KEGG   PATHWAY: bta05418
Entry
bta05418                    Pathway                                
Name
Fluid shear stress and atherosclerosis - Bos taurus (cow)
Description
Shear stress represents the frictional force that the flow of blood exerts at the endothelial surface of the vessel wall and plays a central role in vascular biology and contributes to the progress of atherosclerosis. Sustained laminar flow with high shear stress upregulates expressions of endothelial cell (EC) genes and proteins that are protective against atherosclerosis. The key shear stress-induced transcription factors that govern the expression of these genes are Kruppel-like factor 2 (KLF2) and nuclear factor erythroid 2-like 2 (Nrf2). On the other hand, disturbed flow with associated reciprocating, low shear stress generally upregulates the EC genes and proteins that promote oxidative and inflammatory states in the artery wall, resulting in atherogenesis. Important transcriptional events that reflect this condition of ECs in disturbed flow include the activation of activator protein 1 (AP-1) and nuclear factor kappaB (NF-kappaB).
Class
Human Diseases; Cardiovascular disease
Pathway map
bta05418  Fluid shear stress and atherosclerosis
bta05418

Organism
Bos taurus (cow) [GN:bta]
Gene
100137872  AKT3; RAC-gamma serine/threonine-protein kinase [KO:K04456] [EC:2.7.11.1]
100295687  [KO:K00799] [EC:2.5.1.18]
100295732  MAP2K5; dual specificity mitogen-activated protein kinase kinase 5 [KO:K04463] [EC:2.7.12.2]
100297344  CALM2; calmodulin-2 [KO:K02183]
101906855  [KO:K12160]
104973792  [KO:K02183]
112445052  [KO:K12160]
132342073  SUMO2; small ubiquitin-related modifier 2 isoform X1 [KO:K12160]
132342556  [KO:K00799] [EC:2.5.1.18]
132346316  [KO:K12160]
280726  ASS1; argininosuccinate synthase [KO:K01940] [EC:6.3.4.5]
280795  FOS; protein c-Fos [KO:K04379]
280831  JUN; transcription factor Jun [KO:K04448]
280943  TNF; tumor necrosis factor [KO:K03156]
280950  TXN; thioredoxin [KO:K03671]
280979  ACTB; actin, cytoplasmic 1 [KO:K05692]
280991  AKT1; RAC-alpha serine/threonine-protein kinase [KO:K04456] [EC:2.7.11.1]
281020  BCL2; apoptosis regulator Bcl-2 [KO:K02161]
281040  CAV1; caveolin-1 [KO:K06278]
281043  CCL2; C-C motif chemokine 2 precursor [KO:K14624]
281073  CHUK; inhibitor of nuclear factor kappa-B kinase subunit alpha [KO:K04467] [EC:2.7.11.10]
281108  CTSV; cathepsin L2 precursor [KO:K01365] [EC:3.4.22.15]
281111  CYBA; cytochrome b-245 light chain [KO:K08009]
281137  EDN1; endothelin-1 precursor [KO:K16366]
281237  IFNG; interferon gamma precursor [KO:K04687]
281250  IL1A; interleukin-1 alpha precursor [KO:K04383]
281251  IL1B; interleukin-1 beta precursor [KO:K04519]
281345  NCF1; neutrophil cytosol factor 1 [KO:K08011]
281346  NCF2; neutrophil cytosol factor 2 [KO:K08010]
281356  NPPC; C-type natriuretic peptide precursor [KO:K12336]
281407  PLAT; tissue-type plasminogen activator precursor [KO:K01343] [EC:3.4.21.68]
281440  RAC1; ras-related C3 botulinum toxin substrate 1 [KO:K04392]
