KEGG   PATHWAY: ko05417
Entry
ko05417                     Pathway                                
Name
Lipid and atherosclerosis
Description
Atherosclerosis is a chronic inflammatory disease marked by a narrowing of the arteries from lipid-rich plaques present within the walls of arterial blood vessels. It represents the root cause of the majority of cardiovascular diseases (CVDs) and their complications, including conditions such as coronary artery disease, myocardial infarction and stroke.  An elevated level of low density lipoprotein (LDL) cholesterol constitutes a major risk factor for genesis of atherosclerosis. LDL can accumulate within the blood vessel wall and undergo modification by oxidation. Oxidized LDL (oxLDL) leads to endothelial dysfunction leading to expression of adhesion molecules and recruitment of monocyte in subendothelial space. The monocytes proliferate, differentiate into macrophages, and take up the lipoproteins, forming cholesterol-engorged "foam cells." With the time, the foam cells die, leaving a 'necrotic core' of crystalline cholesterol and cell debris. Smooth muscle cells proliferate and migrate into the region, laying down a protective cap over the lesion. Lectin-like oxidized low-density lipoprotein receptor-1 (LOX-1), which mediates the recognition and internalization of oxLDL, is involved in all of these events critical in the pathogenesis of atherosclerosis.
Class
Human Diseases; Cardiovascular disease
Pathway map
ko05417  Lipid and atherosclerosis
ko05417

Disease
H02505  Atherosclerosis
Orthology
K14462  apolipoprotein B
K08760  apolipoprotein A-IV
K08757  apolipoprotein A-I
K12473  low-density lipoprotein receptor
K08763  oxidised low-density lipoprotein receptor 1
K12330  Rho guanine nucleotide exchange factor 1
K01388  matrix metalloproteinase-1 (interstitial collagenase) [EC:3.4.24.7]
K04513  Ras homolog gene family, member A
K17388  Rho-associated protein kinase 2 [EC:2.7.11.39]
K13242  nitric-oxide synthase, endothelial [EC:1.14.13.39]
K00922  phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha/beta/delta [EC:2.7.1.153]
K02649  phosphoinositide-3-kinase regulatory subunit alpha/beta/delta
K04456  RAC serine/threonine-protein kinase [EC:2.7.11.1]
K02159  apoptosis regulator BAX
K02158  Bcl-2-antagonist of cell death
K04570  Bcl-2-like 1 (apoptosis regulator Bcl-X)
K02161  apoptosis regulator Bcl-2
K04440  mitogen-activated protein kinase 8/9/10 (c-Jun N-terminal kinase) [EC:2.7.11.24]
K04564  superoxide dismutase, Fe-Mn family [EC:1.15.1.1]
K02677  classical protein kinase C alpha type [EC:2.7.11.13]
K09364  POU domain transcription factor, class 2
K03160  tumor necrosis factor receptor superfamily member 5
K03161  tumor necrosis factor ligand superfamily member 5
K07408  cytochrome P450 family 1 subfamily A1 [EC:1.14.14.1]
K17683  cytochrome P450 family 2 subfamily A6 [EC:1.14.14.-]
K17709  cytochrome P450 family 2 subfamily B6 [EC:1.14.14.-]
K17718  cytochrome P450 family 2 subfamily C8 [EC:1.14.14.1]
K17719  cytochrome P450 family 2 subfamily C9 [EC:1.14.14.51 1.14.14.52 1.14.14.53 1.14.14.-]
K07418  cytochrome P450 family 2 subfamily J [EC:1.14.14.1 1.14.14.73 1.14.14.74 1.14.14.75]
K19722  receptor for advanced glycosylation end products
