Transmembrane signaling pathway mediates oxidized low-density lipoprotein-induced expression of plasminogen activator inhibitor-1 in vascular endothelial cells

Sangle, Ganesh V.; Zhao, Ruozhi; Shen, Garry X.

doi:10.1152/ajpendo.90415.2008

Cited by 30 publications

(20 citation statements)

References 60 publications

(81 reference statements)

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“…The ROCK inhibitor fasudil led to a 54% reduction in atherosclerosis in ApoE-null mice (1984), confirming a prior observation using another ROCK inhibitor in LDLR KO mice which resulted in a 35% reduction in aortic sinus lesions (1128). Finally, activation of the Ras, Raf, ERK1/2 cascade leads to increase PAI-1 expression in response to oxLDL through the LOX-1 receptor (1536).…”

Section: Role Of the Oxidized Ldl Receptorsupporting

confidence: 76%

Molecular Biology of Atherosclerosis

Hopkins

2013

Physiological Reviews

382

344

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At least 468 individual genes have been manipulated by molecular methods to study their effects on the initiation, promotion, and progression of atherosclerosis. Most clinicians and many investigators, even in related disciplines, find many of these genes and the related pathways entirely foreign. Medical schools generally do not attempt to incorporate the relevant molecular biology into their curriculum. A number of key signaling pathways are highly relevant to atherogenesis and are presented to provide a context for the gene manipulations summarized herein. The pathways include the following: the insulin receptor (and other receptor tyrosine kinases); Ras and MAPK activation; TNF-␣ and related family members leading to activation of NF-B; effects of reactive oxygen species (ROS) on signaling; endothelial adaptations to flow including G protein-coupled receptor (GPCR) and integrin-related signaling; activation of endothelial and other cells by modified lipoproteins; purinergic signaling; control of leukocyte adhesion to endothelium, migration, and further activation; foam cell formation; and macrophage and vascular smooth muscle cell signaling related to proliferation, efferocytosis, and apoptosis. This review is intended primarily as an introduction to these key signaling pathways. They have become the focus of modern atherosclerosis research and will undoubtedly provide a rich resource for future innovation toward intervention and prevention of the number one cause of death in the modern world.

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Section: Role Of the Oxidized Ldl Receptorsupporting

confidence: 76%

Molecular Biology of Atherosclerosis

Hopkins

2013

Physiological Reviews

382

344

View full text Add to dashboard Cite

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“…However, we found that CD32 activation was requisite for CRP-induced PAI-1 expression in HCAEC (Figure 8), in agreement with a previous report. 35 Although the ability of LOX-1 to increase PAI-1 expression by oxidized low-density lipoprotein has been recently shown in the same cell type, 59 we found that LOX-1 blockade failed to prevent PAI-1 upregulation by CRP (Figure 8). The explanation for the observed inconsistency in LOX-1-and CD32-dependent induction of PAI-1 by CRP in intact vessels versus HCAEC in the present study remains unclear.…”

Section: Discussionmentioning

confidence: 47%

Selective Activation of Lectin-Like Oxidized Low-Density Lipoprotein Receptor-1 Mediates C-Reactive Protein–Evoked Endothelial Vasodilator Dysfunction in Coronary Arterioles

Hein

Qamirani

Ren

et al. 2014

Circulation Research

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I nflammation-related cardiovascular disturbance is regarded as a pivotal event in the development of atherosclerosis. 1 C-reactive protein (CRP), a biomarker of inflammation and cardiovascular deterioration, is becoming an emerging risk factor for cardiovascular disease. The landmark Justification for the Use of statins in Prevention: an Intervention Trial Evaluating Rosuvastatin (JUPITER) study recently showed that statin therapy significantly reduced the CRP levels, along with the incidence of major cardiovascular events, in apparently healthy individuals with elevated CRP (≥2 µg/mL). 2,3Despite the lack of direct evidence for a causal link of CRP, accumulating findings suggest that CRP is actively involved in promoting adverse cardiovascular outcomes because of its proatherogenic effects on vascular cells. 4 In cell culture models, CRP, at relatively high pharmacological concentrations (25-100 µg/mL), has been shown to elevate reactive oxygen species generation from vascular cells 5,6 and impair nitric oxide (NO) synthase (NOS) activity and NO production, 7,8 as well as prostacyclin (PGI 2 ) release, 5 from endothelial cells. Extending the studies from a homogeneous cell type in culture, we recently demonstrated in intact coronary arterioles that CRP, at a clinically relevant concentration (7 µg/mL), impairs endothelium-dependent NO-mediated and PGI 2 -mediated dilations by reducing NO bioavailability 9 and inhibiting PGI 2 synthase activation, respectively.10 The detrimental effect of CRP on vasodilator function depended on endothelial production of reduced form of nicotinamide dinucleotide phosphate (NAD[P]H) oxidase-derived superoxide

