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Physiological and therapeutic regulation of PCSK9 activity in cardiovascular disease.

ABSTRACT: Ischemic heart disease is the main cause of death worldwide and is accelerated by increased levels of low-density lipoprotein cholesterol (LDL-C). Proprotein convertase subtilisin/kexin type 9 (PCSK9) is a potent circulating regulator of LDL-C through its ability to induce degradation of the LDL receptor (LDLR) in the lysosome of hepatocytes. Only in the last few years, a number of breakthroughs in the understanding of PCSK9 biology have been reported illustrating how PCSK9 activity is tightly regulated at several levels by factors influencing its transcription, secretion, or by extracellular inactivation and clearance. Two humanized antibodies directed against the LDLR-binding site in PCSK9 received approval by the European and US authorities and additional PCSK9 directed therapeutics are climbing up the phases of clinical trials. The first outcome data of the PCSK9 inhibitor evolocumab reported a significant reduction in the composite endpoint (cardiovascular death, myocardial infarction, or stroke) and further outcome data are awaited. Meanwhile, it became evident that PCSK9 has (patho)physiological roles in several cardiovascular cells. In this review, we summarize and discuss the recent biological and clinical data on PCSK9, the regulation of PCSK9, its extra-hepatic activities focusing on cardiovascular cells, molecular concepts to target PCSK9, and finally briefly summarize the data of recent clinical studies.

SUBMITTER: Glerup S

PROVIDER: S-EPMC5403857 | biostudies-literature | 2017 May

REPOSITORIES: biostudies-literature

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Physiological and therapeutic regulation of PCSK9 activity in cardiovascular disease.

Glerup Simon S Schulz Rainer R Laufs Ulrich U Schlüter Klaus-Dieter KD

Basic research in cardiology 20170424 3

Ischemic heart disease is the main cause of death worldwide and is accelerated by increased levels of low-density lipoprotein cholesterol (LDL-C). Proprotein convertase subtilisin/kexin type 9 (PCSK9) is a potent circulating regulator of LDL-C through its ability to induce degradation of the LDL receptor (LDLR) in the lysosome of hepatocytes. Only in the last few years, a number of breakthroughs in the understanding of PCSK9 biology have been reported illustrating how PCSK9 activity is tightly r ...[more]

PMID: 28439730

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Project description:Background and objectivesProprotein convertase subtilisin/kexin type 9 (PCSK9) is a key regulator of lipid homeostasis. Studies investigating the association between PCSK9 and cardiovascular disease in large cohorts of patients with CKD are limited.Design, setting, participants, & measurementsThe association of PCSK9 concentrations with prevalent and incident cardiovascular disease was investigated in 5138 White participants of the German Chronic Kidney Disease study with a median follow-up of 6.5 years. Inclusion criteria were eGFR of 30-60 or >60 ml/min per 1.73 m2 in the presence of overt proteinuria (urine albumin-creatinine ratio >300 mg/g or equivalent). Prevalent cardiovascular disease was defined as a history of nonfatal myocardial infarction, coronary artery bypass grafting, percutaneous transluminal coronary angioplasty, carotid arteries interventions, and stroke. Incident major adverse cardiovascular disease events included death from cardiovascular causes, acute nonfatal myocardial infarction, and nonfatal stroke.ResultsMedian PCSK9 concentration in the cohort was 285 ng/ml (interquartile range, 231-346 ng/ml). There was no association between PCSK9 concentrations and baseline eGFR and albuminuria. With each 100-ng/ml increment of PCSK9, the odds for prevalent cardiovascular disease (n=1284) were 1.22-fold (95% confidence interval, 1.12 to 1.34; P<0.001) higher in a model with extended adjustment for major confounders. This association was stronger in nonstatin than statin users (P value for interaction =0.009). During follow-up, 474 individuals experienced a major adverse cardiovascular disease event, and participants in PCSK9 quartiles 2-4 had a 32%-47% higher risk compared with those in quartile 1 (P<0.05). Subgroup analysis revealed that this association was restricted to those participants who already had cardiovascular disease at baseline (all hazard ratios >1.75; P=0.01). In addition, PCSK9 showed a valuable gain in classification accuracy for both prevalent cardiovascular disease (net reclassification index =0.27; 95% confidence interval, 0.20 to 0.33) and incident major adverse cardiovascular disease events during follow-up (net reclassification index =0.10; 95% confidence interval, 0.01 to 0.21) when added to an extended adjustment model.ConclusionsOur findings reveal no relation of PCSK9 with baseline eGFR and albuminuria but a significant association between higher PCSK9 concentrations and risk of cardiovascular disease independent of traditional risk factors, including LDL cholesterol levels.Clinical Trial registry name and registration number: German Chronic Kidney Disease Study (GCKD), DRKS 00003971.

Dataset Information

Physiological and therapeutic regulation of PCSK9 activity in cardiovascular disease.

Publications

Physiological and therapeutic regulation of PCSK9 activity in cardiovascular disease.

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