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A High-Throughput Luciferase Assay to Evaluate Proteolysis of the Single-Turnover Protease PCSK9
Published on: August 28, 2018
Cholesterol and stroke: Roll of PCSK9 inhibitors
L Castilla-Guerra1, M C Fernández-Moreno2, M A Rico-Corral1
1Servicio de Medicina Interna, Unidad de Riesgo Vascular, Hospital Virgen Macarena, Sevilla, España.
Introduction:
Proprotein convertase subtilisin/kexin type 9 (PCSK9) plays an important role in the modulation of plasma levels of low density lipoprotein cholesterol (LDLC). PCSK9 binds to the LDL receptor (LDLR), disrupts its endocytic recycling itinerary and directs it to lysosomal degradation. Activation of PCSK9 can thus decrease the expression of LDLR in the liver and inhibit LDL uptake, which leads to hypercholesterolaemia.
Development:
Currently we now know that different polymorphisms of PCSK9 are associated with the occurrence of ischaemic stroke. On the other hand, PCSK9 inhibitors prevent binding of PCSK9 to LDLR and inhibit degradation of LDLR, which results in increased hepatic uptake of LDL and lower LDL levels in blood. Different phase 2 and 3 studies, including OSLER and ODYSSEY LONG-TERM, have demonstrated the efficacy and safety of the new monoclonal antibodies against PCSK9 such as evolucumab and alirocumab, and the first exploratory analyses have shown evidence of their efficacy in decreasing vascular events, including stroke.
Conclusions:
Although few strokes have been reported by these studies, new ongoing trials examining the cardiovascular effects of evolucumab (FOURIER study), alirocumab (ODYSSEY OUTCOMES study), and bococizumab (SPIRE-1 and SPIRE-2 studies) will reveal the true potential of these drugs, particularly for the prevention of stroke.
Insights
Proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors lower LDL cholesterol by increasing LDL receptor recycling. Ongoing trials will determine their effectiveness in preventing strokes.
Area of Science:
- Biochemistry
- Cardiovascular Medicine
- Genetics
Background:
- Proprotein convertase subtilisin/kexin type 9 (PCSK9) regulates low-density lipoprotein cholesterol (LDLC) levels.
- PCSK9 targets the LDL receptor (LDLR) for lysosomal degradation, reducing hepatic LDL uptake and increasing plasma LDLC.
- PCSK9 activation contributes to hypercholesterolemia.
Purpose of the Study:
- To evaluate the role of PCSK9 in ischemic stroke.
- To assess the efficacy of PCSK9 inhibitors in reducing vascular events, including stroke.
Main Methods:
- Review of existing Phase 2 and 3 studies (e.g., OSLER, ODYSSEY LONG-TERM) on PCSK9 inhibitors.
- Analysis of exploratory data on stroke reduction.
- Consideration of ongoing cardiovascular trials (FOURIER, ODYSSEY OUTCOMES, SPIRE-1, SPIRE-2).
Main Results:
- PCSK9 polymorphisms are linked to ischemic stroke risk.
- PCSK9 inhibitors increase hepatic LDLR expression and LDL clearance, lowering blood LDL levels.
- Early studies show PCSK9 inhibitors reduce vascular events, including stroke.
Conclusions:
- PCSK9 inhibitors demonstrate efficacy in lowering LDL cholesterol and show potential in reducing vascular events.
- Further large-scale trials are necessary to confirm the stroke prevention capabilities of PCSK9 inhibitors like evolucumab, alirocumab, and bococizumab.
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