학술논문
Circular RNA circZFPM2 regulates cardiomyocyte hypertrophy and survival.
Document Type
Academic Journal
Author
Neufeldt D; Institute of Molecular and Translational Therapeutic Strategies, Hannover Medical School, Hannover, Germany.; Schmidt A; Institute of Molecular and Translational Therapeutic Strategies, Hannover Medical School, Hannover, Germany.; Fraunhofer Institute for Toxicology and Experimental Medicine (ITEM), Hannover, Germany.; Mohr E; Institute of Molecular and Translational Therapeutic Strategies, Hannover Medical School, Hannover, Germany.; Lu D; Institute of Molecular and Translational Therapeutic Strategies, Hannover Medical School, Hannover, Germany.; Center for Translational Regenerative Medicine, Hannover Medical School, Hannover, Germany.; Chatterjee S; Institute of Molecular and Translational Therapeutic Strategies, Hannover Medical School, Hannover, Germany.; Center for Translational Regenerative Medicine, Hannover Medical School, Hannover, Germany.; Fuchs M; Fraunhofer Institute for Toxicology and Experimental Medicine (ITEM), Hannover, Germany.; Xiao K; Fraunhofer Institute for Toxicology and Experimental Medicine (ITEM), Hannover, Germany.; Pan W; Institute of Molecular and Translational Therapeutic Strategies, Hannover Medical School, Hannover, Germany.; Cushman S; Institute of Molecular and Translational Therapeutic Strategies, Hannover Medical School, Hannover, Germany.; Jahn C; Institute of Molecular and Translational Therapeutic Strategies, Hannover Medical School, Hannover, Germany.; Juchem M; Institute of Molecular and Translational Therapeutic Strategies, Hannover Medical School, Hannover, Germany.; Fraunhofer Institute for Toxicology and Experimental Medicine (ITEM), Hannover, Germany.; Hunkler HJ; Institute of Molecular and Translational Therapeutic Strategies, Hannover Medical School, Hannover, Germany.; Cipriano G; Institute of Molecular and Translational Therapeutic Strategies, Hannover Medical School, Hannover, Germany.; Jürgens B; Institute of Molecular and Translational Therapeutic Strategies, Hannover Medical School, Hannover, Germany.; Schmidt K; Institute of Molecular and Translational Therapeutic Strategies, Hannover Medical School, Hannover, Germany.; Fraunhofer Institute for Toxicology and Experimental Medicine (ITEM), Hannover, Germany.; Groß S; Institute of Molecular and Translational Therapeutic Strategies, Hannover Medical School, Hannover, Germany.; Jung M; Institute of Molecular and Translational Therapeutic Strategies, Hannover Medical School, Hannover, Germany.; Hoepfner J; Institute of Molecular and Translational Therapeutic Strategies, Hannover Medical School, Hannover, Germany.; Weber N; Institute of Molecular and Translational Therapeutic Strategies, Hannover Medical School, Hannover, Germany.; Foo R; Institute of Molecular and Cell Biology, AStar, Singapore, Singapore.; Pich A; Institute of Toxicology, Hannover Medical School, Hannover, Germany.; Core Facility Proteomics, Institute of Toxicology, Hannover, Germany.; Zweigerdt R; Center for Translational Regenerative Medicine, Hannover Medical School, Hannover, Germany.; Leibniz Research Laboratories for Biotechnology and Artificial Organs (LEBAO), Department of Cardiothoracic, Transplantation and Vascular Surgery, Hannover Medical School, Hannover, Germany.; Kraft T; Institute for Molecular and Cell Physiology, Hannover Medical School, Hannover, Germany.; Thum T; Institute of Molecular and Translational Therapeutic Strategies, Hannover Medical School, Hannover, Germany. thum.thomas@mh-hannover.de.; Center for Translational Regenerative Medicine, Hannover Medical School, Hannover, Germany. thum.thomas@mh-hannover.de.; Bär C; Institute of Molecular and Translational Therapeutic Strategies, Hannover Medical School, Hannover, Germany. baer.christian@mh-hannover.de.; Center for Translational Regenerative Medicine, Hannover Medical School, Hannover, Germany. baer.christian@mh-hannover.de.; Fraunhofer Institute for Toxicology and Experimental Medicine (ITEM), Hannover, Germany. baer.christian@mh-hannover.de.
Source
Publisher: Steinkopff Country of Publication: Germany NLM ID: 0360342 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1435-1803 (Electronic) Linking ISSN: 03008428 NLM ISO Abbreviation: Basic Res Cardiol Subsets: MEDLINE
Subject
Language
English
Abstract
Hypertrophic cardiomyopathy (HCM) constitutes the most common genetic cardiac disorder. However, current pharmacotherapeutics are mainly symptomatic and only partially address underlying molecular mechanisms. Circular RNAs (circRNAs) are a recently discovered class of non-coding RNAs and emerged as specific and powerful regulators of cellular functions. By performing global circRNA-specific next generation sequencing in cardiac tissue of patients with hypertrophic cardiomyopathy compared to healthy donors, we identified circZFPM2 (hsa_circ_0003380). CircZFPM2, which derives from the ZFPM2 gene locus, is a highly conserved regulatory circRNA that is strongly induced in HCM tissue. In vitro loss-of-function experiments were performed in neonatal rat cardiomyocytes, human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs), and HCM-patient-derived hiPSC-CMs. A knockdown of circZFPM2 was found to induce cardiomyocyte hypertrophy and compromise mitochondrial respiration, leading to an increased production of reactive oxygen species and apoptosis. In contrast, delivery of recombinant circZFPM2, packaged in lipid-nanoparticles or using AAV-based overexpression, rescued cardiomyocyte hypertrophic gene expression and promoted cell survival. Additionally, HCM-derived cardiac organoids exhibited improved contractility upon CM-specific overexpression of circZFPM2. Multi-Omics analysis further promoted our hypothesis, showing beneficial effects of circZFPM2 on cardiac contractility and mitochondrial function. Collectively, our data highlight that circZFPM2 serves as a promising target for the treatment of cardiac hypertrophy including HCM.
(© 2024. The Author(s).)
(© 2024. The Author(s).)