KEGG PATHWAY: hsa05418

PATHWAY: hsa05418

Entry

hsa05418                    Pathway

Name

Fluid shear stress and atherosclerosis - Homo sapiens (human)

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

hsa05418

Fluid shear stress and atherosclerosis

Drug

D09670

Sotatercept (USAN/INN)

Organism

Homo sapiens (human) [GN:hsa]

Gene

3320	HSP90AA1; heat shock protein 90 alpha family class A member 1 [KO:K04079]

3326	HSP90AB1; heat shock protein 90 alpha family class B member 1 [KO:K04079]

7184	HSP90B1; heat shock protein 90 beta family member 1 [KO:K09487]

4846	NOS3; nitric oxide synthase 3 [KO:K13242] [EC:1.14.13.39]

857	CAV1; caveolin 1 [KO:K06278]

858	CAV2; caveolin 2 [KO:K12958]

859	CAV3; caveolin 3 [KO:K12959]

810	CALML3; calmodulin like 3 [KO:K02183]

805	CALM2; calmodulin 2 [KO:K02183]

808	CALM3; calmodulin 3 [KO:K02183]

801	CALM1; calmodulin 1 [KO:K02183]

163688

CALML6; calmodulin like 6 [KO:K02183]

51806

CALML5; calmodulin like 5 [KO:K02183]

91860

CALML4; calmodulin like 4 [KO:K02183]

2817	GPC1; glypican 1 [KO:K08107]

6382	SDC1; syndecan 1 [KO:K06257]

6383	SDC2; syndecan 2 [KO:K16336]

6385	SDC4; syndecan 4 [KO:K16338]

59341

TRPV4; transient receptor potential cation channel subfamily V member 4 [KO:K04973]

9817	KEAP1; kelch like ECH associated protein 1 [KO:K10456]

4780	NFE2L2; NFE2 like bZIP transcription factor 2 [KO:K05638]

3162	HMOX1; heme oxygenase 1 [KO:K00510] [EC:1.14.14.18]

221357

GSTA5; glutathione S-transferase alpha 5 [KO:K00799] [EC:2.5.1.18]

2939	GSTA2; glutathione S-transferase alpha 2 [KO:K00799] [EC:2.5.1.18]

2941	GSTA4; glutathione S-transferase alpha 4 [KO:K00799] [EC:2.5.1.18]

119391

GSTO2; glutathione S-transferase omega 2 [KO:K00799] [EC:2.5.1.18]

2948	GSTM4; glutathione S-transferase mu 4 [KO:K00799] [EC:2.5.1.18]

2953	GSTT2; glutathione S-transferase theta 2 (gene/pseudogene) [KO:K00799] [EC:2.5.1.18]

2952	GSTT1; glutathione S-transferase theta 1 [KO:K00799] [EC:2.5.1.18]

2947	GSTM3; glutathione S-transferase mu 3 [KO:K00799] [EC:2.5.1.18]

4257	MGST1; microsomal glutathione S-transferase 1 [KO:K00799] [EC:2.5.1.18]

4259	MGST3; microsomal glutathione S-transferase 3 [KO:K00799] [EC:2.5.1.18]

2944	GSTM1; glutathione S-transferase mu 1 [KO:K00799] [EC:2.5.1.18]

2949	GSTM5; glutathione S-transferase mu 5 [KO:K00799] [EC:2.5.1.18]

4258	MGST2; microsomal glutathione S-transferase 2 [KO:K00799] [EC:2.5.1.18]

2938	GSTA1; glutathione S-transferase alpha 1 [KO:K00799] [EC:2.5.1.18]

2946	GSTM2; glutathione S-transferase mu 2 [KO:K00799] [EC:2.5.1.18]

2940	GSTA3; glutathione S-transferase alpha 3 [KO:K00799] [EC:2.5.1.18]

9446	GSTO1; glutathione S-transferase omega 1 [KO:K00799] [EC:2.5.1.18]

653689

GSTT2B; glutathione S-transferase theta 2B [KO:K00799] [EC:2.5.1.18]

2950	GSTP1; glutathione S-transferase pi 1 [KO:K23790] [EC:2.5.1.18]

1728	NQO1; NAD(P)H quinone dehydrogenase 1 [KO:K00355] [EC:1.6.5.2]

8878	SQSTM1; sequestosome 1 [KO:K14381]

7295	TXN; thioredoxin [KO:K03671]

25828

TXN2; thioredoxin 2 [KO:K03671]

