PCSK9 inhibition and inflammation: A narrative review

Ruscica, Massimiliano; Tokgözoğlu, Lâle; Corsini, Alberto; Sirtori, Cesare R.

doi:10.1016/j.atherosclerosis.2019.07.015

Cited by 88 publications

(56 citation statements)

References 156 publications

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“…PCSK9 induces inflammation in atherosclerosis independently from its hyperlipidemic effect 37) . Disturbed ox-LDL uptake/cholesterol efflux balance and accumulation of ox-LDL stimulates the overlying endothelial cells to produce proinflammatory molecule (Fig.…”

Section: Pcsk9 In Vascular Inflammationmentioning

confidence: 99%

An Update on the Role of PCSK9 in Atherosclerosis

Yurtseven

Ural

Baysal

et al. 2020

JAT

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The official journal of the Japan Atherosclerosis Society and the Asian Pacific Society of Atherosclerosis and Vascular Diseases Review Atherosclerosis is initiated by functional changes in the endothelium accompanied by accumulation, oxidation, and glycation of LDL-cholesterol in the inner layer of the arterial wall and continues with the expression of adhesion molecules and release of chemoattractants. PCSK9 is a proprotein convertase that increases circulating LDL levels by directing hepatic LDL receptors into lysosomes for degradation. The effects of PCSK9 on hepatic LDL receptors and contribution to atherosclerosis via the induction of hyperlipidemia are well defined. Monoclonal PCSK9 antibodies that block the effects of PCSK9 on LDL receptors demonstrated beneficial results in cardiovascular outcome trials. In recent years, extrahepatic functions of PCSK9, particularly its direct effects on atherosclerotic plaques have received increasing attention. Experimental trials have revealed that PCSK9 plays a significant role in every step of atherosclerotic plaque formation. It contributes to foam cell formation by increasing the uptake of LDL by macrophages via scavenger receptors and inhibiting cholesterol efflux from macrophages. It induces the expression of inflammatory cytokines, adhesion molecules, and chemoattractants, thereby increasing monocyte recruitment, inflammatory cell adhesion, and inflammation at the atherosclerotic vascular wall. Moreover, low shear stress is associated with increased PCSK9 expression. PCSK9 may induce endothelial cell apoptosis and autophagy and stimulate the differentiation of smooth muscle cells from the contractile phenotype to synthetic phenotype. Increasing evidence indicates that PCSK9 is a molecular target in the development of novel approaches toward the prevention and treatment of atherosclerosis. This review focuses on the molecular roles of PCSK9 in atherosclerotic plaque formation.

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Section: Pcsk9 In Vascular Inflammationmentioning

confidence: 99%

An Update on the Role of PCSK9 in Atherosclerosis

Yurtseven

Ural

Baysal

et al. 2020

JAT

Self Cite

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“…The antiinflammatory effects of HDL/SP1 occur partially because of the capacity of ApoM(þ)HDL to act as a biased agonist of the S1P1 endothelial cell receptor, partially explaining the cardiovascular protective functions of HDL [18]. The role of inflammation in atherosclerosis development/progression has been recently reviewed [19].…”

Section: Introductionmentioning

confidence: 99%

HDL therapy today: from atherosclerosis, to stent compatibility to heart failure

et al. 2019

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Epidemiologically, high-density lipoprotein (HDL) cholesterol levels have been inversely associated to cardiovascular (CV) events, although a Mendelian Randomisation Study had failed to establish a clear causal role. Numerous atheroprotective mechanisms have been attributed to HDL, the main being the ability to promote cholesterol efflux from arterial walls; anti-inflammatory effects related to HDL ligands such as S1P (sphingosine-1-phosphate), resolvins and others have been recently identified. Experimental studies and early clinical investigations have indicated the potential of HDL to slow progression or induce regression of atherosclerosis. More recently, the availability of different HDL formulations, with different phospholipid moieties, has allowed to test other indications for HDL therapy. Positive reports have come from studies on coronary stent biocompatibility, where the use of HDL from different sources reduced arterial cell proliferation and thrombogenicity. The observation that low HDL-C levels may be associated with an enhanced risk of heart failure (HF) has also suggested that HDL therapy may be applied to this condition. HDL infusions or apoA-I gene transfer were able to reverse heart abnormalities, reduce diastolic resistance and improve cardiac metabolism. HDL therapy may be effective not only in atherosclerosis, but also in other conditions, of relevant impact on human health. KEY MESSAGES High-density lipoproteins have as a major activity that of removing excess cholesterol from tissues (particularly arteries). Knowledge on the activity of high-density lipoproteins on health have however significantly widened. HDL-therapy may help to improve stent biocompatibility and to reduce peripheral arterial resistance in heart failure.

