KEGG   PATHWAY: mcc05418
Entry
mcc05418                    Pathway                                
Name
Fluid shear stress and atherosclerosis - Macaca mulatta (rhesus monkey)
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
mcc05418  Fluid shear stress and atherosclerosis
mcc05418

Organism
Macaca mulatta (rhesus monkey) [GN:mcc]
Gene
702293  HSP90AB1; heat shock protein HSP 90-beta [KO:K04079]
708431  HSP90AA1; heat shock protein 90kDa alpha (cytosolic), class A member 1 [KO:K04079]
699568  HSP90B1; endoplasmin precursor [KO:K09487]
714231  NOS3; nitric oxide synthase, endothelial isoform X1 [KO:K13242] [EC:1.14.13.39]
704449  CAV1; caveolin-1 [KO:K06278]
706980  CAV2; caveolin-2 [KO:K12958]
702163  CAV3; caveolin-3 [KO:K12959]
717686  calmodulin [KO:K02183]
698552  CALM1; calmodulin-1 isoform X1 [KO:K02183]
715270  CALM2; calmodulin-2 [KO:K02183]
703514  CALML6; calmodulin-like protein 6 isoform X1 [KO:K02183]
712159  CALML5; calmodulin-like protein 5 [KO:K02183]
722513  CALML3; calmodulin-like protein 3 [KO:K02183]
716584  CALM3; calmodulin-3 isoform X1 [KO:K02183]
693753  CALML4; LOW QUALITY PROTEIN: calmodulin-like protein 4 [KO:K02183]
706351  calmodulin-like [KO:K02183]
698326  GPC1; glypican-1 precursor [KO:K08107]
701544  SDC1; syndecan-1 isoform X1 [KO:K06257]
703841  SDC2; syndecan-2 precursor [KO:K16336]
710914  SDC4; syndecan-4 precursor [KO:K16338]
709605  TRPV4; transient receptor potential cation channel subfamily V member 4 isoform X1 [KO:K04973]
720514  KEAP1; kelch-like ECH-associated protein 1 [KO:K10456]
707606  NFE2L2; nuclear factor erythroid 2-related factor 2 [KO:K05638]
719266  HMOX1; heme oxygenase 1 [KO:K00510] [EC:1.14.14.18]
709498  GSTA3; glutathione S-transferase A3 [KO:K00799] [EC:2.5.1.18]
697983  MGST2; microsomal glutathione S-transferase 2 precursor [KO:K00799] [EC:2.5.1.18]
700185  GSTT2; glutathione S-transferase theta 2 [KO:K00799] [EC:2.5.1.18]
700314  GSTT1; glutathione S-transferase theta-1 [KO:K00799] [EC:2.5.1.18]
695275  MGST3; microsomal glutathione S-transferase 3 [KO:K00799] [EC:2.5.1.18]
700303  GSTM3; glutathione S-transferase Mu 3 [KO:K00799] [EC:2.5.1.18]
709666  GSTA4; glutathione S-transferase A4 [KO:K00799] [EC:2.5.1.18]
701652  MGST1; microsomal glutathione S-transferase 1 [KO:K00799] [EC:2.5.1.18]
715291  GSTO2; glutathione S-transferase omega-2 [KO:K00799] [EC:2.5.1.18]
709037  GSTA2; glutathione S-transferase alpha 2 [KO:K00799] [EC:2.5.1.18]
709232  GSTA1; glutathione S-transferase alpha 1 [KO:K00799] [EC:2.5.1.18]
709417  glutathione S-transferase A5 [KO:K00799] [EC:2.5.1.18]
699923  GSTM4; glutathione S-transferase Mu 4 [KO:K00799] [EC:2.5.1.18]
699679  glutathione S-transferase theta-4 [KO:K00799] [EC:2.5.1.18]
100426406  GSTM5; glutathione S-transferase Mu 5 [KO:K00799] [EC:2.5.1.18]