4880	NPPC; natriuretic peptide C [KO:K12336]

445	ASS1; argininosuccinate synthase 1 [KO:K01940] [EC:6.3.4.5]

7056	THBD; thrombomodulin [KO:K03907]

5327	PLAT; plasminogen activator, tissue type [KO:K01343] [EC:3.4.21.68]

1003	CDH5; cadherin 5 [KO:K06533]

3791	KDR; kinase insert domain receptor [KO:K05098] [EC:2.7.10.1]

1499	CTNNB1; catenin beta 1 [KO:K02105]

5562	PRKAA1; protein kinase AMP-activated catalytic subunit alpha 1 [KO:K07198] [EC:2.7.11.31]

5563	PRKAA2; protein kinase AMP-activated catalytic subunit alpha 2 [KO:K07198] [EC:2.7.11.31]

5175	PECAM1; platelet and endothelial cell adhesion molecule 1 [KO:K06471]

5290	PIK3CA; phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha [KO:K00922] [EC:2.7.1.153]

5293	PIK3CD; phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit delta [KO:K00922] [EC:2.7.1.153]

5291	PIK3CB; phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit beta [KO:K00922] [EC:2.7.1.153]

5295	PIK3R1; phosphoinositide-3-kinase regulatory subunit 1 [KO:K02649]

5296	PIK3R2; phosphoinositide-3-kinase regulatory subunit 2 [KO:K02649]

8503	PIK3R3; phosphoinositide-3-kinase regulatory subunit 3 [KO:K02649]

207	AKT1; AKT serine/threonine kinase 1 [KO:K04456] [EC:2.7.11.1]

208	AKT2; AKT serine/threonine kinase 2 [KO:K04456] [EC:2.7.11.1]

10000

AKT3; AKT serine/threonine kinase 3 [KO:K04456] [EC:2.7.11.1]

5607	MAP2K5; mitogen-activated protein kinase kinase 5 [KO:K04463] [EC:2.7.12.2]

5598	MAPK7; mitogen-activated protein kinase 7 [KO:K04464] [EC:2.7.11.24]

4205	MEF2A; myocyte enhancer factor 2A [KO:K09260]

4208	MEF2C; myocyte enhancer factor 2C [KO:K04454]

10365

KLF2; KLF transcription factor 2 [KO:K17845]

3674	ITGA2B; integrin subunit alpha 2b [KO:K06476]

3685	ITGAV; integrin subunit alpha V [KO:K06487]

3690	ITGB3; integrin subunit beta 3 [KO:K06493]

6714	SRC; SRC proto-oncogene, non-receptor tyrosine kinase [KO:K05704] [EC:2.7.10.2]

5747	PTK2; protein tyrosine kinase 2 [KO:K05725] [EC:2.7.10.2]

9181	ARHGEF2; Rho/Rac guanine nucleotide exchange factor 2 [KO:K12791]

387	RHOA; ras homolog family member A [KO:K04513]

71	ACTG1; actin gamma 1 [KO:K05692]

60	ACTB; actin beta [KO:K05692]

1843	DUSP1; dual specificity phosphatase 1 [KO:K21278] [EC:3.1.3.16 3.1.3.48]

406902

MIR10A; microRNA 10a [KO:K16864]

