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PCSK9 as a therapeutic target for cardiovascular disease

It is well recognized that the elevated plasma level of low-density lipoprotein-cholesterol (LDL-C) is a major risk factor for atherosclerosis and cardiovascular disease (CVD). Deposition of pro-atherogenic LDL-C, on the intima of arterial wall, contributes to plaque formation and atherosclerosis, w...

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Detalles Bibliográficos
Autor principal: Zhang, Pei-Ying
Formato: Online Artículo Texto
Lenguaje:English
Publicado: D.A. Spandidos 2017
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5403434/
https://www.ncbi.nlm.nih.gov/pubmed/28450903
http://dx.doi.org/10.3892/etm.2017.4055
Descripción
Sumario:It is well recognized that the elevated plasma level of low-density lipoprotein-cholesterol (LDL-C) is a major risk factor for atherosclerosis and cardiovascular disease (CVD). Deposition of pro-atherogenic LDL-C, on the intima of arterial wall, contributes to plaque formation and atherosclerosis, which further leads to lowered blood flow to vital organs and increased risk of CVD. The most commonly used statin therapy is effective in reducing dyslipidemia and preventing cardiovascular events only in about half of the patient population. However, in patients with familial hypercholesterolemia, these drugs were not effective to meet the required goals of lower LDL-C, and to reduce the CVD risk. Furthermore, many patients even develop intolerability to statins and resistance. The identification of pro-protein convertase subtilisin/kexin type 9 (PCSK9) and the association of PCSK9 mutations with familial hypercholesterolemia led to the identification of PCSK9 as a new therapeutic target for lowering LDL-C and dyslipidemia-associated CVD. PCSK9 is found to promote the degradation of LDL-receptor (LDLR), thus rendering it unavailable for recycling to hepatocyte plasma membrane, leading to elevated levels of circulating LDL-C, as it cannot be taken up into cells. While gain-of-function mutations aggravate the degradation of LDLR as in familial hypercholesterolemia whereas loss of function mutations reduce the ability of PCSK9 to promote the degradation of LDLR and thus lower the plasma level of LDL-C and dyslipidemia. Monoclonal antibodies against PCSK9 are currently being tested in clinical trials and are found to be efficacious in countering the activity of PCSK9 and thus control the plasma LDL-C and triglycerides even in statin non-responsive patients and protect against dyslipidemia-related CVD.