Endothelin Antagonism and Interleukin-6 Inhibition Attenuate the Proatherogenic Effects of C-Reactive Protein

Verma, Subodh; Li, Shuhong; Badiwala, Mitesh; Weisel, Richard D.; Fedak, Paul W.M.; Li, Ren‐Ke; Dhillon, Bikramjit; Mickle, Donald A.G.

doi:10.1161/01.cir.0000015126.83143.b4

Cited by 572 publications

(444 citation statements)

References 44 publications

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“…ET-1 synthesis and release were increased on exposure to inflammatory cytokines such as TNFa and C-reactive protein in mesangial and vascular endothelial cells. 25,26 Indeed, the blockade of inflammation by a TNFa inhibitor suppressed renal injury in DOCA-salt rats. 27 In this study, ET-1 expression was increased in association with the upregulation of inflammatory chemokines (TNFa, IL-1b and IFNg) and adhesion molecules (MCP-1 and ICAM-1) in DOCA-salt hypertension, and these effects were counteracted by RGT.…”

Section: Effects Of Rosiglitazone On Doca-salt Hypertension Eh Bae Et Almentioning

confidence: 99%

Rosiglitazone prevents the progression of renal injury in DOCA-salt hypertensive rats

et al. 2010

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This study was designed to evaluate the possible renoprotective effects of rosiglitazone (RGT), a peroxisome proliferatoractivated subtype c receptor agonist, in deoxycorticosterone acetate (DOCA)-salt hypertension and its role in endogenous endothelin-1 (ET-1) production and renal fibrosis associated with inflammation. Rats were implanted with DOCA strips (200 mg kg À1 ) at 1 week after unilateral nephrectomy. DOCA-salt rats received control diet with or without RGT (10 mg kg À1 per day). Systolic blood pressure was measured by the tail-cuff method. Glomerulosclerosis and tubulointerstitial fibrosis were evaluated on kidney sections. The expression of ED-1, cyclooxygenase-2 (COX-2), heat shock protein-25 (HSP25) and transforming growth factor-b1 (TGF-b1) was determined in the kidney by semiquantitative immunoblotting. In DOCA-salt rats, systolic blood pressure was increased, whereas creatinine clearance decreased compared with controls, which were counteracted by RGT treatment. Tubular injury and glomerulosclerois in the histological study were prominent in DOCA-salt rats, which were counteracted by RGT treatment. ET-1 expression was increased in DOCA-salts rats, which was attenuated by RGT treatment. The expression of TGF-b1, ED-1 and COX-2 was increased in DOCA-salt, which was attenuated by RGT treatment. In conclusion, RGT treatment decreases blood pressure and is effective in preventing the progression of renal injury in DOCA-salt hypertension, the mechanisms of which are associated with anti-inflammatory and anti-fibrotic effects through reducing the overexpression of ET-1, ED-1, COX-2 and TGF-b1 in the kidney.

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Section: Effects Of Rosiglitazone On Doca-salt Hypertension Eh Bae Et Almentioning

confidence: 99%

Rosiglitazone prevents the progression of renal injury in DOCA-salt hypertensive rats

et al. 2010

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“…Although its role as a biomarker or a mediator of atherosclerosis is still debated, CRP actively contributes to all stages of atherogenesis, including endothelial dysfunction, atherosclerotic-plaque formation, maturation, destabilization and eventual rupture [1,[7][8][9]. A high concentration of hsCRP has been shown to be a strong independent risk factor for cardiovascular events [1,2,[10][11][12], thus, adding prognostic information to traditional risk factors.…”

Section: Introductionmentioning

confidence: 99%

Effect of atorvastatin on circulating hsCRP concentrations: A sub-study of the Achieve Cholesterol Targets Fast with Atorvastatin Stratified Titration (ACTFAST) study

Gensini¹,

Gori²,

Dilaghi³

et al. 2010

International Journal of Cardiology

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Background: Elevated C-reactive protein (CRP) concentration is a risk factor for cardiovascular events that may add prognostic information. Statin treatment is associated with significant reductions in CRP concentrations, which appear to be unrelated to the magnitude of LDL-cholesterol reduction. We investigated the effect of atorvastatin, across its dose range, on high sensitivity (hs)CRP in subjects at high cardiovascular risk. Methods: ACTFAST was a 12 week, prospective, multicenter, open-label trial in which high-risk subjects were assigned a starting dose of atorvastatin (10,20,40 Results: At baseline, ST subjects had significantly lower hsCRP levels than SF subjects (ST group 2.31, 95% CI 2.15, 2.48 mg/L vs. SF group 3.16, 95% CI 2.98, 3.34 mg/L, p b 0.05). In the SF group, atorvastatin 10 to 80 mg significantly (p b 0.01) reduced hsCRP levels in a dose dependent-manner. In ST group, additional hsCRP reductions were observed over the statin used at baseline, which were not dosedependent. Atorvastatin significantly decreased hsCRP concentrations in subjects with or without diabetes or the metabolic syndrome. Conclusions: Atorvastatin treatment at different doses, particularly 80 mg, significantly reduced hsCRP serum concentrations. This reduction was observed in both SF and ST groups and was independent of the presence of metabolic syndrome and/or diabetes. The beneficial effect of atorvastatin was evident at 6 weeks, supporting the practice of early introduction of higher doses of atorvastatin in high-risk patients.

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“…These studies, using Abs to CRP and ApoB, or labeled LDL, revealed that CRP did not prevent uptake of modified LDL by macrophages. When measured indirectly by CD32 internalization, CRP was found to increase LDL uptake; however, the involvement of CD32 was questioned (29,32). These studies did not reveal the function of CRP in preventing formation of foam cells, probably because Nile red staining was not used to visualize cholesteryl esters.…”

Section: Discussionmentioning

confidence: 99%

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

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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.

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Endothelin Antagonism and Interleukin-6 Inhibition Attenuate the Proatherogenic Effects of C-Reactive Protein

Cited by 572 publications

References 44 publications

Rosiglitazone prevents the progression of renal injury in DOCA-salt hypertensive rats

Rosiglitazone prevents the progression of renal injury in DOCA-salt hypertensive rats

Effect of atorvastatin on circulating hsCRP concentrations: A sub-study of the Achieve Cholesterol Targets Fast with Atorvastatin Stratified Titration (ACTFAST) study

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

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