidylinositol 3-kinase-dependent chromatin-remodeling pathway. J Biol Chem, 280:23371–23379. 2005.
44.
HuddlesonJP, SrinivasanS, AhmadN, LingrelJB. Fluid shear stress induces endothelial KLF2 gene expression through a defined promoter region. Biol Chem, 385:723–729. 2004.
45.
JackleH, RosenbergUB, PreissA, SeifertE, KnippleDC, KienlinA, LehmannR. Molecular analysis of Krüppel, a segmentation gene of Drosophila melanogaster. Cold Spring Harb Symp Quant Biol, 50:465–473. 1985.
46.
JainRK. Molecular regulation of vessel maturation. Nat Med, 9:685–693. 2003.
KatzJP, PerreaultN, GoldsteinBG, ActmanL, McNallySR, SilbergDG, FurthEE, KaestnerKH. Loss of Klf4 in mice causes altered proliferation and differentiation and precancerous changes in the adult stomach. Gastroenterology, 128:935–945. 2005.
49.
KawanamiD, MahabeleshwarGH, LinZ, AtkinsGB, HamikA, HaldarSM, MaemuraK, LamannaJC, JainMK. Krüppel-like factor 2 inhibits hypoxia-inducible factor 1alpha expression and function in the endothelium. J Biol Chem, 284:20522–20530. 2009.
50.
KinderlererAR, AliF, JohnsM, LidingtonEA, LeungV, BoyleJJ, HamdulaySS, EvansPC, HaskardDO, MasonJC. KLF2-dependent, shear stress-induced expression of CD59: a novel cytoprotective mechanism against complement-mediated injury in the vasculature. J Biol Chem, 283:14636–14644. 2008.
51.
KumarA, HoffmanTA, DericcoJ, NaqviA, JainMK, IraniK. Transcriptional repression of Krüppel like factor-2 by the adaptor protein p66shc. FASEB J, 23:4344–4352. 2009.
52.
KumarA, LinZ, SenBanerjeeS, JainMK. Tumor necrosis factor alpha-mediated reduction of KLF2 is due to inhibition of MEF2 by NF-kappaB and histone deacetylases. Mol Cell Biol, 25:5893–5903. 2005.
53.
KuoCT, VeselitsML, BartonKP, LuMM, ClendeninC, LeidenJM. The LKLF transcription factor is required for normal tunica media formation and blood vessel stabilization during murine embryogenesis. Genes Dev, 11:2996–3006. 1997.
54.
KuoCT, VeselitsML, LeidenJM. LKLF: a transcriptional regulator of single-positive T cell quiescence and survival. Science, 277:1986–1990. 1997.
55.
LangilleBL. Remodeling of developing and mature arteries: endothelium, smooth muscle, and matrix. J Cardiovasc Pharmacol, 21,Suppl 1:S11–S17. 1993.
56.
LeeJS, YuQ, ShinJT, SebzdaE, BertozziC, ChenM, MerickoP, StadtfeldM, ZhouD, ChengL, GrafT, MacRaeCA, LeporeJJ, LoCW, KahnML. Klf2 is an essential regulator of vascular hemodynamic forces in vivo. Dev Cell, 11:845–857. 2006.
57.
LeeTS, ChangCC, ZhuY, ShyyJY. Simvastatin induces heme oxygenase-1: a novel mechanism of vessel protection. Circulation, 110:1296–1302. 2004.
LucittiJL, JonesEA, HuangC, ChenJ, FraserSE, DickinsonME. Vascular remodeling of the mouse yolk sac requires hemodynamic force. Development, 134:3317–3326. 2007.
61.
MaheraliN, SridharanR, XieW, UtikalJ, EminliS, ArnoldK, StadtfeldM, YachechkoR, TchieuJ, JaenischR, PlathK, HochedlingerK. Directly reprogrammed fibroblasts show global epigenetic remodeling and widespread tissue contribution. Cell Stem Cell, 1:55–70. 2007.
62.
McCormickSM, EskinSG, McIntireLV, TengCL, LuCM, RussellCG, ChitturKK. DNA microarray reveals changes in gene expression of shear stressed human umbilical vein endothelial cells. Proc Natl Acad Sci U S A, 98:8955–8960. 2001.
63.
