Lipoprotein(a) Catabolism Is Regulated by Proprotein Convertase Subtilisin/Kexin Type 9 through the Low Density Lipoprotein Receptor

Romagnuolo, Rocco; Scipione, Corey A.; Boffa, Michael B.; Marcovina, Santica M.; Seidah, Nabil G.; Koschinsky, Marlys L.

doi:10.1074/jbc.m114.611988

Cited by 187 publications

(173 citation statements)

References 64 publications

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“…Lp(a) has a structure similar to low‐density lipoprotein (LDL) in its lipid core composition in addition to a molecule of apolipoprotein B 100 (apoB), but also contains a unique glycoprotein—apo(a), with strong structural homology with plasminogen 2. Apo(a) contains anything from 3, to more than 50 identically repeated plasminogen‐like kringle IV domains, which gives rise to the heterogeneity in isoform size reported in the population 3. There is a general inverse correlation between the size of the apo(a) isoform and the Lp(a) plasma concentration 2, 3.…”

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confidence: 99%

“…Apo(a) contains anything from 3, to more than 50 identically repeated plasminogen‐like kringle IV domains, which gives rise to the heterogeneity in isoform size reported in the population 3. There is a general inverse correlation between the size of the apo(a) isoform and the Lp(a) plasma concentration 2, 3. The variation in the concentration of Lp(a) is primarily controlled by the level of synthesis rather than catabolism, with as much as 90% of the variation being genetically determined based on variation in the gene encoding apo(a) ( LPA ) located on chromosome 6q26‐27 3, 4…”

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confidence: 99%

“…Uptake via the LDL receptor (LDLR) may not be a major pathway of Lp(a) metabolism (however, the studies in familial hypercholesterolemia patients with null LDLR allele confirmed the important role of the receptor), and very low‐density lipoprotein receptor, LDL receptor‐related protein 1, megalin/gp33018, scavenger receptor class B type 1, and plasminogen receptors might also play an important role 3. The catabolism pathway of Lp(a) is therefore mainly sustained by the liver, spleen, and kidney 3, 4. Lp(a) concentrations are also dependent on the rate of hepatic apo(a) and apoB 100 secretion, what might also be the mechanism (together with the metabolism with LDLR) responsible for the Lp(a) reducing effect of proprotein convertase subtilisin/kexin type 9 inhibitors 3, 5…”

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confidence: 99%

“…Aside from its role as a recognized independent CVD biomarker, the physiological function of Lp(a) still is not completely understood 1, 2, 3, 4, 6. Because of its structural similarity to plasminogen and tissue plasminogen activator, it competes with plasminogen for its binding site, leading to reduced fibrinolysis, and as a result of the stimulation of secretion of plasminogen activator inhibitor‐1, Lp(a) leads to thrombogenesis 1, 2, 3.…”

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confidence: 99%

“…Lp(a) also carries cholesterol and binds atherogenic proinflammatory oxidized phospholipids, which attract inflammatory cells to vessel walls and leads to smooth muscle cell proliferation. In consequence, Lp(a) strongly contributes to the process of atherogenesis 1, 2, 3, 4…”

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confidence: 99%

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confidence: 99%

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confidence: 99%

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confidence: 99%

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confidence: 99%

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A phase 1 study to evaluate the safety and LDL cholesterol–lowering effects of RG7652, a fully human monoclonal antibody against proprotein convertase subtilisin/kexin type 9

