Circulating Levels of Proprotein Convertase Subtilisin/Kexin Type 9 and Arterial Stiffness in a Large Population Sample: Data From the Brisighella Heart Study

Ruscica, Massimiliano; Ferri, Nicola; Fogacci, Federica; Rosticci, Martina; Botta, Margherita; Marchianò, Silvia; Magni, Paolo; D’Addato, Sergio; Giovannini, Marina; Borghi, Claudio; Cicero, Arrigo Francesco Giuseppe

doi:10.1161/jaha.117.005764

Cited by 77 publications

(53 citation statements)

References 38 publications

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“…This evidence is in line with previous studies reporting a positive association between PCSK9 and endothelial function markers, e.g. blood pressure and arterial stiffness (132,(150)(151)(152).…”

Section: Cardiovascular Outcomes Research With Pcsk9 Inhibition In Susupporting

confidence: 93%

Lipid lowering drugs and inflammatory changes: an impact on cardiovascular outcomes?

et al. 2018

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Inflammatory changes are responsible for maintenance of the atherosclerotic process and may underlie some of the most feared vascular complications. Among the multiple mechanisms of inflammation, the arterial deposition of lipids and particularly of cholesterol crystals is the one responsible for the activation of inflammasome NLRP3, followed by the rise of circulating markers, mainly C-reactive protein (CRP). Elevation of lipoproteins, LDL but also VLDL and remnants, associates with increased inflammatory changes and coronary risk. Lipid lowering medications can reduce cholesterolemia and CRP: patients with elevations of both are at greatest cardiovascular (CV) risk and receive maximum benefit from therapy. Evaluation of the major drug series indicates that statins exert the largest LDL and CRP reduction, accompanied by reduced CV events. Other drugs, mainly active on the triglyceride/HDL axis, for example, PPAR agonists, may improve CRP and the lipid pattern, especially in patients with metabolic syndrome. PCSK9 antagonists, the newest most potent medications, do not induce significant changes in inflammatory markers, but patients with the highest baseline CRP levels show the best CV risk reduction. Parallel evaluation of lipids and inflammatory changes clearly indicates a significant link, both guiding to patients at highest risk, and to the best pharmacological approach. Key messages Lipid lowering agents with "pleiotropic" effects provide a more effective approach to CV prevention In CANTOS study, patients achieving on-treatment hsCRP concentrations ≤2 mg/L had a higher benefit in terms of reduction in major CV events The anti-inflammatory activity of PCSK9 antagonists appears to be of a minimal extent.

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Section: Cardiovascular Outcomes Research With Pcsk9 Inhibition In Susupporting

confidence: 93%

Lipid lowering drugs and inflammatory changes: an impact on cardiovascular outcomes?

et al. 2018

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“…LDL contribute to transport of PCSK9 in plasma [6,8], and indeed in our entire cohort we confirmed a positive association of PCSK9 to LDL-C and apoB as previously reported [30,[36][37][38]. In support to the role of LDL in PCSK9 transport, using an approach similar to the one used in the present study it has been shown that carriers of familial hypobetalipoproteinemia due to mutations in apoB (FHBL1) or in ANGPTL3 (FHBL2), characterized by very low circulating LDL, have significantly reduced plasma PCSK9 levels [34,36].…”

Section: Accepted Manuscriptsupporting

confidence: 91%

Plasma PCSK9 levels and lipoprotein distribution are preserved in carriers of genetic HDL disorders

Ruscica

Simonelli

Botta

et al. 2018

Biochimica et Biophysica Acta (BBA) - Molecular and Cell Biolog

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Proprotein convertase subtilisin/kexin 9 (PCSK9), a protein regulating the number of cell-surface LDL receptors (LDLR), circulates partially associated to plasma lipoproteins. How this interaction alters PCSK9 plasma levels is still unclear. In the present study, we took advantage of the availability of a large cohort of carriers of genetic HDL disorders to evaluate how HDL defects affect plasma PCSK9 levels and its distribution among lipoproteins. Plasma PCSK9 concentrations were determined by ELISA in carriers of mutations in LCAT, ABCA1, or APOAI genes, and lipoprotein distribution was analyzed by FPLC. Carriers of one or two mutations in the LCAT gene show plasma PCSK9 levels comparable to that of unaffected family controls (homozygotes, 159.4 ng/mL (124.9;243.3); heterozygotes, 180.3 ng/mL (127.6;251.5) and controls, 190.4 ng/mL (146.7;264.4); P for trend = 0.33). Measurement of PCSK9 in plasma of subjects carrying mutations in ABCA1 or APOAI genes confirmed normal values. When fractionated by FPLC, PCSK9 peaked in a region between LDL and HDL in control subjects. In carriers of all HDL defects, lipoprotein profile shows a strong reduction of HDL, but the distribution of PCSK9 was superimposable to that of controls. In conclusion, the present study demonstrates that in genetically determined low HDL states plasma PCSK9 concentrations and lipoprotein distribution are preserved, thus suggesting that HDL may not be involved in PCSK9 transport in plasma.