7132	TNFRSF1A; TNF receptor superfamily member 1A [KO:K03158]

3554	IL1R1; interleukin 1 receptor type 1 [KO:K04386]

7850	IL1R2; interleukin 1 receptor type 2 [KO:K04387]

6885	MAP3K7; mitogen-activated protein kinase kinase kinase 7 [KO:K04427] [EC:2.7.11.25]

8517	IKBKG; inhibitor of nuclear factor kappa B kinase regulatory subunit gamma [KO:K07210]

1147	CHUK; component of inhibitor of nuclear factor kappa B kinase complex [KO:K04467] [EC:2.7.11.10]

3551	IKBKB; inhibitor of nuclear factor kappa B kinase subunit beta [KO:K07209] [EC:2.7.11.10]

4790	NFKB1; nuclear factor kappa B subunit 1 [KO:K02580]

5970	RELA; RELA proto-oncogene, NF-kB subunit [KO:K04735]

4217	MAP3K5; mitogen-activated protein kinase kinase kinase 5 [KO:K04426] [EC:2.7.11.25]

6416	MAP2K4; mitogen-activated protein kinase kinase 4 [KO:K04430] [EC:2.7.12.2]

5609	MAP2K7; mitogen-activated protein kinase kinase 7 [KO:K04431] [EC:2.7.12.2]

5599	MAPK8; mitogen-activated protein kinase 8 [KO:K04440] [EC:2.7.11.24]

5602	MAPK10; mitogen-activated protein kinase 10 [KO:K04440] [EC:2.7.11.24]

5601	MAPK9; mitogen-activated protein kinase 9 [KO:K04440] [EC:2.7.11.24]

5608	MAP2K6; mitogen-activated protein kinase kinase 6 [KO:K04433] [EC:2.7.12.2]

5600	MAPK11; mitogen-activated protein kinase 11 [KO:K04441] [EC:2.7.11.24]

6300	MAPK12; mitogen-activated protein kinase 12 [KO:K04441] [EC:2.7.11.24]

5603	MAPK13; mitogen-activated protein kinase 13 [KO:K04441] [EC:2.7.11.24]

1432	MAPK14; mitogen-activated protein kinase 14 [KO:K04441] [EC:2.7.11.24]

2353	FOS; Fos proto-oncogene, AP-1 transcription factor subunit [KO:K04379]

3725	JUN; Jun proto-oncogene, AP-1 transcription factor subunit [KO:K04448]

4313	MMP2; matrix metallopeptidase 2 [KO:K01398] [EC:3.4.24.24]

4318	MMP9; matrix metallopeptidase 9 [KO:K01403] [EC:3.4.24.35]

1514	CTSL; cathepsin L [KO:K01365] [EC:3.4.22.15]

6347	CCL2; C-C motif chemokine ligand 2 [KO:K14624]

7412	VCAM1; vascular cell adhesion molecule 1 [KO:K06527]

3383	ICAM1; intercellular adhesion molecule 1 [KO:K06490]

6401	SELE; selectin E [KO:K06494]

7124	TNF; tumor necrosis factor [KO:K03156]

3552	IL1A; interleukin 1 alpha [KO:K04383]

3553	IL1B; interleukin 1 beta [KO:K04519]

3458	IFNG; interferon gamma [KO:K04687]

5154	PDGFA; platelet derived growth factor subunit A [KO:K04359]

5155	PDGFB; platelet derived growth factor subunit B [KO:K17386]

1906	EDN1; endothelin 1 [KO:K16366]

7422	VEGFA; vascular endothelial growth factor A [KO:K05448]

652	BMP4; bone morphogenetic protein 4 [KO:K04662]

659	BMPR2; bone morphogenetic protein receptor type 2 [KO:K04671] [EC:2.7.11.30]

92	ACVR2A; activin A receptor type 2A [KO:K04670] [EC:2.7.11.30]

93	ACVR2B; activin A receptor type 2B [KO:K13596] [EC:2.7.11.30]

90	ACVR1; activin A receptor type 1 [KO:K04675] [EC:2.7.11.30]

657	BMPR1A; bone morphogenetic protein receptor type 1A [KO:K04673] [EC:2.7.11.30]

658	BMPR1B; bone morphogenetic protein receptor type 1B [KO:K13578] [EC:2.7.11.30]

27035

NOX1; NADPH oxidase 1 [KO:K08008]

1535	CYBA; cytochrome b-245 alpha chain [KO:K08009]

653361

NCF1; neutrophil cytosolic factor 1 [KO:K08011]

4688	NCF2; neutrophil cytosolic factor 2 [KO:K08010]

5879	RAC1; Rac family small GTPase 1 [KO:K04392]

5880	RAC2; Rac family small GTPase 2 [KO:K07860]

5881	RAC3; Rac family small GTPase 3 [KO:K07861]

5590	PRKCZ; protein kinase C zeta [KO:K18952] [EC:2.7.11.13]

51588

PIAS4; protein inhibitor of activated STAT 4 [KO:K16065] [EC:2.3.2.27]

7157	TP53; tumor protein p53 [KO:K04451]

6612	SUMO3; small ubiquitin like modifier 3 [KO:K12160]

6613	SUMO2; small ubiquitin like modifier 2 [KO:K12160]

7341	SUMO1; small ubiquitin like modifier 1 [KO:K12160]

387082

SUMO4; small ubiquitin like modifier 4 [KO:K12160]

596	BCL2; BCL2 apoptosis regulator [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