KEGG   PATHWAY: rno05418
Entry
rno05418                    Pathway                                
Name
Fluid shear stress and atherosclerosis - Rattus norvegicus (rat)
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
rno05418  Fluid shear stress and atherosclerosis
rno05418

Organism
Rattus norvegicus (rat) [GN:rno]
Gene
299331  Hsp90aa1; heat shock protein HSP 90-alpha [KO:K04079]
301252  Hsp90ab1; heat shock protein HSP 90-beta [KO:K04079]
362862  Hsp90b1; endoplasmin precursor [KO:K09487]
24600  Nos3; nitric oxide synthase 3 [KO:K13242] [EC:1.14.13.39]
25404  Cav1; caveolin-1 isoform alpha [KO:K06278]
363425  Cav2; caveolin-2 [KO:K12958]
29161  Cav3; caveolin-3 [KO:K12959]
364774  Calml5; calmodulin-like protein 5 [KO:K02183]
307100  Calml3; calmodulin-like protein 3 [KO:K02183]
691455  Calml4; calmodulin-like protein 4 [KO:K02183]
24242  Calm1; calmodulin-1 [KO:K02183]
24244  Calm3; calmodulin-3 [KO:K02183]
50663  Calm2; calmodulin-2 [KO:K02183]
58920  Gpc1; glypican-1 precursor [KO:K08107]
25216  Sdc1; syndecan-1 precursor [KO:K06257]
25615  Sdc2; syndecan-2 precursor [KO:K16336]
24771  Sdc4; syndecan-4 precursor [KO:K16338]
66026  Trpv4; transient receptor potential cation channel subfamily V member 4 [KO:K04973]
117519  Keap1; kelch-like ECH-associated protein 1 [KO:K10456]
83619  Nfe2l2; nuclear factor erythroid 2-related factor 2 isoform 2 [KO:K05638]
24451  Hmox1; heme oxygenase 1 [KO:K00510] [EC:1.14.14.18]
81869  Gstm7; glutathione S-transferase Mu 7 [KO:K00799] [EC:2.5.1.18]
24421  Gsta1; glutathione S-transferase alpha-3 [KO:K00799] [EC:2.5.1.18]
24422  Gsta2; glutathione S-transferase alpha-1 [KO:K00799] [EC:2.5.1.18]
24424  Gstm2; glutathione S-transferase Mu 2 [KO:K00799] [EC:2.5.1.18]
25260  Gstt1; glutathione S-transferase theta-1 [KO:K00799] [EC:2.5.1.18]
29487  Gstt2; glutathione S-transferase theta-2 [KO:K00799] [EC:2.5.1.18]
57298  Gstm3; glutathione S-transferase Mu 3 [KO:K00799] [EC:2.5.1.18]
295037  Mgst2; microsomal glutathione S-transferase 2 [KO:K00799] [EC:2.5.1.18]
171341  Mgst1; microsomal glutathione S-transferase 1 [KO:K00799] [EC:2.5.1.18]
64352  Gstm5; glutathione S-transferase Mu 5 [KO:K00799] [EC:2.5.1.18]
289197  Mgst3; microsomal glutathione S-transferase 3 [KO:K00799] [EC:2.5.1.18]
114846  Gsto1; glutathione S-transferase omega-1 [KO:K00799] [EC:2.5.1.18]
300850  Gsta4; glutathione S-transferase alpha-4 [KO:K00799] [EC:2.5.1.18]
309465  Gsto2; glutathione S-transferase omega-2 [KO:K00799] [EC:2.5.1.18]
499689  Gstm4; glutathione S-transferase Mu 4 [KO:K00799] [EC:2.5.1.18]
24423  Gstm1; glutathione S-transferase Mu 1 [KO:K00799] [EC:2.5.1.18]
494499  Gsta5; glutathione S-transferase alpha-2 [KO:K00799] [EC:2.5.1.18]
494500  Gsta3; glutathione S-transferase alpha-5 isoform 1 [KO:K00799] [EC:2.5.1.18]
499688  Gstm6; glutathione S-transferase Mu 6 [KO:K00799] [EC:2.5.1.18]
