학술논문
Impact of DYRK1A Expression on TNNT2 Splicing and Daunorubicin Toxicity in Human iPSC-Derived Cardiomyocytes.
Document Type
Academic Journal
Author
Cejas RB; Department of Pharmaceutical Sciences, School of Pharmacy and Pharmaceutical Sciences, The State University of New York at Buffalo, Buffalo, NY, 14214, USA.; Tamaño-Blanco M; Department of Pharmaceutical Sciences, School of Pharmacy and Pharmaceutical Sciences, The State University of New York at Buffalo, Buffalo, NY, 14214, USA.; Fontecha JE; Group for Applied Mathematical Modeling and Analytics (GAMMA), Industrial and Systems Engineering, The State University of New York at Buffalo, Buffalo, NY, 14214, USA.; Blanco JG; Department of Pharmaceutical Sciences, School of Pharmacy and Pharmaceutical Sciences, The State University of New York at Buffalo, Buffalo, NY, 14214, USA. jgblanco@buffalo.edu.
Source
Publisher: Humana Press Country of Publication: United States NLM ID: 101135818 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1559-0259 (Electronic) Linking ISSN: 15307905 NLM ISO Abbreviation: Cardiovasc Toxicol Subsets: MEDLINE
Subject
Language
English
Abstract
Cardiac troponin T (encoded by TNNT2) is involved in the contraction of cardiomyocytes during beating. The alternative splicing of TNNT2 results in four transcript variants with differential Ca 2+ sensitivity. The splicing of TNNT2 involves phosphorylation of the splicing factor SRSF6 by DYRK1A. Altered TNNT2 splicing patterns have been identified in failing human hearts. There is a paucity of studies describing DYRK1A-SRSF6-TNNT2 interplays in human cardiomyocytes. Also, it is not known whether the sensitivity of cardiomyocytes to cardiotoxic anthracyclines is modified in the context of variable DYRK1A-TNNT2 expression. In this study, we investigated the impact of DYRK1A on the endogenous expression of TNNT2 splicing variants in iPSC-derived cardiomyocytes. We also examined whether DYRK1A expression modifies the sensitivity of cardiomyocytes to the cardiotoxic drug daunorubicin (DAU). DYRK1A over-expression increased the abundance of TNNT2 fetal variants by ~ 58% whereas the abundance of the adult cTnT3 variant decreased by ~ 27%. High DYRK1A expression increased the phosphorylation of SRSF6 by ~ 25-65%. DAU cytotoxicity was similar between cardiomyocytes with variable levels of DYRK1A expression. DYRK1A over-expression ameliorated the impact of DAU on beating frequency. This study lays the foundation to further investigate the contribution of variable DYRK1A-TNNT2 expression to Ca 2+ handling and beating in human cardiomyocytes.
(© 2022. The Author(s).)
(© 2022. The Author(s).)