281484  SELE; E-selectin precursor [KO:K06494]
281529  THBD; thrombomodulin precursor [KO:K03907]
281542  TP53; cellular tumor antigen p53 [KO:K04451]
281557  TXN2; thioredoxin, mitochondrial precursor [KO:K03671]
281572  VEGFA; vascular endothelial growth factor A isoform 3 precursor [KO:K05448]
281598  ACVR2A; activin receptor type-2A precursor [KO:K04670] [EC:2.7.11.30]
281805  GSTA2; glutathione S-transferase A2 [KO:K00799] [EC:2.5.1.18]
281806  GSTP1; glutathione S-transferase P [KO:K23790]
281832  HSP90AA1; heat shock protein HSP 90-alpha [KO:K04079]
281839  ICAM1; intercellular adhesion molecule 1 precursor [KO:K06490]
281854  IKBKB; inhibitor of nuclear factor kappa-B kinase subunit beta [KO:K07209] [EC:2.7.11.10]
281855  IKBKG; NF-kappa-B essential modulator [KO:K07210]
281875  ITGAV; integrin alpha-V precursor [KO:K06487]
282118  VCAM1; vascular cell adhesion molecule 1 precursor [KO:K06527]
282131  ACVR2B; activin receptor type-2B precursor [KO:K13596] [EC:2.7.11.30]
282303  PECAM1; platelet endothelial cell adhesion molecule precursor [KO:K06471]
282306  PIK3CA; phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit alpha isoform [KO:K00922] [EC:2.7.1.153]
282307  PIK3R1; phosphatidylinositol 3-kinase regulatory subunit alpha [KO:K02649]
282308  PIK3R2; phosphatidylinositol 3-kinase regulatory subunit beta [KO:K02649]
282527  TNFRSF1A; tumor necrosis factor receptor superfamily member 1A precursor [KO:K03158]
282642  ITGB3; integrin beta-3 precursor [KO:K06493]
282646  HSP90B1; endoplasmin precursor [KO:K09487]
282871  MMP9; matrix metalloproteinase-9 precursor [KO:K01403] [EC:3.4.24.35]
282872  MMP2; 72 kDa type IV collagenase precursor [KO:K01398] [EC:3.4.24.24]
286807  SUMO2; small ubiquitin-related modifier 2 [KO:K12160]
286865  PIK3R3; phosphatidylinositol 3-kinase regulatory subunit gamma [KO:K02649]
286877  PRKCZ; protein kinase C zeta type [KO:K18952] [EC:2.7.11.13]
286883  MAP2K6; dual specificity mitogen-activated protein kinase kinase 6 [KO:K04433] [EC:2.7.12.2]
287024  NOS3; nitric oxide synthase, endothelial [KO:K13242] [EC:1.14.13.39]
326597  CALM; calmodulin [KO:K02183]
327671  RAC2; ras-related C3 botulinum toxin substrate 2 [KO:K07860]
327709  GSTM1; glutathione S-transferase Mu 1 [KO:K00799] [EC:2.5.1.18]
338045  SQSTM1; sequestosome-1 [KO:K14381]
338049  RHOA; transforming protein RhoA [KO:K04513]
338068  ACVR1; activin receptor type-1 precursor [KO:K04675] [EC:2.7.11.30]
404101  BMPR1A; bone morphogenetic protein receptor type-1A precursor [KO:K04673] [EC:2.7.11.30]
404122  ACTG1; actin, cytoplasmic 2 [KO:K05692]
407127  BMPR2; bone morphogenetic protein receptor type-2 precursor [KO:K04671] [EC:2.7.11.30]
407128  BMPR1B; bone morphogenetic protein receptor type-1B [KO:K13578] [EC:2.7.11.30]
407170  KDR; vascular endothelial growth factor receptor 2 precursor [KO:K05098] [EC:2.7.10.1]
407216  BMP4; bone morphogenetic protein 4 precursor [KO:K04662]
407231  MEF2A; myocyte-specific enhancer factor 2A [KO:K09260]