K08008  NADPH oxidase 1
K21421  NADPH oxidase 2 [EC:1.-.-.-]
K08011  neutrophil cytosolic factor 1
K08009  cytochrome b-245, alpha polypeptide
K08010  neutrophil cytosolic factor 2
K08012  neutrophil cytosolic factor 4
K04392  Ras-related C3 botulinum toxin substrate 1
K05704  tyrosine-protein kinase Src [EC:2.7.10.2]
K04447  Janus kinase 2 [EC:2.7.10.2]
K04692  signal transducer and activator of transcription 3
K04393  cell division control protein 42
K04430  mitogen-activated protein kinase kinase 4 [EC:2.7.12.2]
K04431  mitogen-activated protein kinase kinase 7 [EC:2.7.12.2]
K04379  proto-oncogene protein c-fos
K04448  transcription factor AP-1
K14624  C-C motif chemokine 2
K06490  intercellular adhesion molecule 1
K10030  interleukin 8
K04432  mitogen-activated protein kinase kinase 3 [EC:2.7.12.2]
K04433  mitogen-activated protein kinase kinase 6 [EC:2.7.12.2]
K04441  p38 MAP kinase [EC:2.7.11.24]
K02833  GTPase HRas
K07827  GTPase KRas
K07828  GTPase NRas
K04371  mitogen-activated protein kinase 1/3 [EC:2.7.11.24]
K04735  transcription factor p65
K02580  nuclear factor NF-kappa-B p105 subunit
K06494  selectin, endothelial cell
K06496  selectin, platelet
K06527  vascular cell adhesion molecule 1
K01394  matrix metalloproteinase-3 (stromelysin 1, progelatinase) [EC:3.4.24.17]
K01403  matrix metalloproteinase-9 (gelatinase B) [EC:3.4.24.35]
K04390  tumor necrosis factor receptor superfamily member 6
K04519  interleukin 1 beta
K05405  interleukin 6
K03156  tumor necrosis factor superfamily, member 2
K04077  chaperonin GroEL [EC:5.6.1.7]
K03283  heat shock 70kDa protein 1/6/8
K26598  heat shock 70kDa protein 2
K09489  heat shock 70kDa protein 4
K04079  molecular chaperone HtpG
K09487  heat shock protein 90kDa beta
K10159  toll-like receptor 2
K05399  lipopolysaccharide-binding protein
K04391  monocyte differentiation antigen CD14
K05400  lymphocyte antigen 96
K10160  toll-like receptor 4
K05403  toll-interleukin 1 receptor (TIR) domain-containing adaptor protein
K04729  myeloid differentiation primary response protein MyD88
K04733  interleukin-1 receptor-associated kinase 4 [EC:2.7.11.1]
K04730  interleukin-1 receptor-associated kinase 1 [EC:2.7.11.1]
K03175  TNF receptor-associated factor 6 [EC:2.3.2.27]
K04403  TAK1-binding protein 1
K04404  TAK1-binding protein 2
K04427  mitogen-activated protein kinase kinase kinase 7 [EC:2.7.11.25]
K04467  inhibitor of nuclear factor kappa-B kinase subunit alpha [EC:2.7.11.10]
K07209  inhibitor of nuclear factor kappa-B kinase subunit beta [EC:2.7.11.10]
K07210  inhibitor of nuclear factor kappa-B kinase subunit gamma
K04734  NF-kappa-B inhibitor alpha
K05409  TRIF-related adaptor molecule
K05842  toll-like receptor adapter molecule 1
K03174  TNF receptor-associated factor 3
K10645  E3 ubiquitin-protein ligase mind-bomb [EC:2.3.2.27]
K12650  TRAF family member-associated NF-kappa-B activator
K07211  inhibitor of nuclear factor kappa-B kinase subunit epsilon [EC:2.7.11.10]
K05410  TANK-binding kinase 1 [EC:2.7.11.10]
K09447  interferon regulatory factor 7
K05411  interferon regulatory factor 3
K05414  interferon alpha
K05415  interferon beta
K06259  CD36 antigen
K08530  peroxisome proliferator-activated receptor gamma
K08524  retinoid X receptor alpha
K08525  retinoid X receptor beta