501110  Gsta6; glutathione S-transferase A6 [KO:K00799] [EC:2.5.1.18]
499422  Gstt3; glutathione S-transferase, theta 3 [KO:K00799] [EC:2.5.1.18]
686922  Gstt4; glutathione S-transferase theta-4 [KO:K00799] [EC:2.5.1.18]
295362  Gstm6l; glutathione S-transferase, mu 6-like [KO:K00799] [EC:2.5.1.18]
498340  Mgst3l1; glutathione S-transferase 3, mitochondrial-like [KO:K00799] [EC:2.5.1.18]
24426  Gstp1; glutathione S-transferase P [KO:K23790] [EC:2.5.1.18]
100911464  glutathione S-transferase P-like [KO:K23790] [EC:2.5.1.18]
293656  Gstp3; Glutathione S-transferase P-like isoform 2 [KO:K23790] [EC:2.5.1.18]
24314  Nqo1; NAD(P)H dehydrogenase [quinone] 1 [KO:K00355] [EC:1.6.5.2]
113894  Sqstm1; sequestosome-1 isoform 1 [KO:K14381]
116484  Txn1; thioredoxin [KO:K03671]
79462  Txn2; thioredoxin, mitochondrial precursor [KO:K03671]
114593  Nppc; C-type natriuretic peptide precursor [KO:K12336]
25698  Ass1; argininosuccinate synthase [KO:K01940] [EC:6.3.4.5]
83580  Thbd; thrombomodulin precursor [KO:K03907]
25692  Plat; tissue-type plasminogen activator precursor [KO:K01343] [EC:3.4.21.68]
307618  Cdh5; cadherin-5 [KO:K06533]
25589  Kdr; vascular endothelial growth factor receptor 2 precursor [KO:K05098] [EC:2.7.10.1]
84353  Ctnnb1; catenin beta-1 [KO:K02105]
65248  Prkaa1; 5'-AMP-activated protein kinase catalytic subunit alpha-1 [KO:K07198] [EC:2.7.11.31]
78975  Prkaa2; 5'-AMP-activated protein kinase catalytic subunit alpha-2 [KO:K07198] [EC:2.7.11.31]
29583  Pecam1; platelet endothelial cell adhesion molecule precursor [KO:K06471]
85243  Pik3cb; phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit beta isoform [KO:K00922] [EC:2.7.1.153]
170911  Pik3ca; phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit alpha isoform [KO:K00922] [EC:2.7.1.153]
366508  Pik3cd; phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit delta isoform [KO:K00922] [EC:2.7.1.153]
134484121  LOW QUALITY PROTEIN: phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit alpha isoform-like [KO:K00922] [EC:2.7.1.153]
25513  Pik3r1; phosphatidylinositol 3-kinase regulatory subunit alpha [KO:K02649]
60664  Pik3r3; phosphatidylinositol 3-kinase regulatory subunit gamma [KO:K02649]
29741  Pik3r2; phosphatidylinositol 3-kinase regulatory subunit beta [KO:K02649]
24185  Akt1; RAC-alpha serine/threonine-protein kinase [KO:K04456] [EC:2.7.11.1]
25233  Akt2; RAC-beta serine/threonine-protein kinase [KO:K04456] [EC:2.7.11.1]
29414  Akt3; RAC-gamma serine/threonine-protein kinase [KO:K04456] [EC:2.7.11.1]
29568  Map2k5; dual specificity mitogen-activated protein kinase kinase 5 isoform a [KO:K04463] [EC:2.7.12.2]
114509  Mapk7; mitogen-activated protein kinase 7 [KO:K04464] [EC:2.7.11.24]
309957  Mef2a; myocyte-specific enhancer factor 2A [KO:K09260]
