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https://www.readbyqxmd.com/read/28535426/new-role-of-pcsk9-in-atherosclerotic-inflammation-promotion-involving-the-tlr4-nf-%C3%AE%C2%BAb-pathway
#1
Zhi-Han Tang, Juan Peng, Zhong Ren, Jing Yang, Ting-Ting Li, Tao-Hua Li, Zuo Wang, Dang-Heng Wei, Lu-Shan Liu, Xi-Long Zheng, Zhi-Sheng Jiang
BACKGROUND AND AIMS: Proprotein convertase subtilisin/kexin 9 (PCSK9) has emerged as a popular target in the development of new cholesterol-lowering drugs and therapeutic interventions for atherosclerosis. PCSK9 could accelerate atherosclerosis through mechanisms beyond the degradation of the hepatic low-density lipoprotein receptor. Several clinical studies suggested that PCSK9 is involved in atherosclerotic inflammation. Accordingly, this study aimed to explore the role of PCSK9 in vascular inflammation that promotes atherosclerotic progression...
April 29, 2017: Atherosclerosis
https://www.readbyqxmd.com/read/28535232/therapies-that-target-pcsk9-effective-at-reducing-ldl-cholesterol
#2
Anita Slomski
No abstract text is available yet for this article.
May 23, 2017: JAMA: the Journal of the American Medical Association
https://www.readbyqxmd.com/read/28534160/micrornas-new-therapeutic-targets-for-familial-hypercholesterolemia
#3
REVIEW
Amir Abbas Momtazi, Maciej Banach, Matteo Pirro, Evan A Stein, Amirhossein Sahebkar
Familial hypercholesterolemia (FH) is the most common inherited form of dyslipidemia and a major cause of premature cardiovascular disease. Management of FH mainly relies on the efficiency of treatments that reduce plasma low-density lipoprotein (LDL) cholesterol (LDL-C) concentrations. MicroRNAs (miRs) have been suggested as emerging regulators of plasma LDL-C concentrations. Notably, there is evidence showing that miRs can regulate the post-transcriptional expression of genes involved in the pathogenesis of FH, including LDLR, APOB, PCSK9, and LDLRAP1...
May 22, 2017: Clinical Reviews in Allergy & Immunology
https://www.readbyqxmd.com/read/28532784/update-on-the-use-of-pcsk9-inhibitors-in-adults-recommendations-from-an-expert-panel-of-the-national-lipid-association
#4
Carl E Orringer, Terry A Jacobson, Joseph J Saseen, Alan S Brown, Antonio M Gotto, Joyce L Ross, James A Underberg
An Expert Panel convened by the National Lipid Association was charged with updating the recommendations on the use of proprotein convertase subtilisin/kexin type 9 (PCSK9) antibody therapy that were provided by the 2015 National Lipid Association Recommendations for the Patient-Centered Management of Dyslipidemia: Part 2. Recent studies have demonstrated the efficacy of these agents in reducing low-density lipoprotein cholesterol and non-high-density lipoprotein cholesterol and have confirmed their excellent safety profile...
May 19, 2017: Journal of Clinical Lipidology
https://www.readbyqxmd.com/read/28531826/how-many-familial-hypercholesterolemia-patients-are-eligible-for-pcsk9-inhibition
#5
Luis Masana, Nuria Plana, Sofia Pérez-Calahorra, Daiana Ibarretxe, Itziar Lamiquiz-Moneo, Juan Pedro-Botet, Manuel Suárez-Tembra, Pedro Valdivielso, Emilio Ortega, Fernando Civeira
BACKGROUND AND AIMS: Familial hypercholesterolemia (FH) is a high cardiovascular risk condition. Less than 20% of patients achieve the LDL targets. Although PCSK9 inhibitors improve control and reduce cardiovascular events, official recommendations for their use are restrictive. We aim to assess the number of FH patients suitable for PCSK9 inhibition according to the European guidelines. METHODS: A total of 2685 FH patients, with a minimum follow-up of 6 months, included in the Dyslipidemia Registry of the Spanish Arteriosclerosis Society, were sorted according to the intensity of their lipid-lowering therapy (LLT) and LDL cholesterol levels achieved...