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“…Nuclear proteins were extracted from EC as previously described (23). Doublestrand oligonucleotide corresponding to the Ϫ1,141/Ϫ1,126 bp (AATAGAAATAAAGCAC) region of PAI-1 promoter (GenBank no.…”

Section: Methodsmentioning

confidence: 99%

“…Previous studies in our laboratory demonstrated that oxidized LDL activated PAI-1 promoter in EC, which was associated with an increase of PAI-1 expression in EC (9). Our group recently demonstrated that lectin-like oxidized LDL receptor, H-Ras, and Raf/extracellular signal-regulated kinase pathway mediated oxidized LDL-induced PAI-1 production in EC (23). Oxidized LDL stimulated the generation of reactive oxygen species (ROS) from EC (34).…”

mentioning

confidence: 91%

Involvement of NADPH oxidase in oxidized LDL-induced upregulation of heat shock factor-1 and plasminogen activator inhibitor-1 in vascular endothelial cells

Zhao¹,

Ma²,

Xie³

et al. 2009

American Journal of Physiology-Endocrinology and Metabolism

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. The present study demonstrated that LDL oxidized by copper, iron, or 3-morpholinosydnonimine increased the expression of NADPH oxidase (NOX) 2, PAI-1, and heat shock factor-1 (HSF1) in human umbilical vein EC or coronary artery EC compared with LDL or vehicle. Diphenyleneiodonium, a NOX inhibitor, prevented the increases of the expression of HSF1 and PAI-1 in EC induced by oxidized LDLs. Small-interference RNA (siRNA) for p22 phox , an essential subunit of NOX, prevented oxidized LDL-induced expression of NOX2, HSF1, and PAI-1 in EC. HSF1 siRNA inhibited oxidized LDL-induced expression of PAI-1 and HSF1, but not NOX2, in EC. The binding of HSF1 to PAI-1 promoter and the activity of PAI-1 promoter in EC were enhanced by oxidized LDL. Butylated hydroxytulene, a potent antioxidant, inhibited oxidized LDL-induced release of hydrogen peroxide (H2O2) and the expression of NOX2, HSF1, and PAI-1 in EC. Treatment with H2O2 increased the abundance of NOX2, HSF1, and PAI-1 in EC. The results of the present study indicate that oxidized LDL-induced expression of NOX may lead to the elevated release of reactive oxygen species, the activation of HSF1, and the enhancement of the transcription of PAI-1 gene in cultured vascular EC.

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Transmembrane signaling pathway mediates oxidized low-density lipoprotein-induced expression of plasminogen activator inhibitor-1 in vascular endothelial cells

Abstract: Sangle GV, Zhao R, Shen GX. Transmembrane signaling pathway mediates oxidized low-density lipoprotein-induced expression of plasminogen activator inhibitor-1 in vascular endothelial cells.

Cited by 30 publications

References 60 publications

Molecular Biology of Atherosclerosis

Molecular Biology of Atherosclerosis

Selective Activation of Lectin-Like Oxidized Low-Density Lipoprotein Receptor-1 Mediates C-Reactive Protein–Evoked Endothelial Vasodilator Dysfunction in Coronary Arterioles

Involvement of NADPH oxidase in oxidized LDL-induced upregulation of heat shock factor-1 and plasminogen activator inhibitor-1 in vascular endothelial cells

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