Circulation

Journal: Circulation

Abbreviation

Circulation

Publisher

Lippincott Williams & Wilkins

ISSN

0009-7322
1524-4539

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Publications 1 - 10 of 38

Inhibition of the Hypoxia-Inducible Factor 1 alpha-Induced Cardiospecific HERNA1 Enhance-Templated RNA Protects From Heart Disease
Mirtschink, Peter; Bischof, Corinne; Pham, Minh-Duc; et al. (2019)
Circulation
Background: Enhancers are genomic regulatory elements conferring spatiotemporal and signal-dependent control of gene expression. Recent evidence suggests that enhancers can generate noncoding enhancer RNAs, but their (patho)biological functions remain largely elusive. Methods: We performed chromatin immunoprecipitation–coupled sequencing of histone marks combined with RNA sequencing of left ventricular biopsies from experimental and genetic mouse models of human cardiac hypertrophy to identify transcripts revealing enhancer localization, conservation with the human genome, and hypoxia-inducible factor 1α dependence. The most promising candidate, hypoxia-inducible enhancer RNA (HERNA)1, was further examined by investigating its capacity to modulate neighboring coding gene expression by binding to their gene promoters by using chromatin isolation by RNA purification and λN–BoxB tethering–based reporter assays. The role of HERNA1 and its neighboring genes for pathological stress–induced growth and contractile dysfunction, and the therapeutic potential of HERNA1 inhibition was studied in gapmer-mediated loss-of-function studies in vitro using human induced pluripotent stem cell–derived cardiomyocytes and various in vivo models of human pathological cardiac hypertrophy. Results: HERNA1 is robustly induced on pathological stress. Production of HERNA1 is initiated by direct hypoxia-inducible factor 1α binding to a hypoxia-response element in the histoneH3-lysine27acetylation marks–enriched promoter of the enhancer and confers hypoxia responsiveness to nearby genes including synaptotagmin XVII, a member of the family of membrane-trafficking and Ca2+-sensing proteins and SMG1, encoding a phosphatidylinositol 3-kinase–related kinase. Consequently, a substrate of SMG1, ATP-dependent RNA helicase upframeshift 1, is hyperphoshorylated in a HERNA1- and SMG1-dependent manner. In vitro and in vivo inactivation of SMG1 and SYT17 revealed overlapping and distinct roles in modulating cardiac hypertrophy. Finally, in vivo administration of antisense oligonucleotides targeting HERNA1 protected mice from stress-induced pathological hypertrophy. The inhibition of HERNA1 postdisease development reversed left ventricular growth and dysfunction, resulting in increased overall survival. Conclusions: HERNA1 is a novel heart-specific noncoding RNA with key regulatory functions in modulating the growth, metabolic, and contractile gene program in disease, and reveals a molecular target amenable to therapeutic exploitation.
Innate Signaling Promotes Formation of Regulatory Nitric Oxide-Producing Dendritic Cells Limiting T-Cell Expansion in Experimental Autoimmune Myocarditis
Kania, G.; Siegert, S.; Behnke, S.; et al. (2013)
Circulation
Metabolic Modulator Perhexiline Corrects Energy Deficiency and Improves Exercise Capacity in Symptomatic Hypertrophic Cardiomyopathy
Abozguia, Khalid; Elliott, Perry; McKenna, William; et al. (2010)
Circulation
Cardiac Raptor Ablation Impairs Adaptive Hypertrophy, Alters Metabolic Gene Expression, and Causes Heart Failure in Mice
Shende, Pankaj; Plaisance, Isabelle; Morandi, Christian; et al. (2011)
Circulation
Abstract 12468: One-Year Effects of Randomized High-Intensity Statin versus Placebo on the Bioactive Lipidome: Findings From the JUPITER Trial
Hoshi, Rosangela; Alotaibi, Mona; Liu, Yanyan; et al. (2023)
Circulation ~ Abstracts From the American Heart Association's 2023 Scientific Sessions and the American Heart Association's 2023 Resuscitation Science Symposium
Incremental Value of High-Resolution Myocardial Perfusion Cardiovascular Magnetic Resonance Imaging in Patients with Three-Vessel Coronary Artery Disease
Motwani, Manish; Fairbairn, Timothy A.; Maredia, Neil; et al. (2011)
Circulation
Coronary microvascular dysfunction induced by primary hyperparathyroidism is restored after parathyroidectomy
Osto, Elena; Fallo, Francesco; Pelizzo, Maria R.; et al. (2012)
Circulation
Arrhythmogenic Left Ventricular Cardiomyopathy: Suspected by Cardiac Magnetic Resonance Imaging, Confirmed by Identification of a Novel Plakophilin-2 Variant
Saguner, Ardan M.; Buchmann, Beate; Wyler, Daniel; et al. (2015)
Circulation
Loss of AngiomiR-126 and 130a in Angiogenic Early Outgrowth Cells From Patients With Chronic Heart Failure Role for Impaired In Vivo Neovascularization and Cardiac Repair Capacity
Jakob, Philipp; Doerries, Carola; Briand, Sylvie; et al. (2012)
Circulation
Effect of Randomized Omega-3 Treatment on Downstream Bioactive Lipids and Their Association With Incident Cardiovascular Disease Events: Metabolomic Studies of the Vital and Jupiter Trials
Demler, Olga; Liu, Yanyan; Alotaibi, Mona; et al. (2023)
Circulation

Publications 1 - 10 of 38

Journal: Circulation

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