414735  CDH5; cadherin-5 precursor [KO:K06533]
493642  CAV2; caveolin-2 [KO:K12958]
493719  MGST1; microsomal glutathione S-transferase 1 [KO:K00799] [EC:2.5.1.18]
497024  NFE2L2; nuclear factor erythroid 2-related factor 2 [KO:K05638]
504531  PIK3CD; phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit delta isoform [KO:K00922] [EC:2.7.1.153]
505642  GSTO1; glutathione-S-transferase omega 1 [KO:K00799] [EC:2.5.1.18]
505908  PDGFA; platelet-derived growth factor subunit A precursor [KO:K04359]
505940  ARHGEF2; rho guanine nucleotide exchange factor 2 [KO:K12791]
506093  GSTT4; glutathione S-transferase, theta 4 [KO:K00799] [EC:2.5.1.18]
506270  PTK2; PTK2 protein tyrosine kinase 2 [KO:K05725] [EC:2.7.10.2]
507346  MGST3; glutathione S-transferase 3, mitochondrial [KO:K00799] [EC:2.5.1.18]
508133  SDC4; syndecan-4 [KO:K16338]
508233  RELA; transcription factor p65 [KO:K04735]
512254  MEF2C; myocyte-specific enhancer factor 2C [KO:K04454]
512943  MAPK12; mitogen-activated protein kinase 12 [KO:K04441] [EC:2.7.11.24]
513221  HMOX1; heme oxygenase 1 [KO:K00510] [EC:1.14.14.18]
515011  ITGA2B; integrin alpha-IIb [KO:K06476]
515200  CTSL; procathepsin L precursor [KO:K01365] [EC:3.4.22.15]
515640  IL1R1; interleukin-1 receptor type 1 precursor [KO:K04386]
515700  IL1R2; interleukin-1 receptor type 2 precursor [KO:K04387]
516190  GSTT2; glutathione S-transferase theta-2 [KO:K00799] [EC:2.5.1.18]
517724  GSTT1; glutathione S-transferase theta-1 [KO:K00799] [EC:2.5.1.18]
517948  PIK3CB; phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit beta isoform [KO:K00922] [EC:2.7.1.153]
518114  GPC1; glypican-1 [KO:K08107]
519632  NQO1; NAD(P)H dehydrogenase [quinone] 1 [KO:K00355] [EC:1.6.5.2]
520277  CALM3; calmodulin-3 [KO:K02183]
520404  CALML5; calmodulin-like protein 5 [KO:K02183]
520939  KLF2; Krueppel-like factor 2 [KO:K17845]
521681  NOX1; NADPH oxidase 1 [KO:K08008]
521685  GSTA5; glutathione S-transferase A5 [KO:K00799] [EC:2.5.1.18]
525938  GSTP1; glutathione S-transferase P isoform X1 [KO:K23790]
526469  MAP2K4; dual specificity mitogen-activated protein kinase kinase 4 [KO:K04430] [EC:2.7.12.2]
529146  MAP3K7; mitogen-activated protein kinase kinase kinase 7 [KO:K04427] [EC:2.7.11.25]
529759  SDC1; syndecan-1 precursor [KO:K06257]
532791  KEAP1; kelch-like ECH-associated protein 1 [KO:K10456]
533917  GSTA4; glutathione S-transferase A4 [KO:K00799] [EC:2.5.1.18]
534125  MAPK9; mitogen-activated protein kinase 9 [KO:K04440] [EC:2.7.11.24]
534492  MAPK14; mitogen-activated protein kinase 14 [KO:K04441] [EC:2.7.11.24]
534578  [KO:K06527]
534722  PIAS4; E3 SUMO-protein ligase PIAS4 [KO:K16065] [EC:2.3.2.27]
534923  AKT2; RAC-beta serine/threonine-protein kinase [KO:K04456] [EC:2.7.11.1]
535327  MAPK13; mitogen-activated protein kinase 13 [KO:K04441] [EC:2.7.11.24]
535742  SRC; proto-oncogene tyrosine-protein kinase Src [KO:K05704] [EC:2.7.10.2]
537380  MAP3K5; mitogen-activated protein kinase kinase kinase 5 [KO:K04426] [EC:2.7.11.25]
