Never in mitosis gene A-related kinase-6 deficiency deteriorates diabetic cardiomyopathy via regulating heat shock protein 72
Never in mitosis gene A-related kinase-6 deficiency deteriorates diabetic cardiomyopathy via regulating heat shock protein 72
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DOI：
10.1007/s00109-023-02295-7
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发表时间：
2023-03-03
影响因子：
4.7
通讯作者：
Gao，Lu
中科院分区：
文献类型：
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作者：
Shao，Shuangyin;Xiao，Lili;Gao，Lu
NIMA相关激酶6（NEK 6）是一种细胞周期调控基因，参与心肌肥厚的调控。然而，其在糖尿病诱导的心肌病中的作用尚未完全阐明。本研究旨在阐明NEK 6在糖尿病心肌病中的作用。本研究采用链脲佐菌素（STZ）诱导的小鼠糖尿病心肌病模型和NEK 6基因敲除小鼠，探讨NEK 6在糖尿病心肌病中的作用及机制。对NEK 6敲除小鼠和野生型同窝出生小鼠进行STZ注射（50 mg/kg/天，持续5天）以诱导糖尿病心肌病模型。结果，在最后一次注射STZ后4个月，DCM小鼠显示心脏肥大、纤维化以及收缩和舒张功能障碍。NEK 6缺乏导致恶化的心脏肥大、纤维化和心脏功能障碍。此外，我们观察了糖尿病心肌病病理下NEK 6缺陷小鼠心脏中的炎症和氧化应激。用腺病毒上调新生大鼠心肌细胞中的NEK 6，发现NEK 6改善高糖诱导的炎症和氧化应激。我们的研究结果表明，NEK 6增加了热休克蛋白72（HSP 72）的磷酸化，并增加了PGC-1α和NRF 2的蛋白水平。Co-IP实验证实NEK 6与HSP 72相互作用。当HSP 72沉默时，NEK 6的抗炎和抗氧化应激作用变得模糊。总之，NEK 6可能通过与HSP 72相互作用，促进HSP 72/PGC-1α/NRF 2信号通路，从而保护糖尿病心肌病。NEK 6过表达可减轻高糖诱导的炎症反应和氧化应激反应，NEK 6在糖尿病发生发展中的保护作用机制尚不清楚。结论：糖尿病心肌病的发生发展可能与HSP 72-NRF 2- PGC-1α通路的调节有关，NEK 6可能成为糖尿病心肌病治疗的新靶点。
NIMA (never in mitosis, gene A)-related kinase-6 (NEK6), a cell cycle regulatory gene, was found to regulate cardiac hypertrophy. However, its role in diabetes-induced cardiomyopathy has not been fully elucidated. This research was designed to illustrate the effect of NEK6 involved in diabetic cardiomyopathy. Here we used a streptozotocin (STZ)-induced mice diabetic cardiomyopathy model and NEK6 knockout mice to explore the role and mechanism of NEK6 in diabetic-induced cardiomyopathy. NEK6 knockout mice and wild-type littermates were subjected to STZ injection (50 mg/kg/day for 5 days) to induce a diabetic cardiomyopathy model. As a result, 4 months after final STZ injection, DCM mice revealed cardiac hypertrophy, fibrosis, and systolic and diastolic dysfunction. NEK6 deficiency causes deteriorated cardiac hypertrophy, fibrosis, and cardiac dysfunction. Furthermore, we observed inflammation and oxidative stress in the hearts of NEK6 deficiency mice under diabetic cardiomyopathy pathology. Adenovirus was used to upregulate NEK6 in neonatal rat cardiomyocytes, and it was found that NEK6 ameliorated high glucose-induced inflammation and oxidative stress. Our findings revealed that NEK6 increased the phosphorylation of heat shock protein 72 (HSP72) and increased the protein level of PGC-1α and NRF2. Co-IP assay experiment confirmed that NEK6 interacted with HSP72. When HSP72 was silenced, the anti-inflammation and anti-oxidative stress effects of NEK6 were blurred. In summary, NEK6 may protect diabetic-induced cardiomyopathy by interacting with HSP72 and promoting the HSP72/PGC-1α/NRF2 signaling.Key messagesNEK6 knockout deteriorated cardiac dysfunction, cardiac hypertrophy, fibrosis as well as inflammation response, and oxidative stress.NEK6 overexpression attenuated high glucose induced inflammation and oxidative stress.The underlying mechanisms of the protective role of NEK6 in the development of diabetic cardiomyopathy seem to involve the regulation of HSP72-NRF2- PGC-1α pathway.NEK6 may become a new therapeutic target for diabetic cardiomyopathy.