Prostanoids and NSAIDs in Cardiovascular Biology and Disease

Weksler, B

doi:10.1007/s11883-015-0514-9

Cited by 13 publications

(6 citation statements)

References 62 publications

(54 reference statements)

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“…Eicosanoids mainly act locally by signaling via specific receptors, and modulate many functions such as vasomotor tone, hemostasis, inflammation, and cell proliferation. In the pathological setting of atherosclerosis, eicosanoids play significant roles since they contribute to endothelial dysfunction and cause inflammation, arterial smooth muscle cell hyperplasia and thrombosis 1 .…”

Section: Introductionmentioning

confidence: 99%

Fatty acid desaturase 2 is up-regulated by the treatment with statin through geranylgeranyl pyrophosphate-dependent Rho kinase pathway in HepG2 cells

Tanaka

Ishihara

Suzuki

et al. 2019

Sci Rep

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Statins have been reported to increase the plasma concentration of arachidonic acid (AA), an omega-6 long chain polyunsaturated fatty acid (LCPUFA) in several clinical studies indicating that statins affect the endogenous synthesis of LCUFAs. In the present study, we investigated the roles of the intrinsic mevalonate cascade and Rho-dependent pathway in LCPUFA synthesis, especially focusing on fatty acid desaturases (Fads) 2, using the human hepatocellular carcinoma cell line HepG2. Cell number and the activity of caspase-3 and 7 (caspase-3/7) was measured using a commercial kit. Gene expression was analyzed by quantitative real-time PCR. Protein expression was detected by Western blot analysis. Atorvastatin decreased cell viability and increased caspase-3/7 activity in a dose-dependent manner. At lower concentrations, atorvastatin stimulated both mRNA and protein expression of Fads2, and increased mRNA expression of FADS1 and ELVOL5 . Both mevalonate and geranylgeranyl-pyrophosphate (GGPP), but not cholesterol, fully reversed atorvastatin-induced upregulation of Fads2, and mevalonate-effected reversal was inhibited by treatment with the Rho-associated protein kinase inhibitor Y-27632. These data clearly demonstrated that in human HepG2 cells, statins affect the endogenous synthesis of LCPUFAs by regulation of not only Fads2, but also Fads1 and Elovl5, through the GGPP-dependent Rho kinase pathway.

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Section: Introductionmentioning

confidence: 99%

Fatty acid desaturase 2 is up-regulated by the treatment with statin through geranylgeranyl pyrophosphate-dependent Rho kinase pathway in HepG2 cells

Tanaka

Ishihara

Suzuki

et al. 2019

Sci Rep

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“…PTGS1, constitutively expressed by almost every type of cells, including platelets, is involved in intercellular communication, tissue homeostasis and gastrointestinal protection. PTGS2 is usually absent in endothelial and blood cells but its expression is highly induced by a variety of stimuli (13).…”

Section: Introductionmentioning

confidence: 99%

Prostaglandin-endoperoxide synthase-2 deletion affects the natural trafficking of Annexin A2 in monocytes and favours venous thrombosis in mice