K08526  retinoid X receptor gamma
K05854  tyrosine-protein kinase Lyn [EC:2.7.10.2]
K05725  focal adhesion kinase 1 [EC:2.7.10.2]
K05730  guanine nucleotide exchange factor VAV
K10169  toll-like receptor 6
K04353  Ras-related protein Rap-1A
K07836  Ras-related protein Rap-1B
K12499  C-C motif chemokine 5
K05408  C-C motif chemokine 3
K05505  C-X-C motif chemokine 1/2/3
K05406  interleukin 12A
K05425  interleukin 12B
K12800  NACHT, LRR and PYD domains-containing protein 3
K05482  interleukin 18
K09490  endoplasmic reticulum chaperone BiP [EC:3.6.4.10]
K09054  cyclic AMP-dependent transcription factor ATF-6 alpha
K04452  DNA damage-inducible transcript 3
K10950  ERO1-like protein alpha [EC:1.8.4.-]
K04958  inositol 1,4,5-triphosphate receptor type 1
K04515  calcium/calmodulin-dependent protein kinase (CaM kinase) II [EC:2.7.11.17]
K08860  eukaryotic translation initiation factor 2-alpha kinase 3 [EC:2.7.11.1]
K03237  translation initiation factor 2 subunit 1
K04374  cyclic AMP-dependent transcription factor ATF-4
K08852  serine/threonine-protein kinase/endoribonuclease IRE1 [EC:2.7.11.1 3.1.26.-]
K03173  TNF receptor-associated factor 2 [EC:2.3.2.27]
K04426  mitogen-activated protein kinase kinase kinase 5 [EC:2.7.11.25]
K09027  X box-binding protein 1
K05641  ATP-binding cassette, subfamily A (ABC1), member 1
K05679  ATP-binding cassette, subfamily G (WHITE), member 1
K05638  nuclear factor erythroid 2-related factor 2
K12799  apoptosis-associated speck-like protein containing a CARD
K01370  caspase 1 [EC:3.4.22.36]
K20053  very low-density lipoprotein receptor
K06276  3-phosphoinositide dependent protein kinase-1 [EC:2.7.11.1]
K03083  glycogen synthase kinase 3 beta [EC:2.7.11.26]
K04446  nuclear factor of activated T-cells, cytoplasmic 1
K17332  nuclear factor of activated T-cells, cytoplasmic 2
K17333  nuclear factor of activated T-cells, cytoplasmic 3
K05858  phosphatidylinositol phospholipase C, beta [EC:3.1.4.11]
K01116  phosphatidylinositol phospholipase C, gamma-1 [EC:3.1.4.11]
K02183  calmodulin
K04348  serine/threonine-protein phosphatase 2B catalytic subunit [EC:3.1.3.16]
K06268  serine/threonine-protein phosphatase 2B regulatory subunit
K04721  tumor necrosis factor ligand superfamily member 10
K04722  tumor necrosis factor receptor superfamily member 10A/B
K03158  tumor necrosis factor receptor superfamily member 1A
K04389  tumor necrosis factor ligand superfamily member 6
K04398  caspase 8 [EC:3.4.22.61]
K04726  BH3 interacting domain death agonist
K08738  cytochrome c
K02084  apoptotic protease-activating factor
K04399  caspase 9 [EC:3.4.22.62]
K04396  caspase 6 [EC:3.4.22.59]
K02187  caspase 3 [EC:3.4.22.56]
K04397  caspase 7 [EC:3.4.22.60]
K04451  tumor protein p53
Compound
C00027  Hydrogen peroxide
C00076  Calcium cation
C00187  Cholesterol
C00338  Lipopolysaccharide
C00422  Triacylglycerol
C00704  Superoxide
C00865  Phospholipid
C01245  D-myo-Inositol 1,4,5-trisphosphate
C02530  Cholesterol ester
C05981  Phosphatidylinositol-3,4,5-trisphosphate
C21011  [Protein]-N(epsilon)-(carboxymethyl)lysine
C21012  [Protein]-N(epsilon)-(carboxyethyl)lysine
C21013  [Protein]-pyrraline
C21014  [Protein]-pentosidine
Reference
  Authors
Hopkins PN
  Title
Molecular biology of atherosclerosis.