499497  Mef2c; myocyte-specific enhancer factor 2C isoform 1 [KO:K04454]
306330  Klf2; Krueppel-like factor 2 [KO:K17845]
685269  Itga2b; integrin alpha-IIb precursor [KO:K06476]
296456  Itgav; integrin alpha-V isoform 1 precursor [KO:K06487]
29302  Itgb3; integrin beta-3 precursor [KO:K06493]
83805  Src; proto-oncogene tyrosine-protein kinase Src [KO:K05704] [EC:2.7.10.2]
25614  Ptk2; focal adhesion kinase 1 [KO:K05725] [EC:2.7.10.2]
310635  Arhgef2; rho guanine nucleotide exchange factor 2 [KO:K12791]
117273  Rhoa; transforming protein RhoA [KO:K04513]
297173  RSA-14-44; ras homolog gene family, member A [KO:K04513]
100361457  Actg1l1; actin, gamma 1 propeptide-like [KO:K05692]
81822  Actb; actin, cytoplasmic 1 [KO:K05692]
287876  Actg1; actin, cytoplasmic 2 [KO:K05692]
120098222  POTE ankyrin domain family member F [KO:K05692]
114856  Dusp1; dual specificity protein phosphatase 1 [KO:K21278] [EC:3.1.3.16 3.1.3.48]
100313996  Mir10a; rno-miR-10a-5p [KO:K16864]
25625  Tnfrsf1a; tumor necrosis factor receptor superfamily member 1A precursor [KO:K03158]
25663  Il1r1; interleukin-1 receptor type 1 precursor [KO:K04386]
117022  Il1r2; interleukin-1 receptor type 2 precursor [KO:K04387]
313121  Map3k7; mitogen-activated protein kinase kinase kinase 7 [KO:K04427] [EC:2.7.11.25]
309295  Ikbkg; NF-kappa-B essential modulator [KO:K07210]
309361  Chuk; inhibitor of nuclear factor kappa-B kinase subunit alpha [KO:K04467] [EC:2.7.11.10]
84351  Ikbkb; inhibitor of nuclear factor kappa-B kinase subunit beta [KO:K07209] [EC:2.7.11.10]
81736  Nfkb1; nuclear factor NF-kappa-B p105 subunit isoform 2 [KO:K02580]
309165  Rela; transcription factor p65 [KO:K04735]
365057  Map3k5; mitogen-activated protein kinase kinase kinase 5 [KO:K04426] [EC:2.7.11.25]
287398  Map2k4; dual specificity mitogen-activated protein kinase kinase 4 [KO:K04430] [EC:2.7.12.2]
363855  Map2k7; dual specificity mitogen-activated protein kinase kinase 7 isoform 1 [KO:K04431] [EC:2.7.12.2]
25272  Mapk10; mitogen-activated protein kinase 10 isoform 2 [KO:K04440] [EC:2.7.11.24]
50658  Mapk9; mitogen-activated protein kinase 9 isoform 2 [KO:K04440] [EC:2.7.11.24]
116554  Mapk8; mitogen-activated protein kinase 8 [KO:K04440] [EC:2.7.11.24]
114495  Map2k6; dual specificity mitogen-activated protein kinase kinase 6 [KO:K04433] [EC:2.7.12.2]
81649  Mapk14; mitogen-activated protein kinase 14 [KO:K04441] [EC:2.7.11.24]
60352  Mapk12; mitogen-activated protein kinase 12 [KO:K04441] [EC:2.7.11.24]
29513  Mapk13; mitogen-activated protein kinase 13 [KO:K04441] [EC:2.7.11.24]
689314  Mapk11; mitogen-activated protein kinase 11 [KO:K04441] [EC:2.7.11.24]
314322  Fos; protein c-Fos [KO:K04379]
24516  Jun; transcription factor Jun [KO:K04448]
81686  Mmp2; 72 kDa type IV collagenase precursor [KO:K01398] [EC:3.4.24.24]
81687  Mmp9; matrix metalloproteinase-9 precursor [KO:K01403] [EC:3.4.24.35]