Amadio¹,

Tarantino²,

Sandrini³

et al. 2017

Thromb Haemost

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Deep-vein thrombosis (DVT) is a common condition that often leads to pulmonary thromboembolism (VTE) and death. The role of prostaglandin-endoperoxide synthase (PTGS)2 in arterial thrombosis has been well established, whereas its impact in venous thrombosis remains unclear. Here, we showed that PTGS2 deletion predisposes to venous thrombosis as suggested by greater clot firmness and clot elasticity, by higher plasma levels of functional fibrinogen, factor VIII and PAI-1 activity, and proved by bigger thrombi detected after inferior vena cava ligation (IVCL) compared to WT mice. PTGS2 thrombi have greater fibrin content, higher number of F4/80, TF and ANXA2 cells, and lower S100A10 cells. Remarkably, monocyte depletion reduced thrombus size in mutant mice, suggesting an important role of PTGS2 monocytes in this experimental setting. Interestingly, PTGS2 deletion reduced membrane ANXA2, and total S100A10, promoted assembly of ANXA2/p50NF-kB complex and its nuclear accumulation, and induced TF in peritoneal macrophages, whereas ANXA2 silencing decreased dramatically TF. Finally, Carbaprostacyclin treatment prevented venous thrombus formation induced by IVCL in mutant mice, reduced the ANXA2 binding to p50NF-kB subunit and its nuclear trafficking, and decreased TF in PTGS2 macrophages. PTGS2 deletion, changing the natural distribution of ANXA2 in monocytes/macrophages, increases TF expression and activity predisposing to venous thrombosis. Interestingly, Carbaprostacyclin treatment, inhibiting nuclear ANXA2 trafficking, controls monocyte TF activity and prevents DVT occurrence. Our data are of help in elucidating the mechanisms by which PTGS2 inhibition increases DVT risk, and suggest a new role for ANXA2 in venous thrombosis.

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“…Eicosanoids mainly act locally by signaling via specific receptors, and are able to modulate numerous functions, including vasomotor tone, hemostasis, inflammation and cell proliferation. In the pathological setting of atherosclerosis, eicosanoids serve important roles, since they contribute to endothelial dysfunction and induce inflammation, arterial smooth muscle cell hyperplasia and thrombosis ( 1 ).…”

Section: Introductionmentioning

confidence: 99%

Atorvastatin increases Fads1, Fads2 and Elovl5 gene expression via the geranylgeranyl pyrophosphate-dependent Rho kinase pathway in 3T3-L1 cells

Ishihara

Suzuki

Tanaka

et al. 2017

Molecular Medicine Reports

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Numerous clinical studies have reported that statins increase the plasma concentration of arachidonic acid, which is an ω-6 long-chain polyunsaturated fatty acid (LCPUFA), and decrease the concentrations of eicosapentaenoic acid and docosahexaenoic acid, which are ω-3 LCPUFAs. These findings indicate that statins may affect the endogenous synthesis of LCPUFAs, which is regulated by fatty acid desaturases (FADSs) and elongation of very long-chain fatty acids proteins (ELOVLs). The present study aimed to investigate the roles of the intrinsic mevalonate cascade and Rho-dependent pathway in statin-induced regulation of these desaturases and elongases, as well as cell viability using mouse 3T3-L1 cells. mRNA expression was analyzed by quantitative polymerase chain reaction. Treatment with atorvastatin decreased cell viability and increased the mRNA expression levels of Fads1, Fads2 and ELOVL fatty acid elongase 5 (Elovl5) in a dose-dependent manner. Mevalonate and geranylgeranyl pyrophosphate (GGPP), but not cholesterol, fully reversed the atorvastatin-induced downregulation of cell viability and upregulation of gene expression; however, mevalonate itself did not affect cell viability and gene expression. The Rho-associated protein kinase inhibitor Y-27632 inhibited the mevalonate- and GGPP-mediated reversal of atorvastatin-induced upregulation of Fads1, Fads2 and Elovl5. These findings indicated that statins may affect the endogenous synthesis of LCPUFAs by regulating Fads1, Fads2 and Elovl5 gene expression via the GGPP-dependent Rho kinase pathway in mouse 3T3-L1 cells.

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Prostanoids and NSAIDs in Cardiovascular Biology and Disease

Cited by 13 publications

References 62 publications

Fatty acid desaturase 2 is up-regulated by the treatment with statin through geranylgeranyl pyrophosphate-dependent Rho kinase pathway in HepG2 cells

Fatty acid desaturase 2 is up-regulated by the treatment with statin through geranylgeranyl pyrophosphate-dependent Rho kinase pathway in HepG2 cells

Prostaglandin-endoperoxide synthase-2 deletion affects the natural trafficking of Annexin A2 in monocytes and favours venous thrombosis in mice

Atorvastatin increases Fads1, Fads2 and Elovl5 gene expression via the geranylgeranyl pyrophosphate-dependent Rho kinase pathway in 3T3-L1 cells

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