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Hdac heart

Lillianne H Wright, Daniel J Herr, Symone S Brown, Harinath Kasiganesan, Donald R Menick
Myocardial infarctions (MIs) cause the loss of myocytes due to lack of sufficient oxygenation and latent revascularization. Although the administration of histone deacetylase (HDAC) inhibitors reduces the size of infarctions and improves cardiac physiology in small-animal models of MI injury, the cellular targets of the HDACs, which the drugs inhibit, are largely unspecified. Here, we show that WNT-inducible secreted protein-1 (Wisp-1), a matricellular protein that promotes angiogenesis in cancers as well as cell survival in isolated cardiac myocytes and neurons, is a target of HDACs...
February 22, 2018: JCI Insight
Mark Y Jeong, Ying H Lin, Sara A Wennersten, Kimberly M Demos-Davies, Maria A Cavasin, Jennifer H Mahaffey, Valmen Monzani, Chandrasekhar Saripalli, Paolo Mascagni, T Brett Reece, Amrut V Ambardekar, Henk L Granzier, Charles A Dinarello, Timothy A McKinsey
There are no approved drugs for the treatment of heart failure with preserved ejection fraction (HFpEF), which is characterized by left ventricular (LV) diastolic dysfunction. We demonstrate that ITF2357 (givinostat), a clinical-stage inhibitor of histone deacetylase (HDAC) catalytic activity, is efficacious in two distinct murine models of diastolic dysfunction with preserved EF. ITF2357 blocked LV diastolic dysfunction due to hypertension in Dahl salt-sensitive (DSS) rats and suppressed aging-induced diastolic dysfunction in normotensive mice...
February 7, 2018: Science Translational Medicine
Viviana Meraviglia, Leonardo Bocchi, Roberta Sacchetto, Maria Cristina Florio, Benedetta M Motta, Corrado Corti, Christian X Weichenberger, Monia Savi, Yuri D'Elia, Marcelo D Rosato-Siri, Silvia Suffredini, Chiara Piubelli, Giulio Pompilio, Peter P Pramstaller, Francisco S Domingues, Donatella Stilli, Alessandra Rossini
SERCA2a is the Ca2+ ATPase playing the major contribution in cardiomyocyte (CM) calcium removal. Its activity can be regulated by both modulatory proteins and several post-translational modifications. The aim of the present work was to investigate whether the function of SERCA2 can be modulated by treating CMs with the histone deacetylase (HDAC) inhibitor suberanilohydroxamic acid (SAHA). The incubation with SAHA (2.5 µM, 90 min) of CMs isolated from rat adult hearts resulted in an increase of SERCA2 acetylation level and improved ATPase activity...
January 31, 2018: International Journal of Molecular Sciences
Hui Yan, Shaowei Yi, Hang Zhuang, Lujin Wu, Dao Wen Wang, Jiangang Jiang
Inhibition of histone deacetylase-2 (HDAC2), which is a prohypertrophic factor in the heart, can functionally attenuate cardiac hypertrophy. The present study aimed to investigate whether sphingosine‑1‑phosphate (S1P), which has recently been reported to suppress HDAC2 activity, could ameliorate the cardiac hypertrophic response and improve cardiac function in mice with transverse aortic constriction (TAC), as well as to determine the underlying mechanisms. Briefly, 8‑week‑old male C57BL/6 mice were randomly divided into sham, TAC and TAC + S1P groups; the results indicated that S1P treatment attenuated TAC‑induced cardiac dysfunction...
December 15, 2017: International Journal of Molecular Medicine
Daniel J Herr, Mauhamad Baarine, Sverre E Aune, Xiaoyang Li, Lauren E Ball, John J Lemasters, Craig C Beeson, James C Chou, Donald R Menick
RATIONALE: Recent evidence indicates that histone deacetylase enzymes (HDACs) contribute to ischemia reperfusion (I/R) injury, and pan-HDAC inhibitors have been shown to be cardioprotective when administered either before an ischemic insult or during reperfusion. We have shown previously that selective inhibition of class I HDACs provides superior cardioprotection when compared to pan-HDAC inhibition in a pretreatment model, but selective class I HDAC inhibition has not been tested during reperfusion, and specific targets of class I HDACs in I/R injury have not been identified...
