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https://www.readbyqxmd.com/read/29642711/recent-advances-in-inhibitors-of-sirtuin1-2-an-update-and-perspective
#1
Ziyan Zhou, Tianfang Ma, Qihua Zhu, Yungen Xu, Xiaoming Zha
Sirtuins (SIRT) are coenzyme NAD+ -dependent histone deacetylases for the transfer of modified acetyl groups. Sirtuins are widely involved in various physiological processes and therefore associated with cardiovascular disease, diabetes, Parkinson's disease, cancer and beyond. Consequently, the development of modulators for  sirtuins has considerable clinical value. To date, a variety of SIRT1/2 inhibitors have been reported and none has been approved for the market. This review summarizes the recent progress in the discovery and development of SIRT1/2 inhibitors including their inhibitory potency, structure-activity relationship and binding mode analysis as well as discusses the perspective for the future development of SIRT1/2 inhibitors...
April 12, 2018: Future Medicinal Chemistry
https://www.readbyqxmd.com/read/29588416/programmed-cell-death-5-suppresses-akt-mediated-cytoprotection-of-endothelium
#2
Seung-Hyun Lee, Jaesung Seo, Soo-Yeon Park, Mi-Hyeon Jeong, Hyo-Kyoung Choi, Chan Joo Lee, Mi Jeong Kim, Garam Guk, SooYeon Lee, Hyewon Park, Jae-Wook Jeong, Chang Hoon Ha, Sungha Park, Ho-Geun Yoon
Programmed cell death 5 (PDCD5) has been associated with human cancers as a regulator of cell death; however, the role of PDCD5 in the endothelium has not been revealed. Thus, we investigated whether PDCD5 regulates protein kinase B (PKB/AKT)-endothelial nitric oxide synthase (eNOS)-dependent signal transduction in the endothelium and affects atherosclerosis. Endothelial-specific PDCD5 knockout mice showed significantly reduced vascular remodeling compared with wild-type (WT) mice after partial carotid ligation...
March 27, 2018: Proceedings of the National Academy of Sciences of the United States of America
https://www.readbyqxmd.com/read/29587244/epigenetic-regulation-of-vascular-nadph-oxidase-expression-and-reactive-oxygen-species-production-by-histone-deacetylase-dependent-mechanisms-in-experimental-diabetes
#3
Simona-Adriana Manea, Mihaela-Loredana Antonescu, Ioana Madalina Fenyo, Monica Raicu, Maya Simionescu, Adrian Manea
Reactive oxygen species (ROS) generated by up-regulated NADPH oxidase (Nox) contribute to structural-functional alterations of the vascular wall in diabetes. Epigenetic mechanisms, such as histone acetylation, emerged as important regulators of gene expression in cardiovascular disorders. Since their role in diabetes is still elusive we hypothesized that histone deacetylase (HDAC)-dependent mechanisms could mediate vascular Nox overexpression in diabetic conditions. Non-diabetic and streptozotocin-induced diabetic C57BL/6J mice were randomized to receive vehicle or suberoylanilide hydroxamic acid (SAHA), a pan-HDAC inhibitor...
March 17, 2018: Redox Biology
https://www.readbyqxmd.com/read/29529137/hdac4-regulates-vascular-inflammation-via-activation-of-autophagy
#4
Di Yang, ChenXi Xiao, Fen Long, ZhengHua Su, WanWan Jia, Ming Qin, MengWei Huang, WeiJun Wu, Rinkiko Suguro, XinHua Liu, YiZhun Zhu
Aims: Angiotensin II (Ang II) causes vascular inflammation, leading to vascular endothelial cell dysfunction, and is associated with the development of cardiovascular diseases. Therefore, interventions in inflammation may contribute to the reduction of cardiovascular diseases. Here, we aim to demonstrate that HDAC4, one of class IIa family histone deacetylases (HDACs) members, promotes autophagy-dependent vascular inflammation. Methods and results: By loss-of-function approaches, our study provides the first evidence that HDAC4 mediates Ang II-induced vascular inflammation in vitro and in vivo...