25697  Ctsl; procathepsin L preproprotein [KO:K01365] [EC:3.4.22.15]
287562  Ccl12; C-C motif chemokine ligand 12 precursor [KO:K14624]
24770  Ccl2; C-C motif chemokine 2 precursor [KO:K14624]
25361  Vcam1; vascular cell adhesion protein 1 precursor [KO:K06527]
25464  Icam1; intercellular adhesion molecule 1 precursor [KO:K06490]
25544  Sele; E-selectin precursor [KO:K06494]
24835  Tnf; tumor necrosis factor [KO:K03156]
24493  Il1a; interleukin-1 alpha [KO:K04383]
24494  Il1b; interleukin-1 beta [KO:K04519]
25712  Ifng; interferon gamma precursor [KO:K04687]
25266  Pdgfa; platelet-derived growth factor subunit A precursor [KO:K04359]
24628  Pdgfb; platelet-derived growth factor subunit B precursor [KO:K17386]
24323  Edn1; endothelin-1 preproprotein [KO:K16366]
83785  Vegfa; vascular endothelial growth factor A isoform 6 precursor [KO:K05448]
25296  Bmp4; bone morphogenetic protein 4 precursor [KO:K04662]
140590  Bmpr2; bone morphogenetic protein receptor type-2 precursor [KO:K04671] [EC:2.7.11.30]
29263  Acvr2a; activin receptor type-2A precursor [KO:K04670] [EC:2.7.11.30]
25366  Acvr2b; activin receptor type-2B precursor [KO:K13596] [EC:2.7.11.30]
79558  Acvr1; activin receptor type-1 precursor [KO:K04675] [EC:2.7.11.30]
81507  Bmpr1a; bone morphogenetic protein receptor type-1A precursor [KO:K04673] [EC:2.7.11.30]
310914  Bmpr1b; bone morphogenetic protein receptor type-1B [KO:K13578] [EC:2.7.11.30]
114243  Nox1; NADPH oxidase 1 [KO:K08008]
79129  Cyba; cytochrome b-245 light chain [KO:K08009]
114553  Ncf1; neutrophil cytosolic factor 1 [KO:K08011]
364018  Ncf2; neutrophil cytosol factor 2 [KO:K08010]
363875  Rac1; ras-related C3 botulinum toxin substrate 1 [KO:K04392]
366957  Rac2; ras-related C3 botulinum toxin substrate 2 [KO:K07860]
688319  Rac3; ras-related C3 botulinum toxin substrate 3 [KO:K07861]
25522  Prkcz; protein kinase C zeta type [KO:K18952] [EC:2.7.11.13]
362827  Pias4; E3 SUMO-protein ligase PIAS4 [KO:K16065] [EC:2.3.2.27]
24842  Tp53; cellular tumor antigen p53 [KO:K04451]
499417  Sumo3; small ubiquitin-related modifier 3 [KO:K12160]
690244  Sumo2; small ubiquitin-related modifier 2 [KO:K12160]
301442  Sumo1; small ubiquitin-related modifier 1 [KO:K12160]
120102380  small ubiquitin-related modifier 1-like [KO:K12160]
108351070  Sumo2l1; small ubiquitin-related modifier 2-like [KO:K12160]
120095693  small ubiquitin-related modifier 2-like [KO:K12160]
24224  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
rno04010  MAPK signaling pathway
rno04064  NF-kappa B signaling pathway
rno04151  PI3K-Akt signaling pathway
rno04210  Apoptosis
rno04270  Vascular smooth muscle contraction
rno04510  Focal adhesion
rno04514  Cell adhesion molecules
rno04670  Leukocyte transendothelial migration
KO pathway
ko05418   
LinkDB

DBGET integrated database retrieval system