716078  GSTO1; glutathione S-transferase omega-1 [KO:K00799] [EC:2.5.1.18]
700053  GSTM2; glutathione S-transferase mu 2 [KO:K00799] [EC:2.5.1.18]
700178  GSTM1; glutathione S-transferase Mu 1 [KO:K00799] [EC:2.5.1.18]
706634  glutathione S-transferase theta-2B isoform X1 [KO:K00799] [EC:2.5.1.18]
700446  glutathione S-transferase theta-4 [KO:K00799] [EC:2.5.1.18]
711533  glutathione S-transferase A1-like [KO:K00799] [EC:2.5.1.18]
721704  GSTP1; glutathione S-transferase P [KO:K23790] [EC:2.5.1.18]
705635  NQO1; NAD(P)H dehydrogenase [quinone] 1 [KO:K00355] [EC:1.6.5.2]
705481  SQSTM1; sequestosome-1 [KO:K14381]
712587  TXN; thioredoxin [KO:K03671]
100425664  TXN2; thioredoxin, mitochondrial isoform X1 [KO:K03671]
717026  NPPC; C-type natriuretic peptide precursor [KO:K12336]
702037  argininosuccinate synthase [KO:K01940] [EC:6.3.4.5]
716168  ASS1; argininosuccinate synthase [KO:K01940] [EC:6.3.4.5]
702132  THBD; thrombomodulin precursor [KO:K03907]
704475  PLAT; tissue-type plasminogen activator [KO:K01343] [EC:3.4.21.68]
693297  CDH5; cadherin-5 [KO:K06533]
698293  KDR; vascular endothelial growth factor receptor 2 [KO:K05098] [EC:2.7.10.1]
574265  CTNNB1; catenin beta-1 [KO:K02105]
695558  PRKAA1; 5'-AMP-activated protein kinase catalytic subunit alpha-1 isoform X1 [KO:K07198] [EC:2.7.11.31]
717703  PRKAA2; 5'-AMP-activated protein kinase catalytic subunit alpha-2 [KO:K07198] [EC:2.7.11.31]
718302  PECAM1; platelet endothelial cell adhesion molecule isoform X1 [KO:K06471]
716098  PIK3CB; phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit beta isoform isoform X1 [KO:K00922] [EC:2.7.1.153]
709959  PIK3CA; phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit alpha isoform [KO:K00922] [EC:2.7.1.153]
710552  PIK3CD; phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit delta isoform isoform X1 [KO:K00922] [EC:2.7.1.153]
707310  PIK3R3; phosphatidylinositol 3-kinase regulatory subunit gamma [KO:K02649]
719367  PIK3R2; phosphatidylinositol 3-kinase regulatory subunit beta [KO:K02649]
698996  PIK3R1; phosphatidylinositol 3-kinase regulatory subunit alpha [KO:K02649]
714717  AKT3; RAC-gamma serine/threonine-protein kinase [KO:K04456] [EC:2.7.11.1]
697747  AKT1; RAC-alpha serine/threonine-protein kinase [KO:K04456] [EC:2.7.11.1]
700591  AKT2; RAC-beta serine/threonine-protein kinase [KO:K04456] [EC:2.7.11.1]
711672  MAP2K5; dual specificity mitogen-activated protein kinase kinase 5 isoform X4 [KO:K04463] [EC:2.7.12.2]
702837  MAPK7; mitogen-activated protein kinase 7 isoform X4 [KO:K04464] [EC:2.7.11.24]
708956  MEF2A; myocyte-specific enhancer factor 2A [KO:K09260]
694992  MEF2C; myocyte-specific enhancer factor 2C [KO:K04454]
719492  KLF2; Krueppel-like factor 2 [KO:K17845]
714955  ITGA2B; integrin alpha-IIb isoform X2 [KO:K06476]
707756  ITGAV; integrin alpha-V precursor [KO:K06487]
