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Antisense cardiovascular

Bastian Ramms, Philip L S M Gordts
PURPOSE OF REVIEW: Apolipoprotein (apo) C-III is a key player in triglyceride-rich lipoprotein metabolism and strongly associated with elevated plasma triglyceride levels. Several new studies added important insights on apoC-III and its physiological function confirming its promise as a valid therapeutic target. RECENT FINDINGS: APOC3 is expressed in liver and intestine and regulates triglyceride-rich lipoprotein (TRL) catabolism and anabolism. The transcriptional regulation in both organs requires different regulatory elements...
March 15, 2018: Current Opinion in Lipidology
Vesa M Olkkonen, Juha Sinisalo, Matti Jauhiainen
Remarkably good results have been achieved in the treatment of atherosclerotic cardiovascular diseases (CVD) by using statin, ezetimibe, antihypertensive, antithrombotic, and PCSK9 inhibitor therapies and their proper combinations. However, despite this success, the remaining CVD risk is still high. To target this residual risk and to treat patients who are statin-intolerant or have an exceptionally high CVD risk for instance due to familial hypercholesterolemia (FH), new therapies are intensively sought. One pathway of drug development is targeting the circulating triglyceride-rich lipoproteins (TRL) and their lipolytic remnants, which, according to the current view, confer a major CVD risk...
March 8, 2018: Atherosclerosis
Kyoung Im Cho, Ichiro Sakuma, Il Suk Sohn, Toshio Hayashi, Kazunori Shimada, Kwang Kon Koh
Statins are important for preventing adverse cardiovascular events in patients with both high and low risk of vascular disease, by reducing the levels of low-density lipoprotein cholesterol (LDL-C). However, statins dose-dependently increase adverse effects and increase the risk of type 2 diabetes. Previously, it was hypothesized this was caused by to off-target effects, but recent studies demonstrate it is caused by on-target effects. Nonetheless, the American guidelines recommend the use of high-intensity statin therapy, and extend its use to most people at risk of vascular diseases, particularly older people...
March 2, 2018: Circulation Journal: Official Journal of the Japanese Circulation Society
H S Jeffrey Man, Aravin N Sukumar, Gabrielle C Lam, Paul J Turgeon, Matthew S Yan, Kyung Ha Ku, Michelle K Dubinsky, J J David Ho, Jenny Jing Wang, Sunit Das, Nora Mitchell, Peter Oettgen, Michael V Sefton, Philip A Marsden
Endothelial cell (EC)-enriched protein coding genes, such as endothelial nitric oxide synthase (eNOS), define quintessential EC-specific physiologic functions. It is not clear whether long noncoding RNAs (lncRNAs) also define cardiovascular cell type-specific phenotypes, especially in the vascular endothelium. Here, we report the existence of a set of EC-enriched lncRNAs and define a role for s pliced- t ranscript e ndothelial- e nriched lncRNA (STEEL) in angiogenic potential, macrovascular/microvascular identity, and shear stress responsiveness...
February 21, 2018: Proceedings of the National Academy of Sciences of the United States of America
Priska Stahel, Changting Xiao, Robert A Hegele, Gary F Lewis
Despite the effectiveness of low-density lipoprotein (LDL)-lowering strategies for the treatment of diabetic dyslipidemia, significant residual risk of atherosclerotic cardiovascular disease remains. Residual risk might in part be explained by lipid abnormalities that go beyond LDL cholesterol elevation, collectively termed the "atherogenic dyslipidemia complex (ADC)," consisting of hypertriglyceridemia, elevated small dense LDL particles, reduced high-density lipoprotein cholesterol, and high-density lipoprotein particle numbers, increased remnant lipoproteins, and postprandial hyperlipidemia...
December 15, 2017: Canadian Journal of Cardiology
Børge G Nordestgaard, Stephen J Nicholls, Anne Langsted, Kausik K Ray, Anne Tybjærg-Hansen
New treatment opportunities are emerging in the field of lipid-lowering therapy through gene-silencing approaches. Both antisense oligonucleotide inhibition and small interfering RNA technology aim to degrade gene mRNA transcripts to reduce protein production and plasma lipoprotein levels. Elevated levels of LDL, remnant lipoproteins, and lipoprotein(a) all cause cardiovascular disease, whereas elevated levels of triglyceride-rich lipoproteins in some patients can cause acute pancreatitis. The levels of each of these lipoproteins can be reduced using gene-silencing therapies by targeting proteins that have an important role in lipoprotein production or removal (for example, the protein products of ANGPTL3, APOB, APOC3, LPA, and PCSK9)...
