Statins and nitric oxide reduce C-reactive protein production while inflammatory conditions persist

Voleti, Bhavya; Agrawal, Alok

doi:10.1016/j.molimm.2005.06.045

Cited by 35 publications

(31 citation statements)

References 51 publications

(64 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…41,42 Given their antiatherogenic and antiinflammatory properties, LXR agonists have been proposed as promising therapeutic approach to treat cardiovascular disease. 38 To determine the effect of synthetic LXR ligands on cytokine-induced CRP expression, quiescent Hep3B cells were pretreated with T0901317 or GW3965 for 18 hours and stimulated with a combination of IL-1␤ (20 ng/mL) and IL-6 (10 ng/mL) for an additional 24 hours.…”

Section: Lxr Agonists Suppress Crp Expression In Hep3b Cellsmentioning

confidence: 99%

A Nuclear Receptor Corepressor–Dependent Pathway Mediates Suppression of Cytokine-Induced C-Reactive Protein Gene Expression by Liver X Receptor

Blaschke

Takata

Caglayan

et al. 2006

Circulation Research

View full text Add to dashboard Cite

Abstract-C-reactive protein (CRP), the prototypical human acute phase protein, is an independent risk predictor of future cardiovascular events, both in healthy individuals and in patients with known cardiovascular disease. In addition, previous studies indicate that CRP might have direct proatherogenic properties. Ligand activation of the liver X receptor (LXR), a member of the nuclear hormone receptor superfamily, inhibits inflammatory gene expression in macrophages and attenuates the development of atherosclerosis in various animal models. We demonstrate herein that 2 synthetic LXR ligands, T0901317 and GW3965, inhibit interleukin-1␤/interleukin-6 -induced CRP mRNA and protein expression in human hepatocytes. Knockdown of LXR␣/␤ by short interfering RNAs completely abolished the inhibitory effect of the LXR agonist T0901317 on cytokine-induced CRP gene transcription. Transient transfection experiments with 5Ј-deletion CRP promoter constructs identified a region from Ϫ125 to Ϫ256 relative to the initiation site that mediated the inhibitory effect of LXR ligands on CRP gene transcription. Depletion of the nuclear receptor corepressor by specific short interfering RNA increased cytokine-inducible CRP mRNA expression and promoter activity and reversed LXR ligand-mediated repression of CRP gene transcription. Chromatin immunoprecipitation assays indicated that nuclear receptor corepressor is present on the endogenous CRP promoter under basal conditions. Cytokine-induced clearance of nuclear receptor corepressor complexes was inhibited by LXR ligand treatment, maintaining the CRP gene in a repressed state. Finally, treatment of C57Bl6/J mice with LXR ligands attenuated lipopolysaccharide-induced mouse CRP and serum amyloid P component gene expression in the liver, whereas no effect was observed in LXR␣␤ knockout mice. Our observations identify a novel mechanism of inflammatory gene regulation by LXR ligands. Thus, inhibition of CRP expression by LXR agonists may provide a promising approach to impact initiation and progression of atherosclerosis. (Circ Res. 2006;99:e88-e99.)

show abstract

Section: Lxr Agonists Suppress Crp Expression In Hep3b Cellsmentioning

confidence: 99%

A Nuclear Receptor Corepressor–Dependent Pathway Mediates Suppression of Cytokine-Induced C-Reactive Protein Gene Expression by Liver X Receptor

Blaschke

Takata

Caglayan

et al. 2006

Circulation Research

View full text Add to dashboard Cite

show abstract

“…Recently, in ApoB 100/100 Ldlr Ϫ/Ϫ murine model of human-like atherosclerosis, CRP was found to be atheroprotective and the importance of CRP-LDL interaction in this protection was noted (53). Combined data support the view that CRP is beneficial and lowering its serum level may not be advisable (10,54).…”

Section: Discussionmentioning

confidence: 89%

C-Reactive Protein-Bound Enzymatically Modified Low-Density Lipoprotein Does Not Transform Macrophages into Foam Cells

