The influence of lovastatin on thrombomodulin gene expression in vascular endothelial cells--in vitro study.

Góralczyk, Krzysztof; Soszyńska, Krystyna; Haus, Olga; Bielis, Robert; Rość, Danuta

doi:10.2478/v10042-009-0012-4

“…Cholesterol-lowering drugs, called statins or 3-hydroxy-3-methylglutaryl-coenzymeA reductase (HMGCR) inhibitors, are potent TM inducers [9,10,11]. Studies by various groups show that multiple signaling pathways (i.e., mevalonate and nitric oxide pathway) as well as numerous transcription factors (i.e., Kruppel-like transcription factors and heat shock factor 1) play an important role in statin-mediated TM induction [9,11,12,13,14].…”

Section: Introductionmentioning

confidence: 99%

The Vitamin E Analog Gamma-Tocotrienol (GT3) and Statins Synergistically Up-Regulate Endothelial Thrombomodulin (TM)

Pathak

¹

,

Ghosh

²

,

Zhou

³

et al. 2016

IJMS

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Statins; a class of routinely prescribed cholesterol-lowering drugs; inhibit 3-hydroxy-3-methylglutaryl-coenzymeA reductase (HMGCR) and strongly induce endothelial thrombomodulin (TM); which is known to have anti-inflammatory; anti-coagulation; anti-oxidant; and radioprotective properties. However; high-dose toxicity limits the clinical use of statins. The vitamin E family member gamma-tocotrienol (GT3) also suppresses HMGCR activity and induces TM expression without causing significant adverse side effects; even at high concentrations. To investigate the synergistic effect of statins and GT3 on TM; a low dose of atorvastatin and GT3 was used to treat human primary endothelial cells. Protein-level TM expression was measured by flow cytometry. TM functional activity was determined by activated protein C (APC) generation assay. Expression of Kruppel-like factor 2 (KLF2), one of the key transcription factors of TM, was measured by quantitative reverse transcription polymerase chain reaction (qRT-PCR). TM expression increased in a dose-dependent manner after both atorvastatin and GT3 treatment. A combined treatment of a low-dose of atorvastatin and GT3 synergistically up-regulated TM expression and functional activity. Finally; atorvastatin and GT3 synergistically increased KLF2 expression. These findings suggest that combined treatment of statins with GT3 may provide significant health benefits in treating a number of pathophysiological conditions; including inflammatory and cardiovascular diseases.

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“…Cytochalasin D Filamentous actin 10 µM (Sulahian et al, 2008) (Nikkhah et al, 2009) (Cuschieri et al, 2009) Latrunculin B Filamentous actin 5 µM (Huang et al, 2008 (Cammer et al, 2009) continued on next page (Grkovich et al, 2009) (Laitinen et al) (Mallants et al, 2009) lovastatin, sodium salt 3-hydroxy-3methylglutaryl-CoA reductase 10 µM (Mandal et al) (Dalvai and Bystricky, 2010) (Gralczyk et al, 2009) continued from previous page…”

Section: Inhibitor Target Concentration Referencementioning

confidence: 99%

Functional Comparison Of Immunoglobulin G Versus Oxidized Low-Density Lipoprotien Phagocytic Receptors In Human U937 Macrophages

Vance¹

2021

Preprint

0

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Phagocytic macrophages bind to solid oxidized low-density lipoprotein (oxLDL) deposited on the arterial intima, differentiate into foam cells and cause atherosclerosis - the largest cause of mortality in Canada. The mechanism of oxLDL internalization was examined in vitro using differentiated U937 cells exposed to latex microbeads coated with oxLDL or Immunoglobulin G (IgG). Bead internalization was quantified using immunofluorescent staining and laser confocal assays. IgG-mediated engulfment was more rapid than oxLDL-mediated engulfment indicating a qualitatively different internalization pathway. The filamentous actin inhibitors Cytochalasin D (10uM) and Latrunculin B (5uM) completely inhibited phagocytosis of both oxLDL-coated and IgG-coated beads. The Src and Spleen tyrosine kinase inhibitor 3,4-methylenedioxy-beta-nitrostyrene (20 uM), the phospholipase C inhibitor U73122 (5 uM), and the Janus kinase inhibitor AG 490 (25 uM) displayed significant inhibitory effects on the phagocytosis of both IgG and oxLDL microbeads. The specific isoforms of oxLDL and IgG receptor associated enzymes were determined by nano LC-ESI-MS/MS with an LTQ ion trap.

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“…Cytochalasin D Filamentous actin 10 µM (Sulahian et al, 2008) (Nikkhah et al, 2009) (Cuschieri et al, 2009) Latrunculin B Filamentous actin 5 µM (Huang et al, 2008 (Cammer et al, 2009) continued on next page (Grkovich et al, 2009) (Laitinen et al) (Mallants et al, 2009) lovastatin, sodium salt 3-hydroxy-3methylglutaryl-CoA reductase 10 µM (Mandal et al) (Dalvai and Bystricky, 2010) (Gralczyk et al, 2009) continued from previous page…”

Section: Inhibitor Target Concentration Referencementioning

confidence: 99%

Functional Comparison Of Immunoglobulin G Versus Oxidized Low-Density Lipoprotien Phagocytic Receptors In Human U937 Macrophages

Vance¹

2021

Preprint

0

View full text Add to dashboard Cite

Phagocytic macrophages bind to solid oxidized low-density lipoprotein (oxLDL) deposited on the arterial intima, differentiate into foam cells and cause atherosclerosis - the largest cause of mortality in Canada. The mechanism of oxLDL internalization was examined in vitro using differentiated U937 cells exposed to latex microbeads coated with oxLDL or Immunoglobulin G (IgG). Bead internalization was quantified using immunofluorescent staining and laser confocal assays. IgG-mediated engulfment was more rapid than oxLDL-mediated engulfment indicating a qualitatively different internalization pathway. The filamentous actin inhibitors Cytochalasin D (10uM) and Latrunculin B (5uM) completely inhibited phagocytosis of both oxLDL-coated and IgG-coated beads. The Src and Spleen tyrosine kinase inhibitor 3,4-methylenedioxy-beta-nitrostyrene (20 uM), the phospholipase C inhibitor U73122 (5 uM), and the Janus kinase inhibitor AG 490 (25 uM) displayed significant inhibitory effects on the phagocytosis of both IgG and oxLDL microbeads. The specific isoforms of oxLDL and IgG receptor associated enzymes were determined by nano LC-ESI-MS/MS with an LTQ ion trap.

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The influence of lovastatin on thrombomodulin gene expression in vascular endothelial cells--in vitro study.

Cited by 4 publications

References 26 publications

The Vitamin E Analog Gamma-Tocotrienol (GT3) and Statins Synergistically Up-Regulate Endothelial Thrombomodulin (TM)

The Vitamin E Analog Gamma-Tocotrienol (GT3) and Statins Synergistically Up-Regulate Endothelial Thrombomodulin (TM)

Functional Comparison Of Immunoglobulin G Versus Oxidized Low-Density Lipoprotien Phagocytic Receptors In Human U937 Macrophages

Functional Comparison Of Immunoglobulin G Versus Oxidized Low-Density Lipoprotien Phagocytic Receptors In Human U937 Macrophages

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