  Journal
Physiol Rev 93:1317-542 (2013)
DOI:10.1152/physrev.00004.2012
Reference
  Authors
Weber C, Noels H
  Title
Atherosclerosis: current pathogenesis and therapeutic options.
  Journal
Nat Med 17:1410-22 (2011)
DOI:10.1038/nm.2538
Reference
  Authors
Tabas I, Garcia-Cardena G, Owens GK
  Title
Recent insights into the cellular biology of atherosclerosis.
  Journal
J Cell Biol 209:13-22 (2015)
DOI:10.1083/jcb.201412052
Reference
  Authors
Tall AR, Yvan-Charvet L
  Title
Cholesterol, inflammation and innate immunity.
  Journal
Nat Rev Immunol 15:104-16 (2015)
DOI:10.1038/nri3793
Reference
  Authors
Kattoor AJ, Goel A, Mehta JL
  Title
LOX-1: Regulation, Signaling and Its Role in Atherosclerosis.
  Journal
Antioxidants (Basel) 8:E218 (2019)
DOI:10.3390/antiox8070218
Reference
  Authors
Mehta JL, Li D
  Title
Identification, regulation and function of a novel lectin-like oxidized low-density lipoprotein receptor.
  Journal
J Am Coll Cardiol 39:1429-35 (2002)
DOI:10.1016/s0735-1097(02)01803-x
Reference
  Authors
Li D, Mehta JL
  Title
Intracellular signaling of LOX-1 in endothelial cell apoptosis.
  Journal
Circ Res 104:566-8 (2009)
DOI:10.1161/CIRCRESAHA.109.194209
Reference
  Authors
Lubrano V, Balzan S
  Title
LOX-1 and ROS, inseparable factors in the process of endothelial damage.
  Journal
Free Radic Res 48:841-8 (2014)
DOI:10.3109/10715762.2014.929122
Reference
  Authors
Xu S, Ogura S, Chen J, Little PJ, Moss J, Liu P
  Title
LOX-1 in atherosclerosis: biological functions and pharmacological modifiers.
  Journal
Cell Mol Life Sci 70:2859-72 (2013)
DOI:10.1007/s00018-012-1194-z
Reference
  Authors
Mitra S, Goyal T, Mehta JL
  Title
Oxidized LDL, LOX-1 and atherosclerosis.
  Journal
Cardiovasc Drugs Ther 25:419-29 (2011)
DOI:10.1007/s10557-011-6341-5
Reference
  Authors
Lu J, Mitra S, Wang X, Khaidakov M, Mehta JL
  Title
Oxidative stress and lectin-like ox-LDL-receptor LOX-1 in atherogenesis and tumorigenesis.
  Journal
Antioxid Redox Signal 15:2301-33 (2011)
DOI:10.1089/ars.2010.3792
Reference
  Authors
Ou HC, Song TY, Yeh YC, Huang CY, Yang SF, Chiu TH, Tsai KL, Chen KL, Wu YJ, Tsai CS, Chang LY, Kuo WW, Lee SD
  Title
EGCG protects against oxidized LDL-induced endothelial dysfunction by inhibiting LOX-1-mediated signaling.
  Journal
J Appl Physiol (1985) 108:1745-56 (2010)
DOI:10.1152/japplphysiol.00879.2009
Reference
  Authors
Chen XP, Zhang TT, Du GH
  Title
Lectin-like oxidized low-density lipoprotein receptor-1, a new promising target for the therapy of atherosclerosis?
  Journal
Cardiovasc Drug Rev 25:146-61 (2007)
DOI:10.1111/j.1527-3466.2007.00009.x
Reference
  Authors
Mattaliano MD, Wooters J, Shih HH, Paulsen JE
  Title
ROCK2 associates with lectin-like oxidized LDL receptor-1 and mediates oxidized LDL-induced IL-8 production.
