Reduction of In-Stent Restenosis by Cholesteryl Ester Transfer Protein Inhibition

Wu, Ben J.; Li, Yue; Sun, Yidan; Shrestha, Sudichhya; Hou, Liming; Johns, Douglas G.; Barter, Philip J.; Rye, Kerry Anne

doi:10.1161/atvbaha.117.310051

Cited by 18 publications

(16 citation statements)

References 44 publications

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“…Further, In the DEFINE study with anacetrapib, there were no significant changes in C-reactive protein levels [120]. The potential significance of a focal anti-inflammatory activity of anacetrapib is supported by the very recently described reduction of in-stent restenosis in rabbits treated with the analog des-fluoro anacetrapib [121], also confirming prior data showing reduced intimal hyperplasia and functional endothelial regeneration with this agent [121].…”

supporting

confidence: 77%

Present therapeutic role of cholesteryl ester transfer protein inhibitors

Ferri

Corsini

Sirtori

et al. 2018

Pharmacological Research

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Therapeutic interventions aimed at increasing high-density lipoprotein (HDL) levels in order to reduce the residual cardiovascular (CV) risk of optimally drug treated patients have not provided convincing results, so far. Transfer of cholesterol from extrahepatic tissues to the liver appears to be the major atheroprotective function of HDL, and an elevation of HDL levels could represent an effective strategy. Inhibition of the cholesteryl ester transfer protein (CETP), raising HDL-cholesterol (HDL-C) and apolipoprotein A-I (apoA-I) levels, reduces low-density lipoprotein-cholesterol (LDL-C) and apoB levels, thus offering a promising approach. Despite the beneficial influence on cholesterol metabolism, off-target effects and lack of reduction in CV events and mortality (with torcetrapib, dalcetrapib and evacetrapib) highlighted the complex mechanism of CETP inhibition. After the failure of the above mentioned inhibitors in phase III clinical development, possibly due to the short duration of the trials masking benefit, the secondary prevention REVEAL trial has recently shown that the inhibitor anacetrapib significantly raised HDL-C (+104%), reduced LDL-C (-18%), with a protective effect on major coronary events (RR, 0.91; 95%CI, 0.85-0.97; p = 0.004). Whether LDL-C lowering fully accounts for the CV benefit or if HDL-C-rise is a crucial factor still needs to be determined, although the reduction of non-HDL (-18%) and Lp(a) (-25%), should be also taken into account. In spite of the positive results of the REVEAL Study, Merck decided not to proceed in asking regulatory approval for anacetrapib. Dalcetrapib (Dal-GenE study) and CKD-519 remain the two molecules within this area still in clinical development.

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supporting

confidence: 77%

Present therapeutic role of cholesteryl ester transfer protein inhibitors

Ferri

Corsini

Sirtori

et al. 2018

Pharmacological Research

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“…43,44 A recent study showed that increasing HDL via CETP inhibition inhibited neointimal hyperplasia in ballooninjured rabbits, that the benefit was attributed to the antiinflammatory properties of HDL. 45 In fact, it has previously been demonstrated that low HDL-C in healthy subjects was associated with an increased inflammatory response to an LPS challenge, 21 further supporting the anti-inflammatory role of endogenous HDL. It is thus tempting to speculate that CETP-expressing species have increased flexibility to respond to invading Gram-negative organisms that release endotoxin/ LPS.…”

Section: Discussionmentioning

confidence: 89%

“…Upon LPS administration, reduced plasma CETP concentration results in increased HDL, which has well‐documented anti‐inflammatory properties . A recent study showed that increasing HDL via CETP inhibition inhibited neointimal hyperplasia in balloon‐injured rabbits, that the benefit was attributed to the anti‐inflammatory properties of HDL . In fact, it has previously been demonstrated that low HDL‐C in healthy subjects was associated with an increased inflammatory response to an LPS challenge, further supporting the anti‐inflammatory role of endogenous HDL.…”

Section: Discussionmentioning

confidence: 91%

Lipopolysaccharide Lowers Cholesteryl Ester Transfer Protein by Activating F4/80 ⁺ Clec4f ⁺ Vsig4 ⁺ Ly6C ⁻ Kupffer Cell Subsets