January 2018: Journal of Molecular and Cellular Cardiology
Sara Saffar Soflaei, Amir Abbas Momtazi, Muhammed Majeed, Giuseppe Derosa, Pamela Maffioli, Amirhossein Sahebkar
BACKGROUND: Histone deacetylases (HDACs) are a group of histone modification enzymes with pivotal role in disease pathogenesis especially in cancer development. Increased activity of certain types of HDACs and positive effects of HDAC inhibition has been shown in several types of cancers. Furthermore, few HDAC inhibitors have been approved by the FDA for cancer treatment, and this has generated interest in finding new HDAC inhibitors as potential anti-cancer agents. Curcumin, a natural polyphenol extracted from turmeric, is a safe and bioactive phytochemical with a wide range of molecular targets and pharmacological activities including promising anti-cancer properties...
November 14, 2017: Current Pharmaceutical Design
Ting-I Lee, Kuan-Jen Bai, Yao-Chang Chen, Ting-Wei Lee, Cheng-Chih Chung, Wen-Chih Tsai, Shin-Yi Tsao, Yu-Hsun Kao
Autophagy serves a role in preserving cellular homeostasis. Diabetes mellitus (DM) impairs cardiac autophagy and is associated with an accumulation of cytotoxic proteins that may provoke apoptosis and damage cardiomyocytes. Histone deacetylase (HDAC) inhibitors attenuate cardiac fibrosis and inflammation, and improve cardiomyopathy resulting from DM. However, the effect of HDAC inhibition on autophagy in DM cardiomyopathy has not been investigated. The purpose of the present study was to evaluate whether HDAC inhibition modulates cardiac autophagy and to investigate the potential mechanisms in type 2 DM (T2DM) hearts...
January 2018: Molecular Medicine Reports
Weston W Blakeslee, Ying-Hsi Lin, Matthew S Stratton, Philip D Tatman, Tianjing Hu, Bradley S Ferguson, Timothy A McKinsey
Class I histone deacetylase (HDAC) inhibitors block hypertrophy and fibrosis of the heart by suppressing pathological signaling and gene expression programs in cardiac myocytes and fibroblasts. The impact of HDAC inhibition in unstressed cardiac cells remains poorly understood. Here, we demonstrate that treatment of cultured cardiomyocytes with small molecule HDAC inhibitors leads to dramatic induction of c-Jun amino-terminal kinase (JNK)-interacting protein-1 (JIP1) mRNA and protein expression. In contrast to prior findings, elevated levels of endogenous JIP1 in cardiomyocytes failed to significantly alter JNK signaling or cardiomyocyte hypertrophy...
September 5, 2017: Journal of Molecular and Cellular Cardiology
Izabela Piotrowska, Mark Isalan, Michal Mielcarek
Doxorubicin is a potent chemotherapeutic agent that is widely-used to treat a variety of cancers but causes acute and chronic cardiac injury, severely limiting its use. Clinically, the acute side effects of doxorubicin are mostly manageable, whereas the delayed consequences can lead to life-threatening heart failure, even decades after cancer treatment. The cardiotoxicity of doxorubicin is subject to a critical cumulative dose and so dosage limitation is considered to be the best way to reduce these effects...
2017: PloS One
Prerna Kumar, Venkateswara R Gogulamudi, Ramu Periasamy, Giri Raghavaraju, Umadevi Subramanian, Kailash N Pandey
Guanylyl cyclase/natriuretic peptide receptor-A (GC-A/NPRA) plays a critical role in the regulation of blood pressure and fluid volume homeostasis. Mice lacking functional Npr1 (coding for GC-A/NPRA) exhibit hypertension and congestive heart failure. However, the underlying mechanisms remain largely less clear. The objective of the present study was to determine the physiological efficacy and impact of all-trans-retinoic acid (ATRA) and sodium butyrate (NaBu) in ameliorating the renal fibrosis, inflammation, and hypertension in Npr1 gene-disrupted haplotype (1-copy; +/-) mice (50% expression levels of NPRA)...