McKinseyTA, ZhangCL, LuJ, OlsonEN. Signal-dependent nuclear export of a histone deacetylase regulates muscle differentiation. Nature, 408:106–111. 2000.
64.
McKinseyTA, ZhangCL, OlsonEN. Activation of the myocyte enhancer factor-2 transcription factor by calcium/calmodulin-dependent protein kinase-stimulated binding of 14-3-3 to histone deacetylase 5. Proc Natl Acad Sci U S A, 97:14400–14405. 2000.
65.
MeadowsSM, SalangaMC, KriegPA. Krüppel-like factor 2 cooperates with the ETS family protein ERG to activate Flk1 expression during vascular development. Development, 136:1115–1125. 2009.
66.
MusallamKM, DahdalehFS, ShamseddineAI, TaherAT. Incidence and prophylaxis of venous thromboembolic events in multiple myeloma patients receiving immunomodulatory therapy. Thromb Res, 123:679–686. 2009.
67.
NakatakeY, FukuiN, IwamatsuY, MasuiS, TakahashiK, YagiR, YagiK, MiyazakiJ, MatobaR, KoMS, NiwaH. Klf4 cooperates with Oct3/4 and Sox2 to activate the Lefty1 core promoter in embryonic stem cells. Mol Cell Biol, 26:7772–7782. 2006.
68.
NamD, NiCW, RezvanA, SuoJ, BudzynK, LlanosA, HarrisonD, GiddensD, JoH. Partial carotid ligation is a model of acutely induced disturbed flow, leading to rapid endothelial dysfunction and atherosclerosis. Am J Physiol Heart Circ Physiol, 297:H1535–H1543. 2009.
69.
Nusslein-VolhardC, WieschausE. Mutations affecting segment number and polarity in Drosophila. Nature, 287:795–801. 1980.
PreissA, RosenbergUB, KienlinA, SeifertE, JackleH. Molecular genetics of Krüppel, a gene required for segmentation of the Drosophila embryo. Nature, 313:27–32. 1985.
73.
RazaniB, EngelmanJA, WangXB, SchubertW, ZhangXL, MarksCB, MacalusoF, RussellRG, LiM, PestellRG, Di VizioD, HouHJr., KneitzB, LagaudG, ChristGJ, EdelmannW, LisantiMP. Caveolin-1 null mice are viable but show evidence of hyperproliferative and vascular abnormalities. J Biol Chem, 276:38121–38138. 2001.
74.
RheeWJ, NiCW, ZhengZ, ChangK, JoH, BaoG. HuR regulates the expression of stress-sensitive genes and mediates inflammatory response in human umbilical vein endothelial cells. Proc Natl Acad Sci U S A, 107:6858–6863. 2010.
75.
RosenbergUB, PreissA, SeifertE, JackleH, KnippleDC. Production of phenocopies by Krüppel antisense RNA injection into Drosophila embryos. Nature, 313:703–706. 1985.
76.
SaadiS, HolzknechtRA, PatteCP, SternDM, PlattJL. Complement-mediated regulation of tissue factor activity in endothelium. J Exp Med, 182:1807–1814. 1995.
SebzdaE, ZouZ, LeeJS, WangT, KahnML. Transcription factor KLF2 regulates the migration of naive T cells by restricting chemokine receptor expression patterns. Nat Immunol, 9:292–300. 2008.
79.
SegreJA, BauerC, FuchsE. Klf4 is a transcription factor required for establishing the barrier function of the skin. Nat Genet, 22:356–360. 1999.
80.
SenBanerjeeS, LinZ, AtkinsGB, GreifDM, RaoRM, KumarA, FeinbergMW, ChenZ, SimonDI, LuscinskasFW, MichelTM, GimbroneMAJr., Garcia-CardenaG, JainMK. KLF2 Is a novel transcriptional regulator of endothelial proinflammatory activation. J Exp Med, 199:1305–1315. 2004.
81.
Sen-BanerjeeS, MirS, LinZ, HamikA, AtkinsGB, DasH, BanerjeeP, KumarA, JainMK. Krüppel-like factor 2 as a novel mediator of statin effects in endothelial cells. Circulation, 112:720–726. 2005.
82.
ShieldsJM, ChristyRJ, YangVW. Identification and characterization of a gene encoding a gut-enriched Krüppel-like factor expressed during growth arrest. J Biol Chem, 271:20009–20017. 1996.