Tuin

Berbée

et al. 2018

JAHA

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BackgroundLipopolysaccharide (LPS) decreases hepatic CETP (cholesteryl ester transfer protein) expression albeit that the underlying mechanism is disputed. We recently showed that plasma CETP is mainly derived from Kupffer cells (KCs). In this study, we investigated the role of KC subsets in the mechanism by which LPS reduces CETP expression.Methods and ResultsIn CETP‐transgenic mice, LPS markedly decreased hepatic CETP expression and plasma CETP concentration without affecting hepatic macrophage number. This was paralleled by decreased expression of the resting KC markers C‐type lectin domain family 4, member f (Clec4f) and V‐set and immunoglobulin domain containing 4 (Vsig4), while expression of the infiltrating monocyte marker lymphocyte antigen 6 complex locus C (Ly6C) was increased. Simultaneously, the ratio of plasma high‐density lipoprotein‐cholesterol over non–high‐density lipoprotein‐cholesterol transiently increased. After ablation hepatic macrophages via injection with liposomal clodronate, the reappearance of hepatic gene and protein expression of CETP coincided with Clec4f and Vsig4, but not Ly6C. Double‐immunofluorescence staining showed that CETP co‐localized with Clec4f+ KCs and not Ly6C+ monocytes. In humans, microarray gene‐expression analysis of liver biopsies revealed that hepatic expression and plasma level of CETP both correlated with hepatic VSIG4 expression. LPS administration decreased the plasma CETP concentration in humans. In vitro experiments showed that LPS reduced liver X receptor‐mediated CETP expression.ConclusionsHepatic expression of CETP is exclusively confined to the resting KC subset (ie, F4/80+Clec4f+Vsig4+Ly6C−). LPS activated resting KCs, leading to reduction of Clec4f and Vsig4 expression and reduction of hepatic CETP expression, consequently decreasing plasma CETP and raising high‐density lipoprotein (HDL)‐cholesterol. This sequence of events is consistent with the anti‐inflammatory role of HDL in the response to LPS and may be relevant as a defense mechanism against bacterial infections.

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“…47 Consistently, a recent study published in ATVB used a new rabbit CETP knockout model to demonstrate that CETP-deficiency results in elevated HDL-C levels, increased cholesterol efflux capacity of apoB-depleted plasma, markedly reduced levels of VLDL, and protection against cholesterol diet-induced atherosclerosis. 48 Another study found that pharmacological inhibition of CETP activity reduces in-stent restenosis via inhibition of vascular smooth muscle cell proliferation, 49 suggesting that CETP inhibition may be a potential strategy to protect against ASCVD and related vascular damage. Whereas these animal models show beneficial effects of loss of CETP, human studies are less conclusive.…”

Section: High-density Lipoproteinmentioning

confidence: 99%

Highlighting Residual Atherosclerotic Cardiovascular Disease Risk

Matsuura

Kanter

Bornfeldt

2019

ATVB

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Reduction of In-Stent Restenosis by Cholesteryl Ester Transfer Protein Inhibition

Cited by 18 publications

References 44 publications

Present therapeutic role of cholesteryl ester transfer protein inhibitors

Present therapeutic role of cholesteryl ester transfer protein inhibitors

Lipopolysaccharide Lowers Cholesteryl Ester Transfer Protein by Activating F4/80 ⁺ Clec4f ⁺ Vsig4 ⁺ Ly6C ⁻ Kupffer Cell Subsets

Highlighting Residual Atherosclerotic Cardiovascular Disease Risk

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Reduction of In-Stent Restenosis by Cholesteryl Ester Transfer Protein Inhibition

Cited by 18 publications

References 44 publications

Present therapeutic role of cholesteryl ester transfer protein inhibitors

Present therapeutic role of cholesteryl ester transfer protein inhibitors

Lipopolysaccharide Lowers Cholesteryl Ester Transfer Protein by Activating F4/80 + Clec4f + Vsig4 + Ly6C − Kupffer Cell Subsets

Highlighting Residual Atherosclerotic Cardiovascular Disease Risk

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Lipopolysaccharide Lowers Cholesteryl Ester Transfer Protein by Activating F4/80 ⁺ Clec4f ⁺ Vsig4 ⁺ Ly6C ⁻ Kupffer Cell Subsets