February 8, 2018: Nature Reviews. Cardiology
Esther Nuñez-Durán, Mariam Aghajan, Manoj Amrutkar, Silva Sütt, Emmelie Cansby, Sheri L Booten, Andrew Watt, Marcus Ståhlman, Norbert Stefan, Hans-Ulrich Häring, Harald Staiger, Jan Borén, Hanns-Ulrich Marschall, Margit Mahlapuu
Nonalcoholic fatty liver disease (NAFLD) contributes to the pathogenesis of type 2 diabetes and cardiovascular disease, and patients with nonalcoholic steatohepatitis (NASH) are also at risk of developing cirrhosis, liver failure, and hepatocellular carcinoma. To date, no specific therapy exists for NAFLD/NASH, which has been recognized as one of the major unmet medical needs of the twenty-first century. We recently identified serine/threonine protein kinase (STK)25 as a critical regulator of energy homeostasis and NAFLD progression...
January 2018: Hepatology Communications
Elżbieta Wanowska, Magdalena Regina Kubiak, Wojciech Rosikiewicz, Izabela Makałowska, Michał Wojciech Szcześniak
Antisense transcription is a widespread phenomenon in mammalian genomes, leading to production of RNAs molecules referred to as natural antisense transcripts (NATs). NATs apply diverse transcriptional and post-transcriptional regulatory mechanisms to carry out a wide variety of biological roles that are important for the normal functioning of living cells, but their dysfunctions can be associated with human diseases. In this review, we attempt to provide a molecular basis for the involvement of NATs in the etiology of human disorders such as cancers and neurodegenerative and cardiovascular diseases...
January 17, 2018: Wiley Interdisciplinary Reviews. RNA
Xin Su, Dao-Quan Peng
Dyslipidemia, characterized by elevation of plasma low density lipoprotein cholesterol (LDL-C), triglyceride (TG) and reduction of plasma high density lipoprotein cholesterol (HDL-C), has been verified as a causal risk factor for cardiovascular diseases (CVD), leading to a high mortality rate in general population. It is important to understand the molecular metabolism underlying dyslipidemia in order to reduce the risk and to develop effective therapeutic approaches against CVD. ANGPTL3 (human) or Angptl3 (mouse), one member of the angiopoietin-like protein (ANGPTL) family, has been identified as an important regulator of lipid metabolism by inhibiting LPL and EL activity...
January 15, 2018: Lipids in Health and Disease
Liwei Ren, Yuan Sun, Hong Lu, Dien Ye, Lijuan Han, Na Wang, Alan Daugherty, Furong Li, Miaomiao Wang, Fengting Su, Wenjun Tao, Jie Sun, Noam Zelcer, Adam E Mullick, Ah J Danser, Yizhou Jiang, Yongcheng He, Xiongzhong Ruan, Xifeng Lu
Rationale: An elevated level of plasma low-density lipoprotein (LDL) is an established risk factor for cardiovascular disease. Recently, we reported that the (pro)renin receptor ([P]RR) regulates LDL metabolism in vitro via the LDL receptor (LDLR) and SORT1, independently of the renin-angiotensin system. Objective: To investigate the physiological role of [P]RR in lipid metabolism in vivo. Methods and Results: We used N-Acetylgalactosamine (GalNAc) modified antisense oligonucleotides (ASO) to specifically inhibit hepatic [P]RR expression in C57BL/6J mice, and studied the consequences this has on lipid metabolism...
January 4, 2018: Circulation Research
Natalia A Rocha, Cara East, Jun Zhang, Peter A McCullough
PURPOSE OF REVIEW: Apolipoprotein CIII (ApoCIII) is now recognized as a key regulator in severe hypertriglyceridemia, chylomicronemia, and conditions of triglyceride-rich lipoprotein (TRL) remnant excess due to its inhibition of lipoprotein lipase (LPL) and hepatic lipase, leading to decreased hepatic reuptake of TRLs, as well as enhanced synthesis and secretion of VLDL from the liver. ApoCIII gain-of-function mutations are associated with atherosclerosis and coronary heart disease (CHD), and contribute to the development of cardiometabolic syndrome, hypertriglyceridemia, and type 2 diabetes mellitus...
November 9, 2017: Current Atherosclerosis Reports
Anja Vogt
Elevated levels of lipoprotein(a) (Lp(a)) contribute to the risk of early and severe cardiovascular disease (CVD). Recently <50 mg/dl was recommended as the desirable level for clinical use and decision making. All established medical therapies to lower cholesterol levels have no impact on lowering Lp(a) except niacin which is all too often poorly tolerated and not obtainable everywhere. Lipoprotein apheresis is an extracorporeal treatment to lower levels of Lp(a) significantly by > 60%. In some countries it is recommended in very high risk patients with early or progressive CVD...
November 2017: Atherosclerosis. Supplements
Ioanna Gouni-Berthold
Increased triglyceride levels (higher than ∼1000 mg/dL) are associated with an increased risk for pancreatitis. Apolipoprotein-CIII (apo-CIII) plays a key role in the metabolism of triglycerides and triglyceride-rich lipoproteins. While loss of function mutations in the gene encoding apo-CIII (APOC3) are associated with low triglyceride levels and a decreased risk for cardiovascular disease (CVD), overexpression of APOC3 is associated with hypertriglyceridemia. Although many drugs such as fibrates, statins and omega-3 fatty acids modestly decrease triglyceride levels (and apo-CIII concentrations), there are many patients who still have severe hypertriglyceridemia and are at risk for pancreatitis and potentially CVD...