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“…This data excludes the possibility that endotoxin contamination of human recombinant PCSK9 can be responsible for the pro-inflammatory effect observed. Finally, we found a positive correlation between plasma levels of PCSK9 and TNF-α, in a population of overall healthy subjects 17,19 , an observation that further supports the role of PCSK9 on inflammation. Macrophages present in the atherosclerotic plaque are derived, mainly but not exclusively, from circulating monocytes that differentiated into macrophages within the arterial wall 20 .…”

Section: Discussionsupporting

confidence: 81%

“…Both sources can be theoretically possible since both protein and mRNA PCSK9 have been detected in the human atherosclerotic plaques 8,25 . Although the intraplaque concentration of PCSK9 is not known, it is important to underlying that we observed a pro-inflammatory effect on macrophages at relatively low concentrations, starting from 250 ng/ml, thus even below the mean plasma levels found in observational studies 19 .…”

Section: Discussioncontrasting

confidence: 73%

PCSK9 induces a pro-inflammatory response in macrophages

et al. 2017

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Intraplaque release of inflammatory cytokines from macrophages is implicated in atherogenesis by inducing the proliferation and migration of media smooth muscle cells (SMCs). PCSK9 is present and released by SMCs within the atherosclerotic plaque but its function is still unknown. In the present study, we tested the hypothesis that PCSK9 could elicit a pro-inflammatory effect on macrophages. THP-1-derived macrophages and human primary macrophages were exposed to different concentrations (0.250 ÷ 2.5 µg/ml) of human recombinant PCSK9 (hPCSK9). After 24 h incubation with 2.5 µg/ml PCSK9, a significant induction of IL-1β, IL-6, TNF-α, CXCL2, and MCP1 mRNA, were observed in both cell types. Co-culture of THP-1 macrophages with HepG2 overexpressing hPCSK9 also showed the induction of TNF-α (2.4 ± 0.5 fold) and IL-1β (8.6 ± 1.8 fold) mRNA in macrophages. The effect of hPCSK9 on TNF-α mRNA in murine LDLR −/− bone marrow macrophages (BMM) was significantly impaired as compared to wild-type BMM (4.3 ± 1.6 fold vs 31.1 ± 6.1 fold for LDLR −/− and LDLR +/+ , respectively). Finally, a positive correlation between PCSK9 and TNF-α plasma levels of healthy adult subjects (males 533, females 537) was observed (B = 8.73, 95%CI 7.54 ÷ 9.93, p < 0.001). Taken together, the present study provides evidence of a pro-inflammatory action of PCSK9 on macrophages, mainly dependent by the LDLR.The constant and slow development of the atherosclerotic plaque is driven by a failure to resolve the inflammatory response in the arterial wall initiated by the retention of apolipoprotein B (apoB)-containing lipoproteins, mainly the low-density lipoproteins (LDL) 1 . LDL retained in the arterial wall undergo chemical oxidation and then capture, through the scavenger receptors, by infiltrated macrophages, which ultimately become foam cells. The continuing accumulation of LDL fuels not only the formation of foam cells, but also a chronic amplification of the inflammatory response, the main cause of plaque rupture and vascular thrombosis 2 .The study of the central role of macrophages in atherogenesis led to the observation of the presence of two different macrophage populations that can be grossly divided into pro-inflammatory (M1 cells) and anti-inflammatory (M2 cells) based mainly on in vitro criteria 3 . Polarization toward the M1 state is induced by several stimuli in vitro, including Toll-like receptor (TLR) ligands (such as lipopolysaccharide, LPS) and interferon γ.M1 macrophages express several pro-inflammatory mediators, such as inducible nitric oxide synthase, tumor necrosis factor-α (TNF-α), interleukin-1β (IL-1β), IL-6, IL-12, and proteolytic enzymes 3 . The presence of M1 macrophages has been demonstrated in both human and mouse atherosclerotic plaques and is considered the main intravascular source of pro-inflammatory cytokines, responsible for the maintenance of local inflammation and for the extracellular matrix components degradation, thus promoting the disease progression 3 .Since LDL-cholesterol represents the most validated risk fa...

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Circulating Levels of Proprotein Convertase Subtilisin/Kexin Type 9 and Arterial Stiffness in a Large Population Sample: Data From the Brisighella Heart Study

Cited by 77 publications

References 38 publications

Lipid lowering drugs and inflammatory changes: an impact on cardiovascular outcomes?

Lipid lowering drugs and inflammatory changes: an impact on cardiovascular outcomes?

Plasma PCSK9 levels and lipoprotein distribution are preserved in carriers of genetic HDL disorders

PCSK9 induces a pro-inflammatory response in macrophages

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