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“…It promotes the lysosomal degradation of hepatic low-density lipoprotein receptors, resulting in increased circulating LDL cholesterol levels and therefore regarded as a good lowering lipid target. 5,6 Moreover, observational studies suggest a weak positive correlation between PCSK9 and CRP, but a recent review revealed that PCSK9 inhibitors do not alter hs-CRP levels. 6,7 There are inconsistent findings in the association between PCSK9 measured in ethnically diverse cohorts and plasma LDL concentrations.…”

Section: Introductionmentioning

confidence: 99%

“…5,6 Moreover, observational studies suggest a weak positive correlation between PCSK9 and CRP, but a recent review revealed that PCSK9 inhibitors do not alter hs-CRP levels. 6,7 There are inconsistent findings in the association between PCSK9 measured in ethnically diverse cohorts and plasma LDL concentrations. Some studies found PCSK9 level elevated in patients with obesity and T2D and others not.…”

Section: Introductionmentioning

confidence: 99%

<p>Is PCSK9 Associated with Plasma Lipid Levels in a Sub-Saharan African Population of Patients with Obesity and Type 2 Diabetes?</p>

Camille¹,

Mbacham²,

Sobngwi³

et al. 2019

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Proprotein convertase subtilisin/kexin type 9 (PCSK9) is a key regulator of circulating LDL cholesterol. There are inconsistent data in some populations concerning the association between PCSK9, LDL and CRP. The emerging importance of the inhibition of PCSK9 for the treatment of hypercholesterolemia warrants investigations in different populations. The aim of this study from a Sub-Saharan African population was to evaluate the association between PCSK9 and hs-CRP levels and plasma lipid levels in patients with type 2 diabetes (T2D) and obese and lean controls. Patients and methods: A cross-sectional analytical study was conducted in a major hospital in Yaoundé, Cameroon in a cohort of 162 participants (53% females). There were 54 non-obese T2D patients matched for age and sex to 54 obese nondiabetic and 54 nondiabetic lean subjects. PCSK9 level was assessed by sandwich ELISA method and hsCRP by nephelometry. Results: PCSK9 and hs-CRP levels were significantly higher in obese and T2D subjects when compared to lean controls (p<0.001 and p=0.002, respectively). The association between PCSK9 and triglyceride levels in the overall population was gender dependent (p=0.04) and subgroup analysis showed a significant positive correlation between PCSK9 and triglyceride levels in males but not in females (r=0.56, p=0.02 and r=0.2 and p=0.1, respectively). Multilinear regression analysis identified BMI as an independent predictor for PCSK9 levels and this association was maintained after adjustment for confounders; adjusted β-coefficient; 36.1 (95% CI; 29.2-47.4). We did not find an association between PCSK9 and any plasma lipid levels in obese and T2D subjects, nor between PCSK9 and hs-CRP levels. Conclusion: Obese and type 2 diabetes subjects have higher PCSK9 levels when compared to lean controls, suggesting that these metabolic states potentially impact PCSK9 levels in Cameroonian patients.

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PCSK9 inhibition and inflammation: A narrative review

Cited by 88 publications

References 156 publications

An Update on the Role of PCSK9 in Atherosclerosis

An Update on the Role of PCSK9 in Atherosclerosis

HDL therapy today: from atherosclerosis, to stent compatibility to heart failure

<p>Is PCSK9 Associated with Plasma Lipid Levels in a Sub-Saharan African Population of Patients with Obesity and Type 2 Diabetes?</p>

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