February 24, 2018: Cardiovascular Research
https://www.readbyqxmd.com/read/29511860/dj-1-is-involved-in-epigenetic-control-of-sphingosine-1-phosphate-receptor-expression-in-vascular-neointima-formation
#5
Kang Pa Lee, Suji Baek, Seung Hyo Jung, Long Cui, Donghyen Lee, Dong-Youb Lee, Wahn Soo Choi, Hyun Woo Chung, Byeong Han Lee, Bokyung Kim, Kyung Jong Won
DJ-1 and sphingosine-1-phosphate (S1P) receptors (S1PRs) are implicated in the control of physiology and pathophysiology of cardiovascular systems such as blood pressure, atherosclerosis, and restenosis. Here, we investigated whether DJ-1 with antioxidant function participates in the regulation of S1PR1 and S1PR2 expression in vascular smooth muscle cells (VSMCs) and whether this response is related to vascular neointima formation. In vitro studies used cellular migration assay, western blot, reverse transcriptase and real-time PCR analysis, and immunocytochemistry...
March 6, 2018: Pflügers Archiv: European Journal of Physiology
https://www.readbyqxmd.com/read/29482060/inhibition-of-class-iia-histone-deacetylase-activity-by-gallic-acid-sulforaphane-tmp269-and-panobinostat
#6
Sin Young Choi, Hae Jin Kee, Li Jin, Yuhee Ryu, Simei Sun, Gwi Ran Kim, Myung Ho Jeong
Histone deacetylase (HDAC) inhibitors are gaining increasing attention as potential therapeutics for cardiovascular diseases as well as cancer. We recently reported that the class II HDAC inhibitor, MC1568, and the phytochemical, gallic acid, lowered high blood pressure in mouse models of hypertension. We hypothesized that class II HDACs may be involved in the regulation of hypertension. The aim of this study was to determine and compare the effects of well-known HDAC inhibitors (TMP269, panobinostat, and MC1568), phytochemicals (gallic acid, sulforaphane, and piceatannol), and anti-hypertensive drugs (losartan, carvedilol, and furosemide) on activities of class IIa HDACs (HDAC4, 5, 7, and 9)...
February 23, 2018: Biomedicine & Pharmacotherapy, Biomédecine & Pharmacothérapie
https://www.readbyqxmd.com/read/29457866/epigenetic-effects-of-metformin-from-molecular-mechanisms-to-clinical-implications
#7
REVIEW
Stephanie Claire Bridgeman, Gaewyn Colleen Ellison, Phillip Edward Melton, Philip Newsholme, Cyril Desire Sylvain Mamotte
There is a growing body of evidence that links epigenetic modifications to type 2 diabetes. Researchers have more recently investigated effects of commonly used medications, including those prescribed for diabetes, on epigenetic processes. This work reviews the influence of the widely used antidiabetic drug metformin on epigenomics, microRNA levels and subsequent gene expression, and potential clinical implications. Metformin may influence the activity of numerous epigenetic modifying enzymes, mostly by modulating the activation of AMP-activated protein kinase (AMPK)...
February 19, 2018: Diabetes, Obesity & Metabolism
https://www.readbyqxmd.com/read/29446717/activators-of-sirtuin-1-and-their-involvement-in-cardioprotection
#8
Carlotta Granchi, Filippo Minutolo
SIRT1 is a nicotinamide adenosine dinucleotide (NAD+)-dependent deacetylase, which removes acetyl groups from many target proteins, such as histone proteins, transcription factors and cofactors. SIRT1-catalyzed deacetylation of these factors modulates the activity of downstream proteins, thus influencing many biological processes. SIRT1 is involved in the regulation of metabolism, inflammation, and tumor growth. The activity of this enzyme is related to the beneficial health effects of calorie restriction, such as lifespan extension and, in particular, the activation of SIRT1 has a positive impact on the cardiovascular system...
