Department of Pharmaceutical Sciences, School of Pharmacy and Pharmaceutical Sciences, The State University of New York at Buffalo, Buffalo, NY, 14214, USA.
Group for Applied Mathematical Modeling and Analytics (GAMMA), Industrial and Systems Engineering, The State University of New York at Buffalo, Buffalo, NY, 14214, USA.
Cardiovasc Toxicol. 2022 Aug;22(8):701-712. doi: 10.1007/s12012-022-09746-6. Epub 2022 May 21.
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 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 handling and beating in human cardiomyocytes.
心肌肌钙蛋白 T（由 TNNT2 编码）在心肌细胞跳动时参与收缩。TNNT2 的选择性剪接导致具有不同 Ca 敏感性的四个转录变体。TNNT2 的剪接涉及 DYRK1A 对剪接因子 SRSF6 的磷酸化。在衰竭的人心肌中已鉴定出 TNNT2 剪接模式发生改变。描述人类心肌细胞中 DYRK1A-SRSF6-TNNT2 相互作用的研究很少。此外，尚不清楚在可变 DYRK1A-TNNT2 表达的情况下，心肌细胞对心脏毒性蒽环类药物的敏感性是否发生改变。在这项研究中，我们研究了 DYRK1A 对 iPSC 衍生的心肌细胞中 TNNT2 剪接变体的内源性表达的影响。我们还检查了 DYRK1A 表达是否改变了心肌细胞对心脏毒性药物柔红霉素（DAU）的敏感性。DYRK1A 的过表达使 TNNT2 胎儿变体的丰度增加了约 58%，而成人 cTnT3 变体的丰度降低了约 27%。高 DYRK1A 表达使 SRSF6 的磷酸化增加了约 25-65%。在具有不同 DYRK1A 表达水平的心肌细胞中，DAU 的细胞毒性相似。DYRK1A 的过表达减轻了 DAU 对搏动频率的影响。这项研究为进一步研究可变 DYRK1A-TNNT2 表达对人类心肌细胞 Ca 处理和搏动的贡献奠定了基础。