717379  ITGB3; integrin beta-3 [KO:K06493]
701057  SRC; proto-oncogene tyrosine-protein kinase Src [KO:K05704] [EC:2.7.10.2]
700634  PTK2; focal adhesion kinase 1 isoform X8 [KO:K05725] [EC:2.7.10.2]
719369  ARHGEF2; rho guanine nucleotide exchange factor 2 isoform X10 [KO:K12791]
706455  RHOA; transforming protein RhoA [KO:K04513]
713687  ACTG1; actin, cytoplasmic 2 [KO:K05692]
574285  ACTB; actin, cytoplasmic 1 [KO:K05692]
705671  actin, cytoplasmic 2-like [KO:K05692]
702981  DUSP1; dual specificity protein phosphatase 1 [KO:K21278] [EC:3.1.3.16 3.1.3.48]
100315444  MIR10A; mml-miR-10a-5p [KO:K16864]
722033  TNFRSF1A; tumor necrosis factor receptor superfamily member 1A [KO:K03158]
711726  IL1R1; interleukin-1 receptor type 1 [KO:K04386]
711638  IL1R2; interleukin-1 receptor type 2 precursor [KO:K04387]
703101  MAP3K7; mitogen-activated protein kinase kinase kinase 7 isoform X1 [KO:K04427] [EC:2.7.11.25]
701237  IKBKG; NF-kappa-B essential modulator isoform X1 [KO:K07210]
709511  CHUK; inhibitor of nuclear factor kappa-B kinase subunit alpha isoform X3 [KO:K04467] [EC:2.7.11.10]
704683  IKBKB; inhibitor of nuclear factor kappa-B kinase subunit beta [KO:K07209] [EC:2.7.11.10]
710324  NFKB1; nuclear factor NF-kappa-B p105 subunit [KO:K02580]
715919  RELA; transcription factor p65 isoform X1 [KO:K04735]
711382  MAP3K5; mitogen-activated protein kinase kinase kinase 5 isoform X1 [KO:K04426] [EC:2.7.11.25]
718155  MAP2K4; dual specificity mitogen-activated protein kinase kinase 4 isoform X1 [KO:K04430] [EC:2.7.12.2]
710077  MAP2K7; dual specificity mitogen-activated protein kinase kinase 7 isoform X1 [KO:K04431] [EC:2.7.12.2]
699736  MAPK10; mitogen-activated protein kinase 10 isoform 1 [KO:K04440] [EC:2.7.11.24]
711115  MAPK8; mitogen-activated protein kinase 8 isoform X1 [KO:K04440] [EC:2.7.11.24]
715782  MAPK9; mitogen-activated protein kinase 9 isoform X2 [KO:K04440] [EC:2.7.11.24]
693914  MAP2K6; dual specificity mitogen-activated protein kinase kinase 6 [KO:K04433] [EC:2.7.12.2]
715745  MAPK12; mitogen-activated protein kinase 12 isoform X1 [KO:K04441] [EC:2.7.11.24]
715794  MAPK11; mitogen-activated protein kinase 11 [KO:K04441] [EC:2.7.11.24]
718976  MAPK14; mitogen-activated protein kinase 14 isoform X1 [KO:K04441] [EC:2.7.11.24]
719085  MAPK13; mitogen-activated protein kinase 13 isoform X1 [KO:K04441] [EC:2.7.11.24]
702077  FOS; proto-oncogene c-Fos [KO:K04379]
716452  JUN; transcription factor AP-1 [KO:K04448]
698478  MMP2; 72 kDa type IV collagenase [KO:K01398] [EC:3.4.24.24]
708084  MMP9; matrix metalloproteinase-9 precursor [KO:K01403] [EC:3.4.24.35]
694569  CTSL; cathepsin L1 [KO:K01365] [EC:3.4.22.15]
100424037  LOW QUALITY PROTEIN: putative inactive cathepsin L-like protein CTSL3P [KO:K01365] [EC:3.4.22.15]
707167  LOW QUALITY PROTEIN: cathepsin L1-like [KO:K01365] [EC:3.4.22.15]