November 2017: Atherosclerosis. Supplements
Serdal Arslan, Öcal Berkan, Torkia Lalem, Nil Özbilüm, Sabahattin Göksel, Özge Korkmaz, Nilgün Çetin, Yvan Devaux
BACKGROUND AND AIMS: Genetic and environmental factors are important components of the development of atherosclerosis. Long non-coding RNA (lncRNAs) have emerged as regulators of multiple pathophysiological pathways in the cardiovascular system. Here, we investigated potential associations between lncRNAs and atherosclerosis. METHODS: Tissue samples from atherosclerotic coronary artery plaques and non-atherosclerotic internal mammary artery were obtained from 20 patients during coronary artery bypass surgery...
November 2017: Atherosclerosis
Alpo Vuorio, Gerald F Watts, Petri T Kovanen
Approximately 35 million people worldwide suffer from heterozygous familial hypercholesterolaemia (HeFH), a condition characterized by genetically determined life-long elevation of plasma low-density lipoprotein cholesterol (LDL-C). One in three of these patients also inherit an elevated plasma concentration of lipoprotein (a) [Lp(a)], a lipoprotein particle with atherogenic, inflammatory and prothrombotic properties. Accordingly, the combination of high plasma LDL-C and Lp(a) can markedly accelerate premature atherosclerotic cardiovascular disease (ASCVD)...
October 3, 2017: European Heart Journal
Anthony C Keech, Alicia J Jenkins
PURPOSE OF REVIEW: We provide an overview of current evidence about the independent role of high triglyceride levels for cardiovascular risk and for acute pancreatitis. RECENT FINDINGS: Natural experiments of Mendelian randomization have given us a deeper understanding about the molecular pathways involved in triglyceride metabolism. Individuals with low-triglyceride levels generally have lower rates of cardiovascular disease (CVD). There has been a significant growth in the development of new agents that modulate enzymes involved in a variety of aspects of triglyceride packaging into VLDL or chylomicron particles, and triglyceride catabolism...
December 2017: Current Opinion in Lipidology
Anum Saeed, Salim S Virani
Lipoprotein (a) (Lp (a)) is a complex polymorphic lipoprotein. Although structurally similar to low-density lipoprotein, Lp(a) has a glycoprotein, apolipoprotein(a) (apo(a)), attached to the apolipoprotein B-100 component. Several unique properties of Lp(a) can be attributed to the presence of apo(a). Several decades of research has improved our understanding of the structure, biochemistry, and pathophysiology of Lp(a) associated diseases. Genetic, epidemiological, and translational data indicate that elevated Lp(a) levels are likely in the causal pathway for atherosclerotic cardiovascular diseases as well as calcification of the aortic valves...
January 1, 2018: Frontiers in Bioscience (Landmark Edition)
Klaus G Parhofer
PURPOSE OF REVIEW: Although lipid-lowering treatment with statins, ezetimibe, and PCSK9 inhibitors is a very successful strategy to prevent cardiovascular events, there is a need for further drug developments. Not all patients respond sufficiently to the available therapy (very high baseline values, intolerance). Furthermore, patients may be characterized by dyslipidemias not accessible to available drugs such as patients with homozygous familial hypercholesterolemia, chylomicronemia syndrome, or elevated lipoprotein(a)...
December 2017: Current Opinion in Lipidology
Katrina L Ellis, Michael B Boffa, Amirhossein Sahebkar, Marlys L Koschinsky, Gerald F Watts
Lipoprotein(a) [Lp(a)] is a highly heritable cardiovascular risk factor. Although discovered more than 50 years ago, Lp(a) has recently re-emerged as a major focus in the fields of lipidology and preventive cardiology owing to findings from genetic studies and the possibility of lowering elevated plasma concentrations with new antisense therapy. Data from genetic, epidemiological and clinical studies have provided compelling evidence establishing Lp(a) as a causal risk factor for atherosclerotic cardiovascular disease...
October 2017: Progress in Lipid Research
Georgios Polychronopoulos, Konstantinos Tziomalos
Even though statins represent the mainstay of treatment of heterozygous familial hypercholesterolemia (FH), their low-density lipoprotein cholesterol (LDL-C) lowering efficacy is finite and most patients with FH will not achieve LDL-C targets with statin monotherapy. Addition of ezetimibe with or without bile acid sequestrants will also not lead to treatment goals in many of these patients, particularly in those with established cardiovascular disease. In this selected subgroup of the FH population, proprotein convertase subtilisin-kexin type 9 (PCSK9) inhibitors provide substantial reductions in LDL-C levels, reduce cardiovascular morbidity and appear to be safe...
December 2017: Expert Review of Clinical Pharmacology
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