February 13, 2018: Current Medicinal Chemistry
https://www.readbyqxmd.com/read/29425318/albumin-downregulates-klotho-in-tubular-cells
#9
Beatriz Fernandez-Fernandez, M Concepcion Izquierdo, Lara Valiño-Rivas, Dimitra Nastou, Ana B Sanz, Alberto Ortiz, Maria D Sanchez-Niño
Background: Kidney tubular cells are the main sources of Klotho, a protein with phosphaturic action. Genetic Klotho deficiency causes premature cardiovascular aging in mice. Human chronic kidney disease (CKD) is characterized by acquired Klotho deficiency. Despite the lack of uremic toxin accumulation, Category G1 CKD [(normal glomerular filtration rate (GFR)] is already associated with decreased Klotho and with premature cardiovascular aging. Methods: We have explored whether albuminuria, a criterion to diagnose CKD when GFR is normal, may directly decrease Klotho expression in human CKD, preclinical models and cultured tubular cells...
February 7, 2018: Nephrology, Dialysis, Transplantation
https://www.readbyqxmd.com/read/29371598/givinostat-reduces-adverse-cardiac-remodeling-through-regulating-fibroblasts-activation
#10
Marika Milan, Valentina Pace, Fabio Maiullari, Maila Chirivì, Denisa Baci, Silvia Maiullari, Luca Madaro, Sonia Maccari, Tonino Stati, Giuseppe Marano, Giacomo Frati, Pier Lorenzo Puri, Elena De Falco, Claudia Bearzi, Roberto Rizzi
Cardiovascular diseases (CVDs) are a major burden on the healthcare system: indeed, over two million new cases are diagnosed every year worldwide. Unfortunately, important drawbacks for the treatment of these patients derive from our current inability to stop the structural alterations that lead to heart failure, the common endpoint of many CVDs. In this scenario, a better understanding of the role of epigenetics - hereditable changes of chromatin that do not alter the DNA sequence itself - is warranted. To date, hyperacetylation of histones has been reported in hypertension and myocardial infarction, but the use of inhibitors for treating CVDs remains limited...
January 25, 2018: Cell Death & Disease
https://www.readbyqxmd.com/read/29328474/inhibition-of-mir%C3%A2-34a-prevents-endothelial-cell-apoptosis-by-directly-targeting-hdac1-in-the-setting-of-atherosclerosis
#11
Yangwei Li, Kang Zhang, Wei Mao
Despite recent medical advances, atherosclerosis is a global burden accounting for numerous mortalities and hospital admissions. MicroRNAs (miRNAs/miRs) regulate cardiovascular biology and disease, but the role of microRNA‑34a in atherosclerosis remains unclear. In the present study, it was demonstrated that miR‑34a was highly expressed in atherosclerotic lesions and oxidized low‑density lipoprotein (Ox‑LDL)‑treated human aortic endothelial cells (HAECs) (atherosclerotic cell model) using reverse transcription‑quantitative polymerase chain reaction...
March 2018: Molecular Medicine Reports
https://www.readbyqxmd.com/read/29299128/estrogen-modulates-vascular-smooth-muscle-cell-function-through-downregulation-of-sirt1
#12
Chien-Hsing Lee, Sheng-Chiang Su, Chi-Fu Chiang, Chu-Yen Chien, Chia-Chen Hsu, Tzu-Yi Yu, Shih-Ming Huang, Yi-Shing Shieh, Hong-Wei Kao, Chien-Sung Tsai, Yi-Jen Hung, Chih-Yuan Lin
Background: There are sex differences in the incidence and severity of cardiovascular disease. Although an estrogen-mediated vasculoprotective effect is widely accepted, clinical trial results have been conflicting and the detailed mechanisms are still unclear. Sirtuin 1 (SIRT1), a class III histone deacetylase, may protect against vascular aging and atherosclerosis; however, the effects of estrogen on SIRT1 expression and vascular smooth muscle cell (VSMC) behavior remain unknown. Materials and Methods: We ovariectomized (OVX) female, wild-type, C57BL/6J mice, which were randomized into non-estrogen- and estrogen-supplemented groups...
