Ezetimibe inhibits platelet activation and uPAR expression on endothelial cells

Becher, Tobias; Schulze, Torsten J.; Schmitt, Melanie A.; El‐Battrawy, Ibrahim; Akın, İbrahim; Kälsch, Thorsten; Borggrefe, Martin; Stach, Ksenija

doi:10.1016/j.ijcard.2016.09.122

Cited by 19 publications

(17 citation statements)

References 31 publications

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“…32 At present, there are few studies on long-term cell cultures of human platelets. The megakaryocytic (Dami), 33,34 monocytic (THP-1), 35 and endothelial cell lines (HUVEC and EA.hy926) 36,37 have been frequently substituted for the study of platelet functions and cardiovascular diseases. In this study, we confirmed that TXS expression in megakaryoblastic Dami cells was higher than in other cell lines we studied, including THP-1, HUVEC, and EA.hy926 cells.…”

Section: Discussionmentioning

confidence: 99%

miR-34b-3p May Promote Antiplatelet Efficiency of Aspirin by Inhibiting Thromboxane Synthase Expression

et al. 2019

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Aspirin has been widely used for the prevention of cardiovascular diseases, but its antiplatelet efficiency varies between individuals. The present study aimed to evaluate response to aspirin based on gene profiles as well as potential regulating pathways using human blood samples and cell lines. Platelet function in patients 50 years or older with coronary artery disease on 100 mg/day aspirin was measured by light transmission aggregometry (LTA) of arachidonic acid (AA)-induced platelet aggregation. The expression of eight candidate genes—PTGS1/COX1, PLA2G4A, PLA2G6, PLA2G7, TBXAS1, TBXA2R, PTGIR, and ITGA2B—and the ingredients involved in AA metabolism were analyzed. Our data showed that the expressions of thromboxane A synthase 1 (TBXAS1), thromboxane synthase (TXS), and thromboxane B2 (TXB2) were increased in the upper quartile of platelet aggregation (LTA-AA_Q4) group compared with the lower quartile of platelet aggregation (LTA-AA_Q1) group. Our bioinformatics analysis suggested that TBXAS1 was targeted by miR-34b-3p via binding to its 3′-UTR, which was subsequently verified experimentally. Although overexpression of miR-34b-3p exhibited no apparent effect on cell proliferation, inhibition of miR-34b-3p promoted megakaryocyte viability. Our data demonstrated that the expression of TBXAS1 was higher in the aspirin hyporesponsiveness group than that in the hyperresponsiveness group, suggesting that high expression of TBXAS1 may be associated with aspirin hyporesponsiveness. miR-34b-3p may regulate the platelet and aspirin response by suppressing TBXAS1 expression and megakaryocyte proliferation.

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Section: Discussionmentioning

confidence: 99%

miR-34b-3p May Promote Antiplatelet Efficiency of Aspirin by Inhibiting Thromboxane Synthase Expression

et al. 2019

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“…Ezetimibe is a top selling hypolipidemic drug for the treatment of cardiovascular disease which acts as a novel selective cholesterol absorption inhibitor to prevent intestinal intake of cholesterol from the diet without affecting the synthesis of cholesterol by the body itself. [1][2][3][4][5] Therefore, the synthesis of ezetimibe has important com- 75 C), which results in low overall yield, high production cost, poor security, and contaminant discharge. 6,7 To explore for the synthesis approaches which meet the concepts of green chemistry is of great value.…”

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Efficient production of an ezetimibe intermediate using carbonyl reductase coupled with glucose dehydrogenase