537631  MAPK10; mitogen-activated protein kinase 10 isoform 2 [KO:K04440] [EC:2.7.11.24]
537703  MAPK7; mitogen-activated protein kinase 7 [KO:K04464] [EC:2.7.11.24]
538954  PRKAA2; 5'-AMP-activated protein kinase catalytic subunit alpha-2 [KO:K07198] [EC:2.7.11.31]
539003  CTNNB1; catenin beta-1 [KO:K02105]
539175  DUSP1; dual specificity protein phosphatase 1 [KO:K21278] [EC:3.1.3.16 3.1.3.48]
539277  CALML4; calmodulin-like protein 4 [KO:K02183]
539941  MAPK8; mitogen-activated protein kinase 8 [KO:K04440] [EC:2.7.11.24]
540106  PDGFB; platelet-derived growth factor subunit B precursor [KO:K17386]
540259  TRPV4; transient receptor potential cation channel subfamily V member 4 [KO:K04973]
540404  PRKAA1; 5'-AMP-activated protein kinase catalytic subunit alpha-1 [KO:K07198] [EC:2.7.11.31]
613905  GSTO2; glutathione S-transferase omega-2 [KO:K00799] [EC:2.5.1.18]
614967  SUMO1; small ubiquitin-related modifier 1 [KO:K12160]
615310  CAV3; caveolin-3 [KO:K12959]
615507  GSTM3; glutathione S-transferase Mu 3 [KO:K00799] [EC:2.5.1.18]
615514  [KO:K00799] [EC:2.5.1.18]
615537  GSTM2; glutathione S-transferase Mu 1 [KO:K00799] [EC:2.5.1.18]
615552  MGST2; microsomal glutathione S-transferase 2 precursor [KO:K00799] [EC:2.5.1.18]
615785  SDC2; syndecan-2 precursor [KO:K16336]
616115  NFKB1; nuclear factor NF-kappa-B p105 subunit [KO:K02580]
617095  CALM1; calmodulin-1 [KO:K02183]
617236  SUMO3; small ubiquitin-related modifier 3 [KO:K12160]
617412  CALML6; LOW QUALITY PROTEIN: calmodulin-like protein 6 [KO:K02183]
618906  MAPK11; mitogen-activated protein kinase 11 [KO:K04441] [EC:2.7.11.24]
619066  RAC3; ras-related C3 botulinum toxin substrate 3 [KO:K07861]
767874  HSP90AB1; heat shock protein HSP 90-beta [KO:K04079]
768055  GSTA3; glutathione S-transferase A4 [KO:K00799] [EC:2.5.1.18]
777644  GSTA1; glutathione S-transferase A1 [KO:K00799] [EC:2.5.1.18]
783879  GSTM1; glutathione S-transferase mu 1 [KO:K00799] [EC:2.5.1.18]
784603  [KO:K12160]
785216  [KO:K00799] [EC:2.5.1.18]
787278  MAP2K7; dual specificity mitogen-activated protein kinase kinase 7 isoform X1 [KO:K04431] [EC:2.7.12.2]
791006  MIR10A; bta-miR-10a [KO:K16864]
791051  MIR10B; bta-miR-10b [KO:K16864]
Compound
C00076  Calcium cation
C00272  Tetrahydrobiopterin
C00518  Hyaluronate
C00533  Nitric oxide
C00607  Chondroitin sulfate
C00704  Superoxide
C00925  Heparan sulfate
C16845  Peroxynitrite
Reference
PMID:21050140
  Authors
Nigro P, Abe J, Berk BC
  Title
Flow shear stress and atherosclerosis: a matter of site specificity.
  Journal
Antioxid Redox Signal 15:1405-14 (2011)
DOI:10.1089/ars.2010.3679
Reference
PMID:26597822
  Authors
McSweeney SR, Warabi E, Siow RC
  Title
Nrf2 as an Endothelial Mechanosensitive Transcription Factor: Going With the Flow.
  Journal
Hypertension 67:20-9 (2016)
DOI:10.1161/HYPERTENSIONAHA.115.06146
Reference
PMID:22076424
  Authors
Heo KS, Fujiwara K, Abe J
  Title
Disturbed-flow-mediated vascular reactive oxygen species induce endothelial dysfunction.
