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https://www.readbyqxmd.com/read/28716988/blood-pressure-lowering-and-safety-improvements-with-liver-angiotensinogen-inhibition-in-models-of-hypertension-and-kidney-injury
#1
Adam E Mullick, Steve T Yeh, Mark J Graham, Jeffery A Engelhardt, Thazha P Prakash, Rosanne M Crooke
Uncontrolled hypertension is an important contributor to cardiovascular disease. Despite the armamentarium of antihypertensive treatments, there remains a need for novel agents effective in individuals who cannot reach acceptable blood pressure levels. Inhibitors targeting the renin-angiotensin-aldosterone system (RAAS) are widely used but may not optimally inhibit RAAS and demonstrate an acceptable safety profile. Experiments were conducted to characterize a series of AGT (angiotensinogen) antisense oligonucleotides (ASOs) and compare their efficacy and tolerability to traditional RAAS blockade...
July 17, 2017: Hypertension
https://www.readbyqxmd.com/read/28670289/non-coding-rna-contribution-to-thoracic-and-abdominal-aortic-aneurysm-disease-development-and-progression
#2
REVIEW
Yuhuang Li, Lars Maegdefessel
Multiple research groups have started to uncover the complex genetic and epigenetic machinery necessary to maintain cardiovascular homeostasis. In particular, the key contribution of non-coding RNAs (ncRNAs) in regulating gene expression has recently received great attention. Aneurysms in varying locations of the aorta are defined as permanent dilations, predisposing to the fatal consequence of rupture. The characteristic pathology of an aneurysm is characterized by progressive vessel wall dilation, promoted by dying vascular smooth muscle cells and limited proliferation, as well as impaired synthesis and degradation of extracellular matrix components, which at least partially is the result of transmural inflammation and its disruptive effect on vessel wall homeostasis...
2017: Frontiers in Physiology
https://www.readbyqxmd.com/read/28629892/engineered-myocardium-model-to-study-the-roles-of-hif-1%C3%AE-and-hif1a-as1-in-paracrine-only-signaling-under-pathological-level-oxidative-stress
#3
Aylin Acun, Pinar Zorlutuna
Studying heart tissue is critical for understanding and developing treatments for cardiovascular diseases. In this work, we fabricated precisely controlled and biomimetic engineered model tissues to study how cell-cell and cell-matrix interactions influence myocardial cell survival upon exposure to pathological level oxidative stress. Specifically, the interactions of endothelial cells (ECs) and cardiomyocytes (CMs), and the role of hypoxia inducible factor-1α (HIF-1α), with its novel alternative regulator, HIF-1α antisense RNA1 (HIF1A-AS1), in these interactions were investigated...
June 16, 2017: Acta Biomaterialia
https://www.readbyqxmd.com/read/28595549/apoc-iii-antisense-oligonucleotides-a-new-option-for-the-treatment-of-hypertriglyceridemia
#4
Joel Schmitz, Ioanna Gouni-Berthold
Elevated triglyceride levels (higher than ~1000 mg/dL) are associated with an increased risk for pancreatitis. Apolipoprotein-CIII (apoC-III) plays a key role in the metabolism of triglycerides and triglyceride-rich lipoproteins. Loss of function mutations in the gene encoding apoC-III (APOC3) are associated with low triglyceride levels and a decreased risk for cardiovascular disease (CVD) while overexpression of APOC3 is associated with hypertriglyceridemia. Although many drugs such as fibrates, statins and omega-3 fatty acids modestly decrease triglyceride levels (and apoC-III concentrations), there are many patients who still have severe hypertriglyceridemia and are at increased risk for pancreatitis and potentially for CVD...
June 8, 2017: Current Medicinal Chemistry
https://www.readbyqxmd.com/read/28550025/30-years-of-the-mineralocorticoid-receptor-mineralocorticoid-receptor-null-mice-informing-cell-type-specific-roles
#5
REVIEW
Timothy J Cole, Morag J Young
The mineralocorticoid receptor (MR) mediates the actions of two important adrenal corticosteroid hormones, aldosterone and cortisol. The cell signalling roles of the MR in vivo have expanded enormously since the cloning of human MR gene 30 years ago and the first MR gene knockout in mice nearly 20 years ago. Complete ablation of the MR revealed important roles postnatally for regulation of kidney epithelial functions, with MR-null mice dying 1-2 weeks postnatally from renal salt wasting and hyperkalaemia, with elevated plasma renin and aldosterone...