574138  CCL2; C-C motif chemokine 2 precursor [KO:K14624]
712036  VCAM1; vascular cell adhesion protein 1 [KO:K06527]
712280  ICAM1; intercellular adhesion molecule 1 precursor [KO:K06490]
701538  SELE; E-selectin [KO:K06494]
715467  TNF; tumor necrosis factor [KO:K03156]
700193  IL1A; interleukin-1 alpha precursor [KO:K04383]
704701  IL1B; interleukin-1 beta precursor [KO:K04519]
574282  IFNG; interferon gamma precursor [KO:K04687]
707725  PDGFA; platelet-derived growth factor subunit A isoform X1 [KO:K04359]
703173  PDGFB; platelet-derived growth factor subunit B [KO:K17386]
699982  EDN1; endothelin-1 [KO:K16366]
574209  VEGFA; vascular endothelial growth factor A isoform 1 precursor [KO:K05448]
694618  BMP4; bone morphogenetic protein 4 isoform X1 [KO:K04662]
704088  BMPR2; bone morphogenetic protein receptor type-2 precursor [KO:K04671] [EC:2.7.11.30]
707017  ACVR2A; activin receptor type-2A isoform X1 [KO:K04670] [EC:2.7.11.30]
696071  ACVR2B; activin receptor type-2B isoform X1 [KO:K13596] [EC:2.7.11.30]
697935  ACVR1; activin receptor type-1 precursor [KO:K04675] [EC:2.7.11.30]
696898  BMPR1A; bone morphogenetic protein receptor type-1A precursor [KO:K04673] [EC:2.7.11.30]
705474  BMPR1B; bone morphogenetic protein receptor type-1B [KO:K13578] [EC:2.7.11.30]
701376  NOX1; NADPH oxidase 1 [KO:K08008]
696748  cytochrome b-245 light chain isoform X2 [KO:K08009]
694207  NCF1; neutrophil cytosol factor 1 [KO:K08011]
715052  NCF2; neutrophil cytosol factor 2 isoform X1 [KO:K08010]
717755  RAC1; ras-related C3 botulinum toxin substrate 1 isoform X1 [KO:K04392]
696709  RAC2; ras-related C3 botulinum toxin substrate 2 [KO:K07860]
719305  RAC3; ras-related C3 botulinum toxin substrate 3 isoform X1 [KO:K07861]
710340  PRKCZ; protein kinase C zeta type isoform X1 [KO:K18952] [EC:2.7.11.13]
714328  PIAS4; E3 SUMO-protein ligase PIAS4 isoform X2 [KO:K16065] [EC:2.3.2.27]
716170  TP53; cellular tumor antigen p53 [KO:K04451]
700556  small ubiquitin-related modifier 2 [KO:K12160]
705512  SUMO2; small ubiquitin-related modifier 2 [KO:K12160]
710764  SUMO3; small ubiquitin-related modifier 3 [KO:K12160]
703644  SUMO1; small ubiquitin-related modifier 1 [KO:K12160]
106995487  small ubiquitin-related modifier 2 [KO:K12160]
695489  small ubiquitin-related modifier 2-like [KO:K12160]
699185  small ubiquitin-related modifier 5 [KO:K12160]
707407  BCL2; apoptosis regulator Bcl-2 [KO:K02161]
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
mcc04010  MAPK signaling pathway
mcc04064  NF-kappa B signaling pathway
mcc04151  PI3K-Akt signaling pathway
mcc04210  Apoptosis
mcc04270  Vascular smooth muscle contraction
mcc04510  Focal adhesion
mcc04514  Cell adhesion molecules
mcc04670  Leukocyte transendothelial migration
KO pathway
ko05418   
LinkDB

DBGET integrated database retrieval system