  Journal
Circ J 75:2722-30 (2011)
DOI:10.1253/circj.CJ-11-1124
Reference
PMID:24573382
  Authors
Wild J, Soehnlein O, Dietel B, Urschel K, Garlichs CD, Cicha I
  Title
Rubbing salt into wounded endothelium: sodium potentiates proatherogenic effects of TNF-alpha under non-uniform shear stress.
  Journal
Thromb Haemost 112:183-95 (2014)
DOI:10.1160/TH13-11-0908
Reference
PMID:21457103
  Authors
Noguchi N, Jo H
  Title
Redox going with vascular shear stress.
  Journal
Antioxid Redox Signal 15:1367-8 (2011)
DOI:10.1089/ars.2011.4011
Reference
PMID:25165867
  Authors
Li X, Yang Q, Wang Z, Wei D
  Title
Shear stress in atherosclerotic plaque determination.
  Journal
DNA Cell Biol 33:830-8 (2014)
DOI:10.1089/dna.2014.2480
Reference
PMID:17599600
  Authors
Chatzizisis YS, Coskun AU, Jonas M, Edelman ER, Feldman CL, Stone PH
  Title
Role of endothelial shear stress in the natural history of coronary atherosclerosis and vascular remodeling: molecular, cellular, and vascular behavior.
  Journal
J Am Coll Cardiol 49:2379-93 (2007)
DOI:10.1016/j.jacc.2007.02.059
Reference
PMID:21733876
  Authors
Lu D, Kassab GS
  Title
Role of shear stress and stretch in vascular mechanobiology.
  Journal
J R Soc Interface 8:1379-85 (2011)
DOI:10.1098/rsif.2011.0177
Reference
PMID:27027326
  Authors
Givens C, Tzima E
  Title
Endothelial Mechanosignaling: Does One Sensor Fit All?
  Journal
Antioxid Redox Signal 25:373-88 (2016)
DOI:10.1089/ars.2015.6493
Reference
PMID:16765337
  Authors
Paravicini TM, Touyz RM
  Title
Redox signaling in hypertension.
  Journal
Cardiovasc Res 71:247-58 (2006)
DOI:10.1016/j.cardiores.2006.05.001
Reference
PMID:19151844
  Authors
Boon RA, Horrevoets AJ
  Title
Key transcriptional regulators of the vasoprotective effects of shear stress.
  Journal
Hamostaseologie 29:39-40, 41-3 (2009)
Reference
PMID:24947523
  Authors
Bryan MT, Duckles H, Feng S, Hsiao ST, Kim HR, Serbanovic-Canic J, Evans PC
  Title
Mechanoresponsive networks controlling vascular inflammation.
  Journal
Arterioscler Thromb Vasc Biol 34:2199-205 (2014)
DOI:10.1161/ATVBAHA.114.303424
Reference
PMID:26822720
  Authors
Brown AJ, Teng Z, Evans PC, Gillard JH, Samady H, Bennett MR
  Title
Role of biomechanical forces in the natural history of coronary atherosclerosis.
  Journal
Nat Rev Cardiol 13:210-20 (2016)
DOI:10.1038/nrcardio.2015.203
Reference
PMID:24876354
  Authors
Zhou J, Li YS, Chien S
  Title
Shear stress-initiated signaling and its regulation of endothelial function.
  Journal
Arterioscler Thromb Vasc Biol 34:2191-8 (2014)
DOI:10.1161/ATVBAHA.114.303422
Reference
PMID:23429585
  Authors
Liu HB, Zhang J, Xin SY, Liu C, Wang CY, Zhao D, Zhang ZR
  Title
Mechanosensitive properties in the endothelium and their roles in the regulation of endothelial function.
  Journal
J Cardiovasc Pharmacol 61:461-70 (2013)
DOI:10.1097/FJC.0b013e31828c0933
Reference
PMID:20032497
  Authors
Boon RA, Leyen TA, Fontijn RD, Fledderus JO, Baggen JM, Volger OL, van Nieuw Amerongen GP, Horrevoets AJ
  Title
KLF2-induced actin shear fibers control both alignment to flow and JNK signaling in vascular endothelium.