July 2017: Journal of Endocrinology
https://www.readbyqxmd.com/read/28538111/cardiovascular-and-metabolic-effects-of-angptl3-antisense-oligonucleotides
#6
Mark J Graham, Richard G Lee, Teresa A Brandt, Li-Jung Tai, Wuxia Fu, Raechel Peralta, Rosie Yu, Eunju Hurh, Erika Paz, Bradley W McEvoy, Brenda F Baker, Nguyen C Pham, Andres Digenio, Steven G Hughes, Richard S Geary, Joseph L Witztum, Rosanne M Crooke, Sotirios Tsimikas
BACKGROUND: Epidemiologic and genomewide association studies have linked loss-of-function variants in ANGPTL3, encoding angiopoietin-like 3, with low levels of plasma lipoproteins. METHODS: We evaluated antisense oligonucleotides (ASOs) targeting Angptl3 messenger RNA (mRNA) for effects on plasma lipid levels, triglyceride clearance, liver triglyceride content, insulin sensitivity, and atherosclerosis in mice. Subsequently, 44 human participants (with triglyceride levels of either 90 to 150 mg per deciliter [1...
July 20, 2017: New England Journal of Medicine
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)...
April 2017: Current Opinion in Pharmacology
https://www.readbyqxmd.com/read/28408313/preventing-cardiovascular-heart-disease-promising-nutraceutical-and-non-nutraceutical-treatments-for-cholesterol-management
#8
REVIEW
T P Johnston, T A Korolenko, M Pirro, A Sahebkar
Hypercholesterolemia is one of the major risk factors for the development of cardiovascular disease. Atherosclerosis resulting from hypercholesterolemia causes many serious cardiovascular diseases. Statins are generally accepted as a treatment of choice for lowering low-density lipoprotein (LDL) cholesterol, which reduces coronary heart disease morbidity and mortality. Since statin use can be associated with muscle problems and other adverse symptoms, non-adherence and discontinuation of statin therapy often leads to inadequate control of plasma cholesterol levels and increased cardiovascular risk...
June 2017: Pharmacological Research: the Official Journal of the Italian Pharmacological Society
https://www.readbyqxmd.com/read/28368771/investigational-therapies-for-hypercholesterolemia
#9
REVIEW
Gerald H Tomkin, Daphne Owens
Cardiovascular morbidity and mortality are of increasing concern, not only to patients but also to the health care profession and service providers. The preventative benefit of treatment of dyslipidaemia is unquestioned but there is a large, so far unmet need to improve clinical outcome. There are exciting new discoveries of targets that may translate into improved clinical outcome. Areas covered: This review highlights some new pathways in cholesterol and triglyceride metabolism and examines new targets, new drugs and new molecules...
May 2017: Expert Opinion on Investigational Drugs
https://www.readbyqxmd.com/read/28365054/lipid-metabolism-and-emerging-targets-for-lipid-lowering-therapy
#10
REVIEW
Daniel Gaudet, Jean-Philippe Drouin-Chartier, Patrick Couture
Cardiovascular disease (CVD) is one of the leading causes of morbidity and mortality worldwide, and dyslipidemia constitutes a major risk factor for CVD and premature atherosclerosis. Therapies to reduce the plasma levels of atherogenic lipoproteins are well established interventions that decrease CVD risk. However, treatment of dyslipidemia with the most widely used lipid-lowering drugs (ie, statins and ezetimibe) often fails to protect a significant proportion of patients from cardiovascular risk. The development of several novel therapies to treat lipid-related disorders and their associated risks is ongoing and includes the following: (1) reducing plasma levels of atherogenic lipoproteins using proprotein convertase subtilisin/kexin type 9 inhibitors, antisense inhibitors of Apolipoprotein (Apo)(a), microsomal triglyceride transfer protein inhibitors, antisense oligonucleotides of ApoB for inhibiting very low-density lipoprotein production, and inhibitors of angiopoietin-like protein 3 or ApoC-III for triglyceride-rich lipoprotein management upstream of low-density lipoprotein production as well as gene replacement therapy to improve low-density lipoprotein and triglyceride-rich lipoprotein clearance; and (2) emerging therapies that target high-density lipoprotein (HDL) and reverse cholesterol transport using cholesteryl ester transfer protein inhibitors, HDL peptide mimetics, and autologous infusion of pre-β HDLs...
July 2017: Canadian Journal of Cardiology
https://www.readbyqxmd.com/read/28329241/lipoprotein-a-the-revenant
#11
Baris Gencer, Florian Kronenberg, Erik S Stroes, François Mach
In the mid-1990s, the days of lipoprotein(a) [Lp(a)] were numbered and many people would not have placed a bet on this lipid particle making it to the next century. However, genetic studies brought Lp(a) back to the front-stage after a Mendelian randomization approach used for the first time provided strong support for a causal role of high Lp(a) concentrations in cardiovascular disease and later also for aortic valve stenosis. This encouraged the use of therapeutic interventions to lower Lp(a) as well numerous drug developments, although these approaches mainly targeted LDL cholesterol, while the Lp(a)-lowering effect was only a 'side-effect'...