  Journal
Am J Physiol Cell Physiol 298:C1180-7 (2010)
DOI:10.1152/ajpcell.00483.2009
Reference
  Authors
Salvador B, Arranz A, Francisco S, Cordoba L, Punzon C, Llamas MA, Fresno M
  Title
Modulation of endothelial function by Toll like receptors.
  Journal
Pharmacol Res 108:46-56 (2016)
DOI:10.1016/j.phrs.2016.03.038
Reference
  Authors
Moore KJ, Sheedy FJ, Fisher EA
  Title
Macrophages in atherosclerosis: a dynamic balance.
  Journal
Nat Rev Immunol 13:709-21 (2013)
DOI:10.1038/nri3520
Reference
  Authors
Butoi E, Gan AM, Manduteanu I
  Title
Molecular and functional interactions among monocytes/macrophages and smooth muscle cells and their relevance for atherosclerosis.
  Journal
Crit Rev Eukaryot Gene Expr 24:341-55 (2014)
DOI:10.1615/critreveukaryotgeneexpr.2014012157
Reference
  Authors
Sheedy FJ, Moore KJ
  Title
IL-1 signaling in atherosclerosis: sibling rivalry.
  Journal
Nat Immunol 14:1030-2 (2013)
DOI:10.1038/ni.2711
Reference
  Authors
Moore KJ, Tabas I
  Title
Macrophages in the pathogenesis of atherosclerosis.
  Journal
Cell 145:341-55 (2011)
DOI:10.1016/j.cell.2011.04.005
Reference
  Authors
Gui T, Shimokado A, Sun Y, Akasaka T, Muragaki Y
  Title
Diverse roles of macrophages in atherosclerosis: from inflammatory biology to biomarker discovery.
  Journal
Mediators Inflamm 2012:693083 (2012)
DOI:10.1155/2012/693083
Reference
  Authors
Collot-Teixeira S, Martin J, McDermott-Roe C, Poston R, McGregor JL
  Title
CD36 and macrophages in atherosclerosis.
  Journal
Cardiovasc Res 75:468-77 (2007)
DOI:10.1016/j.cardiores.2007.03.010
Reference
  Authors
Park YM, Febbraio M, Silverstein RL
  Title
CD36 modulates migration of mouse and human macrophages in response to oxidized LDL and may contribute to macrophage trapping in the arterial intima.
  Journal
J Clin Invest 119:136-45 (2009)
DOI:10.1172/JCI35535
Reference
  Authors
Park YM
  Title
CD36, a scavenger receptor implicated in atherosclerosis.
  Journal
Exp Mol Med 46:e99 (2014)
DOI:10.1038/emm.2014.38
Reference
  Authors
Seimon TA, Nadolski MJ, Liao X, Magallon J, Nguyen M, Feric NT, Koschinsky ML, Harkewicz R, Witztum JL, Tsimikas S, Golenbock D, Moore KJ, Tabas I
  Title
Atherogenic lipids and lipoproteins trigger CD36-TLR2-dependent apoptosis in macrophages undergoing endoplasmic reticulum stress.
  Journal
Cell Metab 12:467-82 (2010)
DOI:10.1016/j.cmet.2010.09.010
Reference
  Authors
Nimgulkar C, Ghosh S, Sankar AB, Uday KP, Surekha MV, Madhusudhanachary P, Annapurna BR, Raghu P, Bharatraj DK
  Title
Combination of spices and herbal extract restores macrophage foam cell migration and abrogates the athero-inflammatory signalling cascade of atherogenesis.
  Journal
Vascul Pharmacol 72:53-63 (2015)
DOI:10.1016/j.vph.2015.02.014
Reference
  Authors
Canton J, Neculai D, Grinstein S
  Title
Scavenger receptors in homeostasis and immunity.
