GRK5的基因催化失活通过失调的p53水平损害小鼠心脏功能。
Genetic Catalytic Inactivation of GRK5 Impairs Cardiac Function in Mice Via Dysregulated P53 Levels.
作者信息
Marzano Federica, Liccardo Daniela, Elia Andrea, Mucio Ines, de Lucia Claudio, Lucchese Anna Maria, Gao Erhe, Ferrara Nicola, Rapacciuolo Antonio, Paolocci Nazareno, Rengo Giuseppe, Koch Walter J, Cannavo Alessandro
机构信息
Department of Advanced Biomedical Sciences, Federico II University of Naples, Naples, Italy.
Department of Translational Medical Sciences, Federico II University of Naples, Naples, Italy.
出版信息
JACC Basic Transl Sci. 2022 Mar 9;7(4):366-380. doi: 10.1016/j.jacbts.2022.01.001. eCollection 2022 Apr.
GRK5's catalytic activity in regulating basal and stressed cardiac function has not been studied. Herein, we studied knock-in mice in which GRK5 was mutated to render it catalytically inactive (K215R). At baseline, GRK5-K215R mice showed a marked decline in cardiac function with increased apoptosis and fibrosis. In vitro, restriction of GRK5 inside the nucleus of cardiomyocytes resulted in enhanced cell death along with higher p53 levels. Moreover, in fibroblasts, we demonstrated that K215R mutation promoted the transition into myofibroblast phenotype. This study provides novel insight into the biological actions of GRK5, that are essential for its future targeting.
GRK5在调节基础和应激心脏功能方面的催化活性尚未得到研究。在此，我们研究了GRK5发生突变使其催化失活（K215R）的基因敲入小鼠。在基线时，GRK5-K215R小鼠表现出心脏功能显著下降，同时细胞凋亡和纤维化增加。在体外，限制GRK5在心肌细胞核内会导致细胞死亡增加以及p53水平升高。此外，在成纤维细胞中，我们证明K215R突变促进了向肌成纤维细胞表型的转变。这项研究为GRK5的生物学作用提供了新的见解，这对其未来的靶向治疗至关重要。
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