Metabolites of Arachidonic Acid and Atherosclerosis

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1 Metabolites of Arachidonic Acid and Atherosclerosis GUO Ge ZU Lingyun GAO Wei The Department of Cardiology Peking University Third Hospital Beijing China DOI /j. issn R A Abstract As the incidence of cardiovascular disease has increased atherosclerosis has become a focal point of medical research. Recent studies have found that the metabolites of arachidonic acid play an important role in the occurrence development and plaque instability of atherosclerosis and are expected to provide new ideas for the prevention and treatment of atherosclerosis. This paper summarizes the relationship between metabolites of arachidonic acid and atherosclerosis. Key words atherosclerosis arachidonic acid metabolic pathways A 2 atherosclerosis AS AS cyclooxygenase COX lipoxygenase LOX P450 cytochrome P450 AS AS CYP COX LOX 1 hydroxyeicosatetraenoic acid HETE AS CYP ω- 2 AS 1 epoxyeicosatrienoic acids EETs HETE 2 AS guogeegg@ sina. com dr_zly@ 126. com

2 527 COX PGH 2 H 2 PGD 2 D 2 PGI 2 PGE 2 E 2 TXA 2 A 2 PGDS PGD 2 PGES PGE 2 PGIS PGI 2 TXS TXA 2 LOX FLP 5-5-HPETE 5- HETE 13-HODE 13- LTA 4 A 4 LTA 4 H LTA 4 LTC 4 S LTC 4 LTB 4 B 4 LTC 4 C 4 LTD 4 D 4 LTE 4 E 4 BLT 1 /BLT 2 LTB 4 CysLT 1 /CysLT 2 CYP P450 EETs seh DHETs 1 2 COX COX COX-1 COX-2 COX-1 mpges-1 COX-2 matrix-degrading metalloproteinase MMP AS COX G 2 MMP H 2 PGI 2 E 2 PGE 2 D 2 PGD 2 A 2 thromboxane A 2 TXA 2 PGE 2 /camp 2. 1 PGI 2 TXA 2 AS PGI 2 COX-2 1 PGE 2 MMP PGI 2 1 TXA 2 COX-2 TXA 2 MMP COX-2 /mpges-1 6 PGE 2 PGD 2 PGI 2 TXA 2 κb nuclear factor kappa B NF-κB AS TXA 2 PGI 2 7 PGD 2 15d-PGJ 2 15-deoxy-α12 14-PGJ 2 NF-κB TXA 2 /PGI 2 γ AS AS 3 PGE 2 AS COX-2 / E -1 microsomal PGE synthase-1 AS MMP-2 MMP-9 MMP-2 MMP-9 4 Cipollone 5 COX-2 / mpges- 8 AS -α 2. 2 PGE 2 PGD 2 AS PGD 2 PGE 2

3 528 9 Cipollone 10 LTB 4 AS AS 60 AS D 3. 2 LTC 4 AS PGD synthase PGDS LTC 4 mpges-1 AS AS mpges-1 PGDS PGE 2 PGD 2 PGE 2 MMP AS LTC 4 LTC 4 COX-2 AS PGDS mpges-1 PGD 2 COX-2 AS mpges-1 PGDS COX-2 61% 14 LTC 4 3 LOX LOX LOX 15-LOX AS LOX 12-LOX 15-LOX 5-LOX 5-LOX 12-LOX 5- FLAP 15-LOX 12-LOX A 4 leukotreines A 4 LTA 4 LTA 4 12-HETE LTA 4 B 4 LTB 4 15-LOX 15-HETE 13- C 4 LTC 4 AS LTC 4 D 4 E 4 AS AS LTB LTB 4 AS LTB 4 AS LTB 4-1 ICAM / AS LTB HETE 5-LOX -1 LTB 4 / LTB 4 CD36 / 4 CYP AS 11 CYP 5-LOX LTB 4 CYP EETs CYP FLAP LTA 4 LTA 4 H Spanbroek 12 AS 4. 1 EETs AS 5-LOX FLAP LTA 4 H EETs 5 6-EET 8 9-EET EET 14 5-LOX 15- EET EET 14 Qiu EET EETs mrna AS EETs AS Ca 2 + K + 5-LOX LTA 4 H K + mrna AS EETs PGI 2 MMP-2 MMP-9 AS 5- EETs EETs LOX 5-LOX E apoe ApoE - / - ApoE - / - LTC 4 LTC 4 mrna 12-LOX 15-LOX 15-HETE HETE ATP

4 EETs AS EETs NF-κB AS EETs seh AS EET NF-κB EETs -α -1 ICAM-1 17 EETs seh EETs AS EETs 26 soluble epoxide HETE hydrolase seh 20-HETE AS dihydroxyeicosatrienoic acids 20-HETE DHETs seh NF-κB ICAM-1-8 AS Ulu 18 ApoE - / - AS AS seh AS 20-HETE 53% EETs /DHETs Han HETE AS EET /DHETs EET / Ⅱ DHETs Wang HETE seh 20- AS 33% 39% HETE 72% seh 20-HETE C seh AS EETs HETE EET EET 5 AS 5 min 20 Dhanasekaran min seh AS left ventricular developed pressure EET EET seh AS EETs AS 30 CYP AS EETs CYP 22 seh EETs 23 EETs Xu 24 db /db 2 CYP db /db atherosclerosis J Luo 25 seh Ephx2 seh 1 Wong BW Meredith A Lin D et al. The biological role of inflammation in. Can J Cardiol Capra V B ck M Barbieri SS et al. Eicosanoids and their drugs in cardiovascular diseases focus on atherosclerosis and stroke J. Med Res Rev Yuhki K Kashiwagi H Kojima F et al. Roles of prostanoids in the pathogene-