Baruch¹,

Luca²,

Kahn³

et al. 2017

Clinical Cardiology

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Background Proprotein convertase subtilisin/kexin type 9 (PCSK9) downregulates low‐density lipoprotein (LDL) receptors, thereby leading to a rise in circulating LDL cholesterol (LDL‐C). RG7652 is a fully human monoclonal antibody against PCSK9. This placebo‐controlled, phase 1 ascending‐dose study in healthy subjects evaluated the safety of RG7652 and its efficacy as a potential LDL‐C–lowering drug. Hypothesis Anti‐PCSK9 antibody therapy safely and effectively reduces LDL‐C. Methods Subjects (N = 80) were randomized into 10 cohorts. Six sequential single‐dose cohorts received 10, 40, 150, 300, 600, or 800 mg of RG7652 via subcutaneous injection. Four multiple‐dose cohorts received 40 or 150 mg of RG7652 once weekly for 4 weeks, either with or without statin therapy (atorvastatin). Results Adverse events (AEs) were generally mild; the most common AEs were temporary injection‐site reactions. No serious AEs, severe AEs, AEs leading to study‐drug discontinuation, or dose‐limiting toxicities were reported. RG7652 monotherapy reduced mean LDL‐C levels by up to 64% and as much as 100 mg/dL at week 2; the effect magnitude and duration increased with dose (≥57 days following a single RG7652 dose ≥300 mg). Exploratory analyses showed reduced oxidized LDL, lipoprotein(a), and lipoprotein‐associated phospholipase A2 with RG7652. Antidrug antibody against RG7652 tested positive in 2 of 60 (3.3%) RG7652‐treated and in 4 of 20 (20.0%) placebo‐treated subjects. Simultaneous atorvastatin administration did not appear to impact the pharmacokinetic profile or lipid‐lowering effects of RG7652. Conclusions Overall, RG7652 elicited substantial and sustained dose‐related LDL‐C reductions with an acceptable safety profile and minimal immunogenicity.

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Design of the randomized, placebo‐controlled evolocumab for early reduction of LDL‐cholesterol levels in patients with acute coronary syndromes (EVOPACS) trial

Koskinas

Windecker

Buhayer³

et al. 2018

Clinical Cardiology

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Statins lower low‐density lipoprotein cholesterol (LDL‐C) and improve clinical outcomes in patients with atherosclerotic cardiovascular disease (CVD). Patients with acute coronary syndromes (ACS) often do not achieve LDL‐C targets despite potent statin treatment, and have a particularly high risk of early recurrent events. Evolocumab, a proprotein convertase subtilisin/kexin type (PCSK9)‐inhibitor resulting in rapid, marked LDL‐C reduction, has been studied in hypercholesterolemic subjects without CVD and stabilized patients with CVD; the feasibility, safety, and efficacy of this treatment initiated in the acute phase of ACS remain unknown. We report the design of evolocumab for early reduction of LDL‐cholesterol levels in patients with ACS (EVOPACS), a phase‐3, multicenter, randomized, double‐blind, placebo‐controlled trial to assess the feasibility, safety, and LDL‐C‐lowering efficacy of evolocumab on top of atorvastatin 40 mg in patients with ACS. The primary endpoint is percent change in LDL‐C from baseline to 8 weeks. Secondary endpoints are adverse events and serious adverse events. Against a background of beneficial cardiovascular effects of statins beyond LDL‐C lowering and in view of preclinical evidence of similar effects of PCSK9 inhibition, the study will also address a variety of exploratory endpoints including the change in C‐reactive protein and other inflammatory biomarkers; platelet reactivity; and occurrence of contrast‐induced acute kidney injury and myocardial injury in patients undergoing cardiac catheterization. An intracoronary imaging sub‐study will investigate the change from baseline in the lipid core burden index in non‐culprit lesions, as assessed by serial near‐infrared spectroscopy. Recruitment began in January 2018 and enrollment of 308 patients is planned.

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Lipoprotein(a) Catabolism Is Regulated by Proprotein Convertase Subtilisin/Kexin Type 9 through the Low Density Lipoprotein Receptor

Cited by 187 publications

References 64 publications

Lipoprotein (a)—We Know So Much Yet Still Have Much to Learn …

Lipoprotein (a)—We Know So Much Yet Still Have Much to Learn …

A phase 1 study to evaluate the safety and LDL cholesterol–lowering effects of RG7652, a fully human monoclonal antibody against proprotein convertase subtilisin/kexin type 9

Design of the randomized, placebo‐controlled evolocumab for early reduction of LDL‐cholesterol levels in patients with acute coronary syndromes (EVOPACS) trial

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