  Journal
Blood 115:2533-42 (2010)
DOI:10.1182/blood-2009-06-228726
Reference
PMID:20353494
  Authors
Whyte JJ, Laughlin MH
  Title
The effects of acute and chronic exercise on the vasculature.
  Journal
Acta Physiol (Oxf) 199:441-50 (2010)
DOI:10.1111/j.1748-1716.2010.02127.x
Reference
PMID:25638487
  Authors
Quillon A, Fromy B, Debret R
  Title
Endothelium microenvironment sensing leading to nitric oxide mediated vasodilation: a review of nervous and biomechanical signals.
  Journal
Nitric Oxide 45:20-6 (2015)
DOI:10.1016/j.niox.2015.01.006
Reference
PMID:15388638
  Authors
Sorescu GP, Song H, Tressel SL, Hwang J, Dikalov S, Smith DA, Boyd NL, Platt MO, Lassegue B, Griendling KK, Jo H
  Title
Bone morphogenic protein 4 produced in endothelial cells by oscillatory shear stress induces monocyte adhesion by stimulating reactive oxygen species production from a nox1-based NADPH oxidase.
  Journal
Circ Res 95:773-9 (2004)
DOI:10.1161/01.RES.0000145728.22878.45
Reference
PMID:23899566
  Authors
Hopkins PN
  Title
Molecular biology of atherosclerosis.
  Journal
Physiol Rev 93:1317-542 (2013)
DOI:10.1152/physrev.00004.2012
Reference
PMID:22003002
  Authors
Johnson BD, Mather KJ, Wallace JP
  Title
Mechanotransduction of shear in the endothelium: basic studies and clinical implications.
  Journal
Vasc Med 16:365-77 (2011)
DOI:10.1177/1358863X11422109
Reference
PMID:23555159
  Authors
Hu LS, George J, Wang JH
  Title
Current concepts on the role of nitric oxide in portal hypertension.
  Journal
World J Gastroenterol 19:1707-17 (2013)
DOI:10.3748/wjg.v19.i11.1707
Reference
PMID:23084990
  Authors
Collins C, Guilluy C, Welch C, O'Brien ET, Hahn K, Superfine R, Burridge K, Tzima E
  Title
Localized tensional forces on PECAM-1 elicit a global mechanotransduction response via the integrin-RhoA pathway.
  Journal
Curr Biol 22:2087-94 (2012)
DOI:10.1016/j.cub.2012.08.051
Reference
PMID:24190880
  Authors
Conway DE, Schwartz MA
  Title
Flow-dependent cellular mechanotransduction in atherosclerosis.
  Journal
J Cell Sci 126:5101-9 (2013)
DOI:10.1242/jcs.138313
Reference
PMID:26212910
  Authors
Chen J, Green J, Yurdagul A Jr, Albert P, McInnis MC, Orr AW
  Title
alphavbeta3 Integrins Mediate Flow-Induced NF-kappaB Activation, Proinflammatory Gene Expression, and Early Atherogenic Inflammation.
  Journal
Am J Pathol 185:2575-89 (2015)
DOI:10.1016/j.ajpath.2015.05.013
Reference
PMID:20538799
  Authors
Nigro P, Abe J, Woo CH, Satoh K, McClain C, O'Dell MR, Lee H, Lim JH, Li JD, Heo KS, Fujiwara K, Berk BC
  Title
PKCzeta decreases eNOS protein stability via inhibitory phosphorylation of ERK5.
  Journal
Blood 116:1971-9 (2010)
DOI:10.1182/blood-2010-02-269134
Related
pathway
bta04010  MAPK signaling pathway
bta04064  NF-kappa B signaling pathway
bta04151  PI3K-Akt signaling pathway
bta04210  Apoptosis
bta04270  Vascular smooth muscle contraction
bta04510  Focal adhesion
bta04514  Cell adhesion molecule (CAM) interaction
bta04670  Leukocyte transendothelial migration
KO pathway
ko05418   

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