May 12, 2017: Atherosclerosis
https://www.readbyqxmd.com/read/28529918/advances-in-dyslipidemia-management-for-prevention-of-atherosclerosis-pcsk9-monoclonal-antibody-therapy-and-beyond
#6
REVIEW
Nathan D Wong, Paul D Rosenblit, Robert S Greenfield
In 2003, select families with familial hypercholesterolemia were first identified to have gain-of-function mutations for proprotein convertase subtilisin kexin type 9 (PCSK9) followed, in 2006, by the identification of those with lifelong low levels of LDL-C and lowered atherosclerotic cardiovascular disease (ASCVD) risk who had loss-of-function PCSK9 mutations. These discoveries led to the rapid development of PSCK9-targeted monoclonal antibody (PCSK9 mAb) therapies and, in 2015, 2 'fully-humanized' PCSK9 mAbs (alirocumab and evolocumab) were marketed in the United States, Europe, and other countries...
April 2017: Cardiovascular Diagnosis and Therapy
https://www.readbyqxmd.com/read/28527325/dyslipidemia-management-update
#7
REVIEW
Yingzi Chang, Jacques Robidoux
Association of hypercholesterolemia and atherosclerotic cardiovascular disease (ASCVD) is well established. Reducing low-density lipoprotein-cholesterol (LDL-C) and raising high-density lipoprotein-cholesterol (HDL-C) have been the therapeutic targets to reduce the risk of ASCVD. Cholesterol-lowering medications have been used to provide both primary and secondary prevention of ASCVD for many years by reducing the absorption and reabsorption, promoting excretion, or decreasing the synthesis of cholesterol. Within the past five years, several new classes of cholesterol-lowering drugs have been tested and approved for patients with hypercholesterolemia that are not well controlled by conventional therapy (ezetimibe, bile-acid sequestrants, and statins)...
May 17, 2017: Current Opinion in Pharmacology
https://www.readbyqxmd.com/read/28521874/sirna-mediated-inhibition-of-srebp-cleavage-activating-protein-reduces-dyslipidemia-in-spontaneously-dysmetabolic-rhesus-monkeys
#8
Beth Ann Murphy, Marija Tadin-Strapps, Kristian Jensen, Robin Mogg, Andy Liaw, Kithsiri Herath, Gowri Bhat, David G McLaren, Stephen F Previs, Shirly Pinto
BACKGROUND: SREBP cleavage-activating protein (SCAP) is a cholesterol binding endoplasmic reticulum (ER) membrane protein that is required to activate SREBP transcription factors. SREBPs regulate genes involved in lipid biosynthesis. They also influence lipid clearance by modulating the expression of LDL receptor (LDLR) and proprotein convertase subtilisin/kexin type 9 (PCSK9) genes. Inhibiting SCAP decreases circulating PCSK9, triglycerides (TG), and LDL-cholesterol (LDL-C), both in vitro and in vivo...
June 2017: Metabolism: Clinical and Experimental
https://www.readbyqxmd.com/read/28515357/e2f1-inhibits-circulating-cholesterol-clearance-by-regulating-pcsk9-expression-in-the-liver
#9
Qiuwen Lai, Albert Giralt, Cédric Le May, Lianjun Zhang, Bertrand Cariou, Pierre-Damien Denechaud, Lluis Fajas
Cholesterol accumulation in the liver is an early event in nonalcoholic fatty liver disease (NAFLD). Here, we demonstrate that E2F1 plays a crucial role in maintaining cellular cholesterol homeostasis by regulating cholesterol uptake via proprotein convertase subtilisin/kexin 9 (PCSK9), an enzyme that promotes low-density lipoprotein receptor (LDLR) degradation upon activation. E2f1-/- mice display reduced total plasma cholesterol levels and increased cholesterol content in the liver. In this study, we show that E2f1 deletion in cellular and mouse models leads to a marked decrease in Pcsk9 expression and an increase in LDLR expression...
May 18, 2017: JCI Insight
https://www.readbyqxmd.com/read/28509674/evidence-for-more-intensive-cholesterol-lowering
#10
Handrean Soran, See Kwok, Safwaan Adam, Jan Hoong Ho, Paul N Durrington
PURPOSE OF REVIEW: In randomized clinical trials, reduction in cardiovascular disease (CVD) risk with cholesterol-lowering drugs correlates with the LDL cholesterol decrease. However, because the majority have investigated a fixed statin dose, current guidelines disagree about the use of statin dose titration or non-statin adjunctive cholesterol-lowering drugs. RECENT FINDINGS: We conducted a meta-analysis of all randomized controlled trials with CVD end-points, comparing two intensities of lipid-lowering regimens within the same population, using varying statins doses and/or potency, ezetimibe or PCSK9 inhibitors and compared the observed number of patients needed to be treated for 10 years to prevent one CVD event (NNT) with NNT predicted from trials of predominantly single-dose statin...
