The D374Y gain-of-function mutant, associated with hypercholesterolemia and early-onset cardiovascular disease, binds the receptor 25 times more tightly than wild-type PCSK9 at neutral pH and remains exclusively in a high-affinity complex at the acidic pH.
The D374Y gain-of-function mutant, associated with hypercholesterolemia and early-onset cardiovascular disease, binds the receptor 25 times more tightly than wild-type PCSK9 at neutral pH and remains exclusively in a high-affinity complex at the acidic pH.
Our data support the concept that the rare allele of the R46L SNP at the PCSK9 locus significantly lowers LDL C, but does not greatly reduce CHD risk in an elderly population with a high prevalence of cardiovascular disease.
PCSK9 inhibition represents a very promising target for reducing LDL-C levels and decreasing the risk of atherosclerotic cardiovascular diseases, but human clinical trials will be crucial to assess the potency and safety of PCSK9 inhibitors.
Proprotein convertase subtilisin/kexin type 9 (PCSK9) has emerged as a novel target for controlling plasma levels of low-density lipoprotein cholesterol (LDL-C) and decreasing the risk of cardiovascular diseases.
Initial data from investigations of PCSK9 inhibition in humans are promising and indicate that PCSK9 inhibition may be a viable new therapeutic option for the treatment of dyslipidemia and associated cardiovascular diseases.
Current research and clinical trial results indicate that a PCSK9 inhibitor may be an exciting new therapeutic drug for the treatment of dyslipidemia and relevant cardiovascular diseases.
A decade after our discovery of the involvement of proprotein convertase subtilisin/kexin type 9 (PCSK9) in cholesterol metabolism through the identification of the first mutations leading to hypercholesterolemia, PCSK9 has become one of the most promising targets in cholesterol and cardiovascular diseases.
Rare gain-of-function PCSK9 variants lead to higher levels of LDL-cholesterol and increased risk of cardiovascular disease; more common loss-of-function PCSK9 variants are associated with reductions in both LDL-cholesterol and risk of cardiovascular disease.
In contrast, humans with high levels of PCSK9 have higher level of plasma LDL-C and significantly enhanced CVD risk during their lifetime, gain-of-function mutations on PCSK9 are, for instance, causatively associated with familial hypercholesterolaemia (FH).
Homozygous autosomal dominant hypercholesterolaemia (hoADH), an orphan disease caused by mutations in low-density lipoprotein receptor (LDLR), apolipoprotein B (APOB), or proprotein convertase subtilisin-kexin type 9 (PCSK9), is characterized by elevated plasma low-density lipoprotein-cholesterol (LDL-C) levels and high risk for premature cardiovascular disease (CVD).
The development of therapeutic approaches that inhibit PCSK9 function has therefore attracted considerable attention from clinicians and the pharmaceutical industry for the management of hypercholesterolemia and its associated cardiovascular disease risk.
Over the last decade, inhibition of Proprotein Convertase Subtilisin/Kexin type 9 (PCSK9) has emerged as a promising target to reduce residual cardiovascular disease risk.
Pharmacologic inhibitors of proprotein convertase subtilisin-kexin type 9 (PCSK9) are being evaluated in clinical trials for the treatment of cardiovascular disease.
The new treatment strategies for lipid-lowering therapy include using proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors as an exciting approach to reduce residual risk of cardiovascular diseases (CVD).
Mechanisms for modulation of those targets are also becoming more diverse while statins remain the backbone of CVD prevention, the new alternatives, such as PCSK9 monoclonals will probably play an important additional role in treatment of patients at risk for CVD.
In the entire cohort, the third vs first tertile of PCSK9 was not associated with the risk of death from any cause (hazard ratio = 1.09, p = 0.367) and from cardiovascular diseases (hazard ratio = 1.09, p = 0.476).
The aim of this review is to outline current findings on the metabolic and dietary regulation of PCSK9 and effects on cholesterol, apoB lipoprotein metabolism, and cardiovascular disease (CVD) risk.