83.
SohnSJ, LiD, LeeLK, WinotoA. Transcriptional regulation of tissue-specific genes by the ERKS mitogen-activated protein kinase. Mol Cell Biol, 25:8553–8566. 2005.
84.
SwamynathanSK, DavisJ, PiatigorskyJ. Identification of candidate Klf4 target genes reveals the molecular basis of the diverse regulatory roles of Klf4 in the mouse cornea. Invest Ophthalmol Vis Sci, 49:3360–3370. 2008.
85.
SwamynathanSK, KatzJP, KaestnerKH, Ashery-PadanR, CrawfordMA, PiatigorskyJ. Conditional deletion of the mouse Klf4 gene results in corneal epithelial fragility, stromal edema, and loss of conjunctival goblet cells. Mol Cell Biol, 27:182–194. 2007.
86.
TakahashiK, YamanakaS. Induction of pluripotent stem cells from mouse embryonic and adult fibroblast cultures by defined factors. Cell, 126:663–676. 2006.
87.
TedescoF, PausaM, NardonE, IntronaM, MantovaniA, DobrinaA. The cytolytically inactive terminal complement complex activates endothelial cells to express adhesion molecules and tissue factor procoagulant activity. J Exp Med, 185:1619–1627. 1997.
88.
TopperJN, CaiJ, FalbD, GimbroneMAJr.Identification of vascular endothelial genes differentially responsive to fluid mechanical stimuli: cyclooxygenase-2, manganese superoxide dismutase, and endothelial cell nitric oxide synthase are selectively up-regulated by steady laminar shear stress. Proc Natl Acad Sci U S A, 93:10417–10422. 1996.
89.
TurnerJ, CrossleyM. Basic Krüppel-like factor functions within a network of interacting haematopoietic transcription factors. Int J Biochem Cell Biol, 31:1169–1174. 1999.
90.
van ThienenJV, FledderusJO, DekkerRJ, RohlenaJ, van IjzendoornGA, KootstraNA, PannekoekH, HorrevoetsAJ. Shear stress sustains atheroprotective endothelial KLF2 expression more potently than statins through mRNA stabilization. Cardiovasc Res, 72:231–240. 2006.
91.
van VlietJ, CroftsLA, QuinlanKG, CzolijR, PerkinsAC, CrossleyM. Human KLF17 is a new member of the Sp/KLF family of transcription factors. Genomics, 87:474–482. 2006.
WuJ, LingrelJB. Krüppel-like factor 2, a novel immediate-early transcriptional factor, regulates IL-2 expression in T lymphocyte activation. J Immunol, 175:3060–3066. 2005.
104.
WuJ, SrinivasanSV, NeumannJC, LingrelJB. The KLF2 transcription factor does not affect the formation of preadipocytes but inhibits their differentiation into adipocytes. Biochemistry, 44:11098–11105. 2005.
105.
YetSF, McA'NultyMM, FoltaSC, YenHW, YoshizumiM, HsiehCM, LayneMD, ChinMT, WangH, PerrellaMA, JainMK, LeeME. Human EZF, a Krüppel-like zinc finger protein, is expressed in vascular endothelial cells and contains transcriptional activation and repression domains. J Biol Chem, 273:1026–1031. 1998.
106.
YoshidaT, GanQ, OwensGK. Krüppel-like factor 4, Elk-1, and histone deacetylases cooperatively suppress smooth muscle cell differentiation markers in response to oxidized phospholipids. Am J Physiol Cell Physiol, 295:C1175–C1182. 2008.
107.
YoshidaT, KaestnerKH, OwensGK. Conditional deletion of Krüppel-like factor 4 delays downregulation of smooth muscle cell differentiation markers but accelerates neointimal formation following vascular injury. Circ Res, 102:1548–1557. 2008.
108.
ZarinsCK, GiddensDP, BharadvajBK, SottiuraiVS, MabonRF, GlagovS. Carotid bifurcation atherosclerosis. Quantitative correlation of plaque localization with flow velocity profiles and wall shear stress. Circ Res, 53:502–514. 1983.
ZhangX, SrinivasanSV, LingrelJB. WWP1-dependent ubiquitination and degradation of the lung Krüppel-like factor, KLF2. Biochem Biophys Res Commun, 316:139–148. 2004.