May 15, 2017: Current Opinion in Lipidology
https://www.readbyqxmd.com/read/28506389/proprotein-convertase-subtilisin-kexin-9%C3%A2-inhibition-in-patients-with-familial-hypercholesterolemia-initial-clinical-experience
#11
Annette M H Galema-Boers, Mattie J Lenzen, Eric J Sijbrands, Jeanine E Roeters van Lennep
BACKGROUND: Despite optimal lipid-lowering therapy, a minority of patients with familial hypercholesterolemia (FH) reach low-density lipoprotein cholesterol (LDL-c) target goals. In randomized trials, proprotein convertase subtilisin/kexin 9 (PCSK9) inhibitors led to impressive LDL-c reductions and a favorable safety profile. However, data about the efficacy and safety outside clinical trials are not available yet. OBJECTIVE: The purpose of the study is to describe efficacy and side effects of PCSK9 inhibitors in FH patients in clinical practice...
May 2017: Journal of Clinical Lipidology
https://www.readbyqxmd.com/read/28505047/advances-in-the-management-of-dyslipidemia
#12
June Kampangkaew, Stephen Pickett, Vijay Nambi
PURPOSE OF REVIEW: Cardiovascular disease is the leading cause of morbidity and mortality in the United States and therapies aimed at lipid modification are important for the reduction of cardiovascular risk. There have been many exciting advances in lipid management over the recent years. This review discusses these recent advances as well as the direction of future studies. RECENT FINDINGS: Several recent clinical trials support low-density lipoprotein cholesterol (LDL-c) reduction beyond maximal statin therapy for improved cardiovascular outcomes...
May 12, 2017: Current Opinion in Cardiology
https://www.readbyqxmd.com/read/28504688/accelerated-atherosclerosis-development-in-c57bl6-mice-by-overexpressing-aav-mediated-pcsk9-and-partial-carotid-ligation
#13
Sandeep Kumar, Dong-Won Kang, Amir Rezvan, Hanjoong Jo
Studying the role of a particular gene in atherosclerosis typically requires a time-consuming and often difficult process of generating double knockouts or transgenics on ApoE(-/-) or LDL receptor (LDLR)(-/-) background. Recently, it was reported that adeno-associated-virus-8 (AAV8)-mediated overexpression of PCSK9 (AAV8-PCSK9) rapidly induced hyperlipidemia. However, using this method in C57BL6 wild-type (C57) mice, it took ~3 months to develop atherosclerosis. Our partial carotid ligation model is used to rapidly develop atherosclerosis by inducing disturbed flow in the left common carotid artery within 2 weeks in ApoE(-/-) or LDLR(-/-) mice...
May 15, 2017: Laboratory Investigation; a Journal of Technical Methods and Pathology
https://www.readbyqxmd.com/read/28502508/plasma-lipoprotein-a-levels-in-patients-with-homozygous-autosomal-dominant-hypercholesterolemia
#14
Barbara Sjouke, Reyhana Yahya, Michael W T Tanck, Joep C Defesche, Jacqueline de Graaf, Albert Wiegman, John J P Kastelein, Monique T Mulder, G Kees Hovingh, Jeanine E Roeters van Lennep
BACKGROUND: Patients with autosomal dominant hypercholesterolemia (ADH), caused by mutations in either low-density lipoprotein receptor (LDLR), apolipoprotein B (APOB), or proprotein convertase subtilisin-kexin type 9 (PCSK9) are characterized by high low-density lipoprotein cholesterol levels and in some studies also high lipoprotein(a) (Lp(a)) levels were observed. The question remains whether this effect on Lp(a) levels is gene-dose-dependent in individuals with either 0, 1, or 2 LDLR or APOB mutations...