Singh¹,

Suresh²,

Prayther³

et al. 2008

The Journal of Immunology

Self Cite

View full text Add to dashboard Cite

The formation of low-density lipoprotein (LDL) cholesterol-loaded macrophage foam cells contributes to the development of atherosclerosis. C-reactive protein (CRP) binds to atherogenic forms of LDL, but the role of CRP in foam cell formation is unclear. In this study, we first explored the binding site on CRP for enzymatically modified LDL (E-LDL), a model of atherogenic LDL to which CRP binds. As reported previously, phosphocholine (PCh) inhibited CRP-E-LDL interaction, indicating the involvement of the PCh-binding site of CRP in binding to E-LDL. However, the amino acids Phe66 and Glu81 in CRP that participate in CRP-PCh interaction were not required for CRP-E-LDL interaction. Surprisingly, blocking of the PCh-binding site with phosphoethanolamine (PEt) dramatically increased the binding of CRP to E-LDL. The PEt-mediated enhancement in the binding of CRP to E-LDL was selective for E-LDL because PEt inhibited the binding of CRP to another PCh-binding site-ligand pneumococcal C-polysaccharide. Next, we investigated foam cell formation by CRP-bound E-LDL. We found that, unlike free E-LDL, CRP-bound E-LDL was inactive because it did not transform macrophages into foam cells. The function of CRP in eliminating the activity of E-LDL to form foam cells was not impaired by the presence of PEt. Combined data lead us to two conclusions. First, PEt is a useful compound because it potentiates the binding of CRP to E-LDL and, therefore, increases the efficiency of CRP to prevent transformation of macrophages into E-LDL-loaded foam cells. Second, the function of CRP to prevent formation of foam cells may influence the process of atherogenesis.

show abstract

“…First, statins, the cholesterol-lowering agents, reduce the risk of atherosclerosis; still many individuals receiving statins and with normal cholesterol levels develop atherosclerosis [30][31][32][33]. We speculate that the CRP-PEt complexes, after binding to native LDL, may cause lowering of the LDL levels because CRP-bound LDL would likely be catabolized.…”

Section: Discussionmentioning

confidence: 98%

Phosphoethanolamine-complexed C-reactive protein: A pharmacological-like macromolecule that binds to native low-density lipoprotein in human serum

Singh

Suresh

Prayther

et al. 2008

Clinica Chimica Acta

Self Cite

View full text Add to dashboard Cite

Background-C-reactive protein (CRP) is an acute phase plasma protein. An important binding specificity of CRP is for the modified forms of low-density lipoprotein (LDL) in which the phosphocholine-binding sites of CRP participate. CRP, however, does not bind to native LDL.Methods-We investigated the interaction of CRP with native LDL using sucrose density gradient ultracentrifugation.Results-We found that the blocking of the phosphocholine-binding sites of CRP with phosphoethanolamine (PEt) converted CRP into a potent molecule for binding to native LDL. In the presence of PEt, CRP acquired the ability to bind to fluid-phase purified native LDL. Because purified native LDL may undergo subtle modifications, we also used whole human serum as the source of native LDL. In the presence of PEt, CRP bound to native LDL in serum also. The effect of PEt on CRP was selective for LDL because PEt-complexed CRP did not bind to high-density lipoprotein in the serum.Conclusions-The pharmacologic intervention of endogenous CRP by PEt-based compounds, or the use of exogenously prepared CRP-PEt complexes, may turn out to be an effective approach to capture native LDL cholesterol in vivo to prevent the development of atherosclerosis.

show abstract

Statins and nitric oxide reduce C-reactive protein production while inflammatory conditions persist

Cited by 35 publications

References 51 publications

A Nuclear Receptor Corepressor–Dependent Pathway Mediates Suppression of Cytokine-Induced C-Reactive Protein Gene Expression by Liver X Receptor

A Nuclear Receptor Corepressor–Dependent Pathway Mediates Suppression of Cytokine-Induced C-Reactive Protein Gene Expression by Liver X Receptor

C-Reactive Protein-Bound Enzymatically Modified Low-Density Lipoprotein Does Not Transform Macrophages into Foam Cells

Phosphoethanolamine-complexed C-reactive protein: A pharmacological-like macromolecule that binds to native low-density lipoprotein in human serum

Contact Info

Product

Resources

About