December 15, 2017: Oncotarget
https://www.readbyqxmd.com/read/29207042/anti-inflammatory-effect-of-lovastatin-is-mediated-via-the-modulation-of-nf-%C3%AE%C2%BAb-and-inhibition-of-hdac1-and-the-pi3k-akt-mtor-pathway-in-raw264-7-macrophages
#13
Hyung-Wook Choi, Pyung-Gyun Shin, Ji-Hyun Lee, Woo-Suk Choi, Min-Jae Kang, Won-Sik Kong, Min-Ji Oh, Yong-Bae Seo, Gun-Do Kim
Lovastatin is a 3-hydroxy-3-methylglutaryl-CoA reductase inhibitor that is clinically used for the prevention of cardiovascular diseases. Although it has been reported that lovastatin has anti-inflammatory properties in several studies, how lovastatin regulates the inflammation is still unclear. To evaluate the effect of lovastatin on nitric oxide production (NO) in RAW264.7 macrophages, NO production assay was performed. Also, cell viability was measured to confirm cytotoxicity. Level of tumor necrosis factor-α (TNF-α) transcription was measured by reverse transcription polymerase chain reaction (RT-PCR) from total RNA in RAW264...
February 2018: International Journal of Molecular Medicine
https://www.readbyqxmd.com/read/29189132/polyphenols-novel-signaling-pathways
#14
Marie-Louise Ricketts, Bradley S Ferguson
BACKGROUND: Cardiovascular disease (CVD) is currently the leading cause of death globally. The metabolic syndrome (MetS), a clustering of risk factors including hypertension, hyperglycemia, elevated low-density lipoprotein (LDL) cholesterol, reduced high-density lipoprotein (HDL) cholesterol and increased visceral adiposity, is a significant risk factor for the development of CVD. Non-alcoholic fatty liver disease (NAFLD), often referred to as the hepatic manifestation of MetS, is a constellation of progressive liver disorders closely linked to obesity, diabetes, and insulin resistance...
November 29, 2017: Current Pharmaceutical Design
https://www.readbyqxmd.com/read/29175209/the-protective-role-of-low-concentration-alcohol-in-high-fructose-induced-adverse-cardiovascular-events-in-mice
#15
Xiaoqi Wu, Bo Pan, Ying Wang, Lingjuan Liu, Xupei Huang, Jie Tian
Cardiovascular disease remains a worldwide public health issue. As fructose consumption is dramatically increasing, it has been demonstrated that a fructose-rich intake would increase the risk of cardiovascular disease. In addition, emerging evidences suggest that low concentration alcohol intake may exert a protective effect on cardiovascular system. This study aimed to investigate whether low-concentration alcohol consumption would prevent the adverse effects on cardiovascular events induced by high fructose in mice...
January 1, 2018: Biochemical and Biophysical Research Communications
https://www.readbyqxmd.com/read/29104258/epigenetic-regulatory-mechanisms-induced-by-resveratrol
#16
REVIEW
Guilherme Felipe Santos Fernandes, Gabriel Dalio Bernardes Silva, Aline Renata Pavan, Diego Eidy Chiba, Chung Man Chin, Jean Leandro Dos Santos
Resveratrol (RVT) is one of the main natural compounds studied worldwide due to its potential therapeutic use in the treatment of many diseases, including cancer, diabetes, cardiovascular diseases, neurodegenerative diseases and metabolic disorders. Nevertheless, the mechanism of action of RVT in all of these conditions is not completely understood, as it can modify not only biochemical pathways but also epigenetic mechanisms. In this paper, we analyze the biological activities exhibited by RVT with a focus on the epigenetic mechanisms, especially those related to DNA methyltransferase (DNMT), histone deacetylase (HDAC) and lysine-specific demethylase-1 (LSD1)...