March 2017: Journal of Clinical Lipidology
https://www.readbyqxmd.com/read/28502498/mature-proprotein-convertase-subtilisin-kexin-type-9-coronary-atheroma-burden-and-vessel-remodeling-in-heterozygous-familial-hypercholesterolemia
#15
Yu Kataoka, Mariko Harada-Shiba, Kazuhiro Nakao, Takahiro Nakashima, Shoji Kawakami, Masashi Fujino, Tomoaki Kanaya, Toshiyuki Nagai, Yoshio Tahara, Yasuhide Asaumi, Mika Hori, Masatsune Ogura, Yoichi Goto, Teruo Noguchi, Satoshi Yasuda
BACKGROUND: Proprotein convertase subtilisin/kexin type 9 (PCSK9), an important contributor to low-density lipoprotein metabolism in heterozygous familial hypercholesterolemia (HeFH), exhibits direct proatherogenic effects. PCSK9 circulates as mature and furin-cleaved forms, which differ in its biological activity. However, it remains to be elucidated whether each PCSK9 subtype has different atherogenic properties. OBJECTIVE: To investigate the association of each PCSK9 subtype with coronary atherosclerosis in HeFH...
March 2017: Journal of Clinical Lipidology
https://www.readbyqxmd.com/read/28495986/pcsk9-inhibition-to-reduce-cardiovascular-risk-tempering-expectations
#16
REVIEW
David D Waters, Priscilla Y Hsue
No abstract text is available yet for this article.
May 12, 2017: Circulation Research
https://www.readbyqxmd.com/read/28495363/app-aplp2-and-lrp1-interact-with-pcsk9-but-are-not-required-for-pcsk9-mediated-degradation-of-the-ldlr-in-vivo
#17
Ting Fu, YangYang Guan, Junjie Xu, Yan Wang
Proprotein convertase subtilisin/kexin type 9 (PCSK9) is a secreted protein that post-transcriptionally regulates the levels of hepatic low-density lipoprotein receptors (LDLRs). PCSK9 binds to the extracellular domain of the LDLR, and the PCSK9-LDLR complex is internalized through canonical clathrin-dependent endocytosis and then delivered to lysosomes for degradation. The mechanism by which PCSK9 blocks recycling of the LDLR has not been fully defined. Previous reports showed that amyloid precursor-like protein 2 (APLP2) interacts with PCSK9, but its role in PCSK9-mediated LDLR degradation remains controversial...
May 8, 2017: Biochimica et Biophysica Acta
https://www.readbyqxmd.com/read/28492287/dyslipidaemia-pcsk9-inhibitors-and-foamy-monocytes-in-familial-hypercholesterolaemia
#18
Huaizhu Wu, Christie M Ballantyne
No abstract text is available yet for this article.
May 11, 2017: Nature Reviews. Cardiology
https://www.readbyqxmd.com/read/28488460/the-efficacy-of-evolocumab-in-the-management-of-hyperlipidemia-a-systematic-review
#19
Lamia AlHajri, Asma AlHadhrami, Shama AlMheiri, Yalwah AlMutawa, Zainab AlHashimi
BACKGROUND: Hyperlipidemia or dyslipidemia has been a concern for a long time, with various guidelines emphasizing the importance of managing the lipid profile to prevent cardiac incidences. Although statins have been found to be highly effective, resistance and intolerability to side effects will continue to be a stumbling block for certain patients. Proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors tackle lipid profile via a novel mechanism and therefore provide an additional effective option for managing lipid profile...
May 2017: Therapeutic Advances in Cardiovascular Disease
https://www.readbyqxmd.com/read/28483459/animal-models-of-atherosclerosis
#20
Besa Emini Veseli, Paola Perrotta, Gregory R A De Meyer, Lynn Roth, Carole Van der Donckt, Wim Martinet, Guido R Y De Meyer
An ideal animal model of atherosclerosis resembles human anatomy and pathophysiology and has the potential to be used in medical and pharmaceutical research to obtain results that can be extrapolated to human medicine. Moreover, it must be easy to acquire, can be maintained at a reasonable cost, is easy to handle and shares the topography of the lesions with humans. In general, animal models of atherosclerosis are based on accelerated plaque formation due to a cholesterol-rich/Western-type diet, manipulation of genes involved in the cholesterol metabolism, and the introduction of additional risk factors for atherosclerosis...
May 5, 2017: European Journal of Pharmacology
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