May 21, 2017: European Heart Journal
https://www.readbyqxmd.com/read/28315297/paxillin-genes-and-actomyosin-contractility-regulate-myotome-morphogenesis-in-zebrafish
#12
Andrew E Jacob, Jeffrey D Amack, Christopher E Turner
Paxillin (Pxn) is a key adapter protein and signaling regulator at sites of cell-extracellular matrix (ECM) adhesion. Here, we investigated the role of Pxn during vertebrate development using the zebrafish embryo as a model system. We have characterized two Pxn genes, pxna and pxnb, in zebrafish that are maternally supplied and expressed in multiple tissues. Gene editing and antisense gene knockdown approaches were used to uncover Pxn functions during zebrafish development. While mutation of either pxna or pxnb alone did not cause gross embryonic phenotypes, double mutants lacking maternally supplied pxna or pxnb displayed defects in cardiovascular, axial, and skeletal muscle development...
May 1, 2017: Developmental Biology
https://www.readbyqxmd.com/read/28287809/increased-risk-of-chd-in-the-presence-of-rs7865618-a-allele-tehran-lipid-and-glucose-study
#13
Samaneh Matoo, Mohammad Sadegh Fallah, Maryam Sadat Daneshpour, Reyhaneh Mousavi, Bahareh Sedaghati Khayat, Mandana Hasanzad, Fereidoun Azizi
BACKGROUND: Recent genome-wide association studies (GWAS) in European populations have indicated that the rs12526453 polymorphism located in phosphatase and actin regulator 1 gene (PHACTR1), mapping to chromosome 6p24 and rs7865618 polymorphism in the cyclin-dependent kinase inhibitor B antisense RNA 1 gene (CDKN2B-AS1) on 9p21.3 are associated with coronary heart disease (CHD). This study was carried out to investigate the association of these polymorphisms and CHD in an Iranian population...
March 2017: Archives of Iranian Medicine
https://www.readbyqxmd.com/read/28243616/data-on-genotypic-distribution-and-linkage-disequilibrium-of-several-anril-polymorphisms-in-hemodialysis-patients
#14
A Arbiol-Roca, A Padró-Miquel, M Hueso, E Navarro, P Alía-Ramos, M T González-Álvarez, I Rama, J Torras, J M Grinyó, J M Cruzado, N Lloberas
A long non-coding RNA called ANRIL located on chromosome 9p21.3 has been identified as a novel genetic factor associated with cardiovascular disease. Investigation of several single nucleotide polymorphisms (SNPs) of Noncoding Antisense RNA in the INK4 Locus (ANRIL) gene are of particular interest. This article reports data related to the research article entitled: "Association of ANRIL gene polymorphisms with major adverse cardiovascular events in hemodialysis patients" (Arbiol-Roca et al. [1]). Data presented show the genotypic distribution of four selected ANRIL SNPs: rs10757278, rs4977574, rs10757274 and rs6475606 in a cohort constituted by 284 hemodialysis patients...
April 2017: Data in Brief
https://www.readbyqxmd.com/read/28209220/very-low-density-lipoprotein-associated-apolipoproteins-predict-cardiovascular-events-and-are-lowered-by-inhibition%C3%A2-of%C3%A2-apoc-iii
#15
Raimund Pechlaner, Sotirios Tsimikas, Xiaoke Yin, Peter Willeit, Ferheen Baig, Peter Santer, Friedrich Oberhollenzer, Georg Egger, Joseph L Witztum, Veronica J Alexander, Johann Willeit, Stefan Kiechl, Manuel Mayr
BACKGROUND: Routine apolipoprotein (apo) measurements for cardiovascular disease (CVD) are restricted to apoA-I and apoB. Here, the authors measured an unprecedented range of apolipoproteins in a prospective, population-based study and relate their plasma levels to risk of CVD. OBJECTIVES: This study sought to measure apolipoproteins directly by mass spectrometry and compare their associations with incident CVD and to obtain a system-level understanding of the correlations of apolipoproteins with the plasma lipidome and proteome...