Zhang

Zhou

et al. 2020

Biotechnology Progress

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Ezetimibe is a top-selling hypolipidemic drug for the treatment of cardiovascular diseases. Biosynthesis of (4S)-3-[(5S)-5-(4-fluorophenyl)-5-hydroxypentanoyl]-4-phenyl-1,3-oxazolidin-2-one ((S)-ET-5) using carbonyl reductase has shown advantages including high catalytic efficiency, excellent stereoselectivity, mild reaction conditions, and environmental friendness, and was considered as the key step for ezetimibe production. The regeneration efficiency of the cofactor, nicotinamide adenine dinucleotide (phosphate) (NAD(P)H) is one of the main restricted factor. Recombinant Escherichia coli strain (smCR125) coexpressing carbonyl reductase (CR125) and glucose dehydrogenase were successfully constructed and applied for the production of (S)-ET-5 for the first time. Without extra addition of the coenzyme NADPH, the yield of 99.8% and the enantiomeric excess (e.e.) of 99.9% were achieved under ET-4 concentration of 200 g/L. Using a substrate fed-batch strategy, under the optimal conditions, the substrate ET-4 concentration was increased to 250 g/L with the yield of 98.9% and the e.e. of 99.9% after 12 hr reaction. The space-time yield of 494.5 g L −1 d −1 and the space-time yield per gram biocatalyst of 24.7 g L −1 d −1 g −1 DCW were achieved, which were higher than ever reported for the biosynthesis of the ezetimibe intermediate.

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“…[8] Ezetimibe targets the Niemann-Pick C1-like 1 (NPC1L1) transporter protein on the plasma membrane and decreases the LDL-C concentration in plasma by blocking exogenous cholesterol absorption. [10] Recent studies describe that ezetimibe alone indicated the same protective effect on the moderate atherosclerotic lesion compared to atorvastatin; the researchers believe that this anti-atherosclerotic effects of ezetimibe might result from lowering serum cholesterol, decreasing circulatory inflammatory cytokines, and inhibiting the macrophage accumulation in lesions. [10] Recent studies describe that ezetimibe alone indicated the same protective effect on the moderate atherosclerotic lesion compared to atorvastatin; the researchers believe that this anti-atherosclerotic effects of ezetimibe might result from lowering serum cholesterol, decreasing circulatory inflammatory cytokines, and inhibiting the macrophage accumulation in lesions.…”

Section: Introductionmentioning

confidence: 99%

“…[9] In addition to its lipid-lowering effect, it has also been shown to attenuate directly the platelet activation and the uPAR expression on endothelial cells, thereby providing further evidence of the possible pleiotropic therapeutic relevance of ezetimibe. [10] Recent studies describe that ezetimibe alone indicated the same protective effect on the moderate atherosclerotic lesion compared to atorvastatin; the researchers believe that this anti-atherosclerotic effects of ezetimibe might result from lowering serum cholesterol, decreasing circulatory inflammatory cytokines, and inhibiting the macrophage accumulation in lesions. [11] [12] The study of new CAI to improve the antihyperlipidemic effect and to give additional choice for the patients has already been acknowledged and recognized.…”

Section: Introductionmentioning

confidence: 99%

Synthesis and Evaluation of 2‐Azetidinone and 1H‐Pyrrole‐2,5‐dione Derivatives as Cholesterol Absorption Inhibitors for Reducing Inflammation Response and Oxidative Stress

Xia

Zhu

Yuan

et al. 2019

Chemistry & Biodiversity

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Excess lipid accumulation can initiate the development and progression of atherosclerotic lesions, thus eventually leading to cardiovascular disease. Lipid-lowering medication therapy is one of the cornerstones of cardiovascular disease therapy. On the basis of the cholesterol absorption inhibitor ezetimibe, we successfully synthesized seven 2-azetidinone derivatives and eighteen 1H-pyrrole-2,5-dione derivatives. Most of the new compounds significantly inhibited cholesterol uptake in vitro. In addition, one of the most active inhibitors, compound 14q, showed no cytotoxicity in L02 and HEK293T cell lines. Further evaluation indicated 14q considerably inhibited the amount of TNF-α, ROS, MDA, and LDH in vitro. Therefore, 14q might be a novel cholesterol absorption inhibitor.

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Ezetimibe inhibits platelet activation and uPAR expression on endothelial cells

Cited by 19 publications

References 31 publications

miR-34b-3p May Promote Antiplatelet Efficiency of Aspirin by Inhibiting Thromboxane Synthase Expression

miR-34b-3p May Promote Antiplatelet Efficiency of Aspirin by Inhibiting Thromboxane Synthase Expression

Efficient production of an ezetimibe intermediate using carbonyl reductase coupled with glucose dehydrogenase

Synthesis and Evaluation of 2‐Azetidinone and 1H‐Pyrrole‐2,5‐dione Derivatives as Cholesterol Absorption Inhibitors for Reducing Inflammation Response and Oxidative Stress

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