September 1, 2017: American Journal of Physiology. Renal Physiology
Weston W Blakeslee, Kimberly M Demos-Davies, Douglas D Lemon, Katharina M Lutter, Maria A Cavasin, Sam Payne, Karin Nunley, Carlin S Long, Timothy A McKinsey, Shelley D Miyamoto
BackgroundHistone deacetylase (HDAC) inhibitors are promising therapeutics for various forms of cardiac diseases. The purpose of this study was to assess cardiac HDAC catalytic activity and expression in children with single ventricle (SV) heart disease of right ventricular morphology, as well as in a rodent model of right ventricular hypertrophy (RVH).MethodsHomogenates of right ventricle (RV) explants from non-failing controls and children born with a SV were assayed for HDAC catalytic activity and HDAC isoform expression...
October 2017: Pediatric Research
Zheng Xu, Qian Tong, Zhiguo Zhang, Shudong Wang, Yang Zheng, Qiuju Liu, Ling-Bo Qian, Shao-Yu Chen, Jian Sun, Lu Cai
Inhibition of total histone deacetylases (HDACs) was phenomenally associated with the prevention of diabetic cardiomyopathy (DCM). However, which specific HDAC plays the key role in DCM remains unclear. The present study was designed to determine whether DCM can be prevented by specific inhibition of HDAC3 and to elucidate the mechanisms by which inhibition of HDAC3 prevents DCM. Type 1 diabetes OVE26 and age-matched wild-type (WT) mice were given the selective HDAC3 inhibitor RGFP966 or vehicle for 3 months...
August 1, 2017: Clinical Science (1979-)
James L Miller, Myriam Rai, Normand L Frigon, Massimo Pandolfo, Juha Punnonen, Jeffrey R Spencer
Friedreich's ataxia (FA) is a progressive neurodegenerative disease caused by reduced levels of the mitochondrial protein frataxin (FXN). Recombinant human erythropoietin (rhEPO) increased FXN protein in vitro and in early clinical studies, while no published reports evaluate rhEPO in animal models of FA. STS-E412 and STS-E424 are novel small molecule agonists of the tissue-protective, but not the erythropoietic EPO receptor. We find that rhEPO, STS-E412 and STS-E424 increase FXN expression in vitro and in vivo...
May 11, 2017: Neuropharmacology
Hong-Yu Duan, Yi Zhang, Kai-Yu Zhou, Chuan Wang, DA-Jian Qiu, Yi-Min Hua
OBJECTIVE: To investigate the effect of histone acetylation/deacetylation imbalances on embryonic hearts of mice and its effect on key genes of planar cell polarity (PCP) pathway-Vangl2, Scrib and Rac1 in H9C2 cells. METHODS: Forty pregnant C57/B6 mice were randomly assigned into three groups: blank group (n=10), vehicle group (n=10), and valproic acid (VPA)-treated group (n=20). In the VPA-treated group, VPA, a histone deacetylase (HDAC) inhibitor, was administered to each individual dam intraperitoneally at a single dose of 700 mg/kg on embryonic day 10...
April 2017: Zhongguo Dang Dai Er Ke za Zhi, Chinese Journal of Contemporary Pediatrics
Shanshan Ai, Yong Peng, Chen Li, Fei Gu, Xianhong Yu, Yanzhu Yue, Qing Ma, Jinghai Chen, Zhiqiang Lin, Pingzhu Zhou, Huafeng Xie, Terence W Prendiville, Wen Zheng, Yuli Liu, Stuart H Orkin, Da-Zhi Wang, Jia Yu, William T Pu, Aibin He
In proliferating cells, where most Polycomb repressive complex 2 (PRC2) studies have been performed, gene repression is associated with PRC2 trimethylation of H3K27 (H3K27me3). However, it is uncertain whether PRC2 writing of H3K27me3 is mechanistically required for gene silencing. Here, we studied PRC2 function in postnatal mouse cardiomyocytes, where the paucity of cell division obviates bulk H3K27me3 rewriting after each cell cycle. EED (embryonic ectoderm development) inactivation in the postnatal heart (Eed(CKO)) caused lethal dilated cardiomyopathy...