November 1, 2017: Nutrients
https://www.readbyqxmd.com/read/28960024/new-aspects-of-vascular-calcification-histone-deacetylases-and-beyond
#17
REVIEW
Duk Hwa Kwon, Young Kook Kim, Hyun Kook
Vascular calcification is a pathologic phenomenon in which calcium phosphate is ectopically deposited in the arteries. Previously, calcification was considered to be a passive process in response to metabolic diseases, vascular or valvular diseases, or even aging. However, now calcification is recognized as a highly-regulated consequence, like bone formation, and many clinical trials have been carried out to elucidate the correlation between vascular calcification and cardiovascular events and mortality. As a result, vascular calcification has been implicated as an independent risk factor in cardiovascular diseases...
November 2017: Journal of Korean Medical Science
https://www.readbyqxmd.com/read/28948877/insights-into-intermolecular-interactions-electrostatic-properties-and-the-stability-of-c646-in-the-binding-pocket-of-p300-histone-acetyltransferase-enzyme-a-combined-molecular-dynamics-and-charge-density-study
#18
Sivanandam Magudeeswaran, Saravanan Kandasamy, Kumaradhas Poomani
Histone acetyltransferases (HATs) and Histone deacetylases (HDACs) are enzymes exhibit important transcription activity. Dysfunction of these enzymes may lead to different diseases including cancer, cardiovascular and other diseases. Therefore, these enzymes are the potential target for the generation of new therapeutics. C646 is a synthetic p300 HAT inhibitor, its structural and the electrostatic properties are the paradigm to understand its activity in the active site of p300 HAT enzyme. The docked C646 molecule in the active site forms expected key intermolecular interactions with the amino acid residues Trp1436, Tyr1467 and one water molecule (W1861); and these interactions are important for acetylation reaction...
September 26, 2017: Journal of Biomolecular Structure & Dynamics
https://www.readbyqxmd.com/read/28928236/histone-deacetylase-inhibition-ameliorates-hypertension-and-hyperglycemia-in-a-model-of-cushing-s-syndrome
#19
Hae-Ahm Lee, Seol-Hee Kang, Mina Kim, Eunjo Lee, Hyun-Min Cho, Eun-Kyung Moon, Inkyeom Kim
Cushing's syndrome (CS) caused by hypercortisolism is occasionally accompanied by metabolic disorders such as hypertension, diabetes mellitus (DM), dyslipidemia, and central obesity. Thus morbidity and mortality, observed in cardiovascular disease, are elevated in patients with CS. We hypothesized that HDAC inhibition (HDACi) decreased transcriptional activity of glucocorticoid receptor (GR), which ameliorates hypertension and hyperglycemia in patients with CS. To establish an animal model of hypercortisolism, Sprague-Dawley rats were infused with adrenocorticotropic hormone (ACTH, 40 ng/day) or dexamethasone (Dex, 10 μg/day) via osmotic minipumps for 4 wk...
January 1, 2018: American Journal of Physiology. Endocrinology and Metabolism
https://www.readbyqxmd.com/read/28923781/low-dose-of-alcohol-attenuates-pro-atherosclerotic-activity-of-thrombin
#20
Masaaki Toda, Toshiaki Totoki, Chizu Nakamura, Taro Yasuma, Corina N D' Alessandro-Gabazza, Rumi Mifuji-Moroka, Kota Nishihama, Motoh Iwasa, Noriyuki Horiki, Esteban C Gabazza, Yoshiyuki Takei
BACKGROUND AND AIMS: Thrombin, the active enzyme of the coagulation system, plays a critical role in the pathogenesis of atherosclerosis. Vascular repair promoted by stromal cell-derived factor-1 is a protective process in atherosclerosis. Consumption of low amount of alcohol is believed to reduce the risk of atherosclerotic cardiovascular disease but the mechanism is unclear. This study evaluated whether alcohol can modulate the expression of stromal cell-derived factor-1 and the pro-atherosclerotic activity of thrombin...
September 5, 2017: Atherosclerosis
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