5 530 sis of cardiovascular diseases J. Int Angiol Suppl Newby AC. Metalloproteinase expression in monocytes and macrophages and its relationship to atherosclerotic plaque instability J. Arterioscler Thromb Vasc Biol Cipollone F Fazia M Iezzi A. Suppression of the functionally coupled cyclooxygenase-2 /prostaglandin E synthase as a basis of simvastatin-dependent plaque stabilization in humans J. Circulation Cipollone F Fazia M Iezzi A. Blockade of the angiotensin Ⅱ type 1 receptor stabilizes atherosclerotic plaques in humans by inhibiting prostaglandin E 2 -dependent matrix metalloproteinase activity J. Circulation Pamukcu B Lip GY Shantsila E. The nuclear factor-kappa B pathway in atherosclerosis a potential therapeutic target for atherothrombotic vascular disease J. Thromb Res Park SW Cho C Cho BN et al. 15-deoxy-Δ prostaglandin J 2 Down- Regulates Activin-Induced Activin Receptor Smad and Cytokines Expression via Suppression of NF- κ B and MAPK Signaling in HepG2 Cells J. PPAR Res Cuccurullo C Fazia ML Mezzetti A et al. COX-2 expression in atherosclerosis the good the bad or the ugly J. Curr Med Chem Cipollone F. The balance between PGD synthase and PGE synthase is a major determinant of atherosclerotic plaque instability in humans J. Arterioscler Thromb Vasc Biol Jala VR Haribabu B. Leukotrienes and atherosclerosis new roles for old mediators J. Trends Immunol Spanbroek R Grabner R Lotzer K et al. Expanding expression of the 5-lipoxygenase pathway within the arterial wall during human atherogenesis J. Proc Natl Acad Sci USA Qiu H Gabrielsen A Agardh HE et al. Expression of 5-lipoxygenase and leukotriene A 4 hydrolase in human atherosclerotic lesions correlates with symptoms of plaque instability J. Proc Natl Acad Sci USA Nobili E Salvado MD Folkersen L et al. Cysteinyl leukotriene signaling aggravates myocardial hypoxia in experimental atherosclerotic heart disease J. PLoS One e Dobrian AD Lieb DC Cole BK et al. Functional and pathological roles of the 12- and 15-lipoxygenases J. Prog Lipid Res Lu T Ye D Wang X et al. Cardiac and vascular KATP channels in rats are activated by endogenous epoxyeicosatrienoic acids through different mechanisms J. J Physiol Pt Fleming I Michaelis UR Bredenk tter D et al. Endothelium-derived hyperpolarizing factor synthase cytochrome P450 2C9 is a functionally significant source of reactive oxygen species in coronary arteries J. Circ Res Ulu A Davis BB Tsai HJ et al. Soluble epoxide hydrolase inhibitors reduce the development of atherosclerosis in apolipoprotein e-knockout mouse model J. J Cardiovasc Pharmacol Wang YX Ulu A Zhang LN et al. Soluble epoxide hydrolase in atherosclerosis J. Curr Atheroscler Rep Nithipatikom K Moore JM Isbell MA et al. Epoxyeicosatrienoic acids in cardioprotection ischemic versus reperfusion injury J. Am J Physiol Heart Circ Physiol H537-H Dhanasekaran A Gruenloh SK Buonaccorsi JN et al. Multiple antiapoptotic targets of the PI3K /Akt survival pathway are activated by epoxyeicosatrienoic acids to protect cardiomyocytes from hypoxia /anoxia J. Am J Physiol Heart Circ Physiol H724-H Xiao B Li X Yan J et al. Overexpression of cytochrome P450 epoxygenases prevents development of hypertension in spontaneously hypertensive rats by enhancing atrial natriuretic peptide J. J Pharmacol Exp Ther Chiamvimonvat N Ho CM Tsai HJ et al. The soluble epoxide hydrolase as a pharmaceutical target for hypertension J. J Cardiovasc Pharmacol Xu X Zhao CX Wang L et al. Increased CYP2J3 expression reduces insulin resistance in fructose-treated rats and db /db mice J. Diabetes Luo P Chang HH Zhou Y et al. Inhibition or deletion of soluble epoxide hydrolase prevents hyperglycemia promotes insulin secretion and reduces islet apoptosis J. J Pharmaol Exp Ther Xu X Zhang XA Wang DW. The roles of CYP450 epoxygenases and metabolites epoxyeicosatrienoic acids in cardiovascular and malignant diseases J. Adv Drug Deliv Rev Han Y Zhao H Tang H et al. 20-Hydroxyeicosatetraenoic acid mediates isolated heart ischemia /reperfusion injury by increasing NADPH oxidase-derived reactive oxygen species production J. Circ J Sodhi K Wu CC Cheng J et al. CYP4A2-induced hypertension is 20- hydroxyeicosatetraenoic acid and angiotensin Ⅱ dependent J. Hypertension Chen L Ackerman R Guo AM. 20-HETE in neovascularization J. Prostaglandins Other Lipid Mediat Ecker J. Profiling eicosanoids and phospholipids using LC-MS /MS principles and recent applications J. J Sep Sci

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