纹蛋白在血管紧张素 II 诱导的小鼠体内心肌细胞和心脏肥大中发挥着重要作用。

IF 6.7 2区 医学 Q1 MEDICINE, RESEARCH & EXPERIMENTAL
Joshua J Cull, Susanna T E Cooper, Hajed O Alharbi, Sonia P Chothani, Owen J L Rackham, Daniel N Meijles, Philip R Dash, Risto Kerkelä, Neil Ruparelia, Peter H Sugden, Angela Clerk
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引用次数: 0

摘要

三种纹蛋白(STRN、STRN3、STRN4)构成了纹蛋白互作磷酸酶和激酶(STRIPAK)复合物的核心。 这些复合物使蛋白磷酸酶 2A (PP2A) 靠近蛋白激酶,从而抑制激酶的活性并调节关键的细胞过程。 我们的目的是确定纹状体蛋白是否在与心肌肥厚和心力衰竭相关的心脏重塑过程中发挥重要作用。 所有纹状体蛋白在对照组人类心脏中均有表达,在衰竭心脏中 STRN 和 STRN3 上调。 我们利用全杂合基因缺失的小鼠来评估 STRN 和 STRN3 在血管紧张素 II(AngII;7 天)诱导的心脏重塑中的作用。 通过超声心动图,我们发现 STRN+/- 或 STRN3+/- 雄性小鼠(8 周)的基线心脏功能或尺寸与野生型同窝小鼠相比没有差异。 杂合基因缺失不会影响小鼠接受 AngII 治疗后的心脏功能,但 STRN+/-(而非 STRN3+/-)小鼠的 AngII 诱导的左心室质量增加受到抑制。组织学染色表明,心肌细胞肥大受到抑制。 为了评估 STRN 在心肌细胞中的作用,我们将 STRN 基因敲除品系转化为诱导性心肌细胞特异性基因缺失。 心肌细胞 STRN 基因敲除对心脏功能或尺寸没有影响,但 AngII 诱导的左心室质量增加受到抑制。 这是抑制心肌细胞肥大和心脏纤维化的结果。 这些数据表明,AngII 对心脏的早期重塑需要心肌细胞纹蛋白,并确定了基于纹蛋白的 STRIPAK 系统是病理性心脏肥大发展过程中的一个信号范例。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
Striatin plays a major role in angiotensin II-induced cardiomyocyte and cardiac hypertrophy in mice in vivo.

The three striatins (STRN, STRN3, STRN4) form the core of STRiatin-Interacting Phosphatase and Kinase (STRIPAK) complexes. These place protein phosphatase 2A (PP2A) in proximity to protein kinases thereby restraining kinase activity and regulating key cellular processes. Our aim was to establish if striatins play a significant role in cardiac remodelling associated with cardiac hypertrophy and heart failure. All striatins were expressed in control human hearts, with up-regulation of STRN and STRN3 in failing hearts. We used mice with global heterozygote gene deletion to assess the roles of STRN and STRN3 in cardiac remodelling induced by angiotensin II (AngII; 7 days). Using echocardiography, we detected no differences in baseline cardiac function or dimensions in STRN+/- or STRN3+/- male mice (8 weeks) compared with wild-type littermates. Heterozygous gene deletion did not affect cardiac function in mice treated with AngII, but the increase in left ventricle mass induced by AngII was inhibited in STRN+/- (but not STRN3+/-) mice. Histological staining indicated that cardiomyocyte hypertrophy was inhibited. To assess the role of STRN in cardiomyocytes, we converted the STRN knockout line for inducible cardiomyocyte-specific gene deletion. There was no effect of cardiomyocyte STRN knockout on cardiac function or dimensions, but the increase in left ventricle mass induced by AngII was inhibited. This resulted from inhibition of cardiomyocyte hypertrophy and cardiac fibrosis. The data indicate that cardiomyocyte striatin is required for early remodelling of the heart by AngII and identify the striatin-based STRIPAK system as a signalling paradigm in the development of pathological cardiac hypertrophy.

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来源期刊
Clinical science
Clinical science 医学-医学:研究与实验
CiteScore
11.40
自引率
0.00%
发文量
189
审稿时长
4-8 weeks
期刊介绍: Translating molecular bioscience and experimental research into medical insights, Clinical Science offers multi-disciplinary coverage and clinical perspectives to advance human health. Its international Editorial Board is charged with selecting peer-reviewed original papers of the highest scientific merit covering the broad spectrum of biomedical specialities including, although not exclusively: Cardiovascular system Cerebrovascular system Gastrointestinal tract and liver Genomic medicine Infection and immunity Inflammation Oncology Metabolism Endocrinology and nutrition Nephrology Circulation Respiratory system Vascular biology Molecular pathology.
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