April 10, 2017: ELife
Saviana A Barbati, Claudia Colussi, Lorenza Bacci, Aurora Aiello, Agnese Re, Egidio Stigliano, Andrea M Isidori, Claudio Grassi, Alfredo Pontecorvi, Antonella Farsetti, Carlo Gaetano, Simona Nanni
This study aims at investigating the epigenetic landscape of cardiomyocytes exposed to elevated glucose levels. High glucose (30 mM) for 72 hours determined some epigenetic changes in mouse HL-1 and rat differentiated H9C2 cardiomyocytes including upregulation of class I and III histone deacetylase protein levels and activity, inhibition of histone acetylase p300 activity, increase in histone H3 lysine 27 trimethylation, and reduction in H3 lysine 9 acetylation. Gene expression analysis focused on cardiotoxicity revealed that high glucose induced markers associated with tissue damage, fibrosis, and cardiac remodeling such as Nexilin (NEXN), versican, cyclic adenosine 5'-monophosphate-responsive element modulator (CREM), and adrenoceptor α2A (ADRA2)...
July 1, 2017: Endocrinology
Nataly Tarasenko, Abraham Nudelman, Gabriela Rozic, Suzanne M Cutts, Ada Rephaeli
The histone deacetylase (HDAC) inhibitory prodrugs of butyric (AN7) and valproic (AN446) acids, which release the active acids upon metabolic degradation, were studied examining their differential effects on the viability, HDAC inhibitory activity and the DNA damage response (DDR), in glioblastoma cell and normal human astrocytes (NHAs). In xenografts of glioblastoma, AN7 or AN446 given or the combination of each of them with Dox augmented the anticancer activity of Dox and protected the heart from its toxicity...
August 2017: Investigational New Drugs
Yang Wu, Yan Leng, Qingtao Meng, Rui Xue, Bo Zhao, Liying Zhan, Zhongyuan Xia
Background. Histone deacetylases (HDACs) play a pivotal role in signaling modification and gene transcriptional regulation that are essential for cardiovascular pathophysiology. Diabetic hearts with higher HDACs activity were more vulnerable to myocardial ischemia/reperfusion (MI/R) injury compared with nondiabetic hearts. We are curious about whether suppression of excessive HDACs activity in diabetic heart protects against MI/R injury. Methods. Diabetic rats were subjected to 45 min of ischemia, followed by 3 h of reperfusion...
2017: Journal of Diabetes Research
Katherine B Schuetze, Matthew S Stratton, Weston W Blakeslee, Michael F Wempe, Florence F Wagner, Edward B Holson, Yin-Ming Kuo, Andrew J Andrews, Tonya M Gilbert, Jacob M Hooker, Timothy A McKinsey
Inhibitors of zinc-dependent histone deacetylases (HDACs) profoundly affect cellular function by altering gene expression via changes in nucleosomal histone tail acetylation. Historically, investigators have employed pan-HDAC inhibitors, such as the hydroxamate trichostatin A (TSA), which simultaneously targets members of each of the three zinc-dependent HDAC classes (classes I, II, and IV). More recently, class- and isoform-selective HDAC inhibitors have been developed, providing invaluable chemical biology probes for dissecting the roles of distinct HDACs in the control of various physiologic and pathophysiological processes...
April 2017: Journal of Pharmacology and Experimental Therapeutics
Vidhi Gaur, Timothy Connor, Kylie Venardos, Darren C Henstridge, Sheree D Martin, Courtney Swinton, Shona Morrison, Kathryn Aston-Mourney, Stefan M Gehrig, Roelof van Ewijk, Gordon S Lynch, Mark A Febbraio, Gregory R Steinberg, Mark Hargreaves, Ken R Walder, Sean L McGee
AIM: To determine the effect of Scriptaid, a compound that can replicate aspects of the exercise adaptive response through disruption of the class IIa histone deacetylase (HDAC) corepressor complex, on muscle insulin action in obesity. MATERIALS AND METHODS: Diet-induced obese mice were administered Scriptaid (1 mg/kg) via daily intraperitoneal injection for 4 weeks. Whole-body and skeletal muscle metabolic phenotyping of mice was performed, in addition to echocardiography, to assess cardiac morphology and function...
February 2, 2017: Diabetes, Obesity & Metabolism
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