February 21, 2017: Journal of the American College of Cardiology
https://www.readbyqxmd.com/read/28192479/comparison-of-zebrafish-tmem88a-mutant-and-morpholino-knockdown-phenotypes
#16
Alexander M J Eve, Elsie S Place, James C Smith
Tmem88a is a transmembrane protein that is thought to be a negative regulator of the Wnt signalling pathway. Several groups have used antisense morpholino oligonucleotides in an effort to characterise the role of tmem88a in zebrafish cardiovascular development, but they have not obtained consistent results. Here, we generate an 8 bp deletion in the coding region of the tmem88a locus using TALENs, and we have gone on to establish a viable homozygous tmem88aΔ8 mutant line. Although tmem88aΔ8 mutants have reduced expression of some key haematopoietic genes, differentiation of erythrocytes and neutrophils is unaffected, contradicting our previous study using antisense morpholino oligonucleotides...
2017: PloS One
https://www.readbyqxmd.com/read/28185213/hyperlipoproteinaemia-a-apheresis-and-emerging-therapies
#17
REVIEW
Anja Vogt
A high level of lipoprotein(a) (Lp(a)) is recognized as an independent and additional cardiovascular risk factor contributing to the risk of early onset and progressive course of cardiovascular disease (CVD). All lipid lowering medications in use mainly lower low density lipoprotein-cholesterol (LDL-c) with no or limited effect on levels of Lp(a). Niacin, the only component lowering Lp(a), is firstly often poorly tolerated and secondly not available anymore in many countries. A level of <50 mg/dl was recommended recently as the cut off level for clinical use and decision making...
March 2017: Clinical Research in Cardiology Supplements
https://www.readbyqxmd.com/read/28174025/effects-of-liposome-based-local-suppression-of-nerve-growth-factor-in-the-bladder-on-autonomic-dysreflexia-during-urinary-bladder-distention-in-rats-with-spinal-cord-injury
#18
Katsumi Kadekawa, Tsuyoshi Yoshizawa, Naoki Wada, Takahiro Shimizu, Tsuyoshi Majima, Pradeep Tyagi, William C de Groat, Kimio Sugaya, Naoki Yoshimura
PURPOSE: To examine (1) whether spinal cord injury (SCI) time-dependently increases the severity of autonomic dysreflexia (AD) and expression levels of bladder nerve growth factor (NGF) protein, and (2) whether local suppression of NGF in the bladder improves SCI-induced AD in rats. MATERIALS AND METHODS: SCI was produced by the transection of the T2/3 spinal cord in female Sprague-Dawley rats. At 4 or 8weeks after SCI, differences in the mean arterial blood pressure (ΔMAP) and heart rate (ΔMHR) during graded increases in intravesical pressure to 20, 40 and 60cm H2O from those before bladder distention and NGF protein levels in the bladder wall were evaluated in spinal intact and SCI rats under urethane anesthesia...
May 2017: Experimental Neurology
https://www.readbyqxmd.com/read/28148841/platelet-localized-fxi-promotes-a-vascular-coagulation-inflammatory-circuit-in-arterial-hypertension
#19
Sabine Kossmann, Jeremy Lagrange, Sven Jäckel, Kerstin Jurk, Moritz Ehlken, Tanja Schönfelder, Yvonne Weihert, Maike Knorr, Moritz Brandt, Ning Xia, Huige Li, Andreas Daiber, Matthias Oelze, Christoph Reinhardt, Karl Lackner, Andras Gruber, Brett Monia, Susanne H Karbach, Ulrich Walter, Zaverio M Ruggeri, Thomas Renné, Wolfram Ruf, Thomas Münzel, Philip Wenzel
Multicellular interactions of platelets, leukocytes, and the blood vessel wall support coagulation and precipitate arterial and venous thrombosis. High levels of angiotensin II cause arterial hypertension by a complex vascular inflammatory pathway that requires leukocyte recruitment and reactive oxygen species production and is followed by vascular dysfunction. We delineate a previously undescribed, proinflammatory coagulation-vascular circuit that is a major regulator of vascular tone, blood pressure, and endothelial function...
February 1, 2017: Science Translational Medicine
https://www.readbyqxmd.com/read/28128058/apolipoprotein-a-antisense-oligonucleotides-a-new-treatment-option-for-lowering-elevated-lipoprotein-a
#20
Julia Schreml, Ioanna Gouni-Berthold
BACKGROUND: Lipoprotein(a) [Lp(a)] is a particle similar to LDL that contains an additional protein called apolipoprotein(a) [apo(a)]. Recent epidemiologic and Mendelian randomization studies have provided evidence that Lp(a) may be causally related to the pathogenesis of atherosclerosis and cardiovascular disease (CVD). While the risk association between Lp(a) concentrations and CVD is weak it seems to be continuous in shape and without an obvious threshold for Lp(a) levels. METHODS: Circulating concentrations of Lp(a) are genetically determined and desirable levels are &amp;amp;amp;amp;amp;amp;lt; 50 mg/dl...
January 25, 2017: Current Pharmaceutical Design
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