  Journal
Nat Rev Immunol 13:621-34 (2013)
DOI:10.1038/nri3515
Reference
  Authors
Erridge C
  Title
The roles of Toll-like receptors in atherosclerosis.
  Journal
J Innate Immun 1:340-9 (2009)
DOI:10.1159/000191413
Reference
  Authors
Seneviratne AN, Sivagurunathan B, Monaco C
  Title
Toll-like receptors and macrophage activation in atherosclerosis.
  Journal
Clin Chim Acta 413:3-14 (2012)
DOI:10.1016/j.cca.2011.08.021
Reference
  Authors
Miller YI, Choi SH, Wiesner P, Fang L, Harkewicz R, Hartvigsen K, Boullier A, Gonen A, Diehl CJ, Que X, Montano E, Shaw PX, Tsimikas S, Binder CJ, Witztum JL
  Title
Oxidation-specific epitopes are danger-associated molecular patterns recognized by pattern recognition receptors of innate immunity.
  Journal
Circ Res 108:235-48 (2011)
DOI:10.1161/CIRCRESAHA.110.223875
Reference
  Authors
Tabas I
  Title
The role of endoplasmic reticulum stress in the progression of atherosclerosis.
  Journal
Circ Res 107:839-50 (2010)
DOI:10.1161/CIRCRESAHA.110.224766
Reference
  Authors
Grootaert MOJ, Moulis M, Roth L, Martinet W, Vindis C, Bennett MR, De Meyer GRY
  Title
Vascular smooth muscle cell death, autophagy and senescence in atherosclerosis.
  Journal
Cardiovasc Res 114:622-634 (2018)
DOI:10.1093/cvr/cvy007
Reference
  Authors
Lipskaia L, Pourci ML, Delomenie C, Combettes L, Goudouneche D, Paul JL, Capiod T, Lompre AM
  Title
Phosphatidylinositol 3-kinase and calcium-activated transcription pathways are required for VLDL-induced smooth muscle cell proliferation.
  Journal
Circ Res 92:1115-22 (2003)
DOI:10.1161/01.RES.0000074880.25540.D0
Reference
  Authors
Cervantes Gracia K, Llanas-Cornejo D, Husi H
  Title
CVD and Oxidative Stress.
  Journal
J Clin Med 6:E22 (2017)
DOI:10.3390/jcm6020022
Reference
  Authors
Hansson GK, Hermansson A
  Title
The immune system in atherosclerosis.
  Journal
Nat Immunol 12:204-12 (2011)
DOI:10.1038/ni.2001
Reference
  Authors
Roy H, Bhardwaj S, Yla-Herttuala S
  Title
Molecular genetics of atherosclerosis.
  Journal
Hum Genet 125:467-91 (2009)
DOI:10.1007/s00439-009-0654-5
Reference
  Authors
Lusis AJ, Fogelman AM, Fonarow GC
  Title
Genetic basis of atherosclerosis: part I: new genes and pathways.
  Journal
Circulation 110:1868-73 (2004)
DOI:10.1161/01.CIR.0000143041.58692.CC
Reference
  Authors
Lusis AJ, Mar R, Pajukanta P
  Title
Genetics of atherosclerosis.
  Journal
Annu Rev Genomics Hum Genet 5:189-218 (2004)
DOI:10.1146/annurev.genom.5.061903.175930
Related
pathway
ko04020  Calcium signaling pathway
ko04115  p53 signaling pathway
ko04141  Protein processing in endoplasmic reticulum
ko04151  PI3K-Akt signaling pathway
ko04210  Apoptosis
ko04620  Toll-like receptor signaling pathway
ko04621  NOD-like receptor signaling pathway
ko04668  TNF signaling pathway
ko04670  Leukocyte transendothelial migration
ko04975  Fat digestion and absorption
ko04979  Cholesterol metabolism
ko05418  Fluid shear stress and atherosclerosis
LinkDB

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