Cathepsin K knockout protects against cardiac dysfunction in diabetic mice.
Cathepsin K knockout protects against cardiac dysfunction in diabetic mice.
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DOI：
10.1038/s41598-017-09037-z
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发表时间：
2017-08-18
影响因子：
4.6
通讯作者：
Nair S
中科院分区：
文献类型：
--
作者：
Guo R;Hua Y;Rogers O;Brown TE;Ren J;Nair S
糖尿病是心血管疾病的主要危险因素，溶酶体半胱氨酸蛋白酶组织蛋白酶K在心脏病理生理中起关键作用。为了扩展我们之前的发现，我们测试了一个假设，即组织蛋白酶K的敲除可以防止糖尿病相关的心脏异常。注射链脲佐菌素（STZ）使野生型小鼠和组织蛋白酶K基因敲除小鼠发生糖尿病。测定体重、器官质量、空腹血糖、能量消耗、心脏几何形状和功能、心脏组织形态学、谷胱甘肽水平和组织蛋白酶K蛋白水平以及与Ca2+处理、钙调磷酸酶/NFAT信号、胰岛素信号、心脏凋亡和纤维化相关的蛋白水平。stz诱导的糖尿病小鼠表现出明显的心功能障碍，细胞内钙处理受到抑制，心脏形态改变，心肌细胞凋亡升高，这些在cathepsin K敲除小鼠中得到缓解。此外，组织蛋白酶K敲除小鼠可以减轻糖尿病小鼠的心脏氧化应激和钙调磷酸酶/NFAT信号。在培养的H9c2成肌细胞中，药物抑制组织蛋白酶K或钙调磷酸酶抑制剂可使细胞免于高糖引发的氧化应激和凋亡。因此，组织蛋白酶K可能是治疗糖尿病相关心功能障碍的潜在靶点。
Diabetes is a major risk factor for cardiovascular disease and the lysosomal cysteine protease cathepsin K plays a critical role in cardiac pathophysiology. To expand upon our previous findings, we tested the hypothesis that, knockout of cathepsin K protects against diabetes-associated cardiac anomalies. Wild-type and cathepsin K knockout mice were rendered diabetic by streptozotocin (STZ) injections. Body weight, organ mass, fasting blood glucose, energy expenditure, cardiac geometry and function, cardiac histomorphology, glutathione levels and protein levels of cathepsin K and those associated with Ca2+ handling, calcineurin/NFAT signaling, insulin signaling, cardiac apoptosis and fibrosis were determined. STZ-induced diabetic mice exhibited distinct cardiac dysfunction, dampened intracellular calcium handling, alterations in cardiac morphology, and elevated cardiomyocyte apoptosis, which were mitigated in the cathepsin K knockout mice. Additionally, cathepsin K knockout mice attenuated cardiac oxidative stress and calcineurin/NFAT signaling in diabetic mice. In cultured H9c2 myoblasts, pharmacological inhibition of cathepsin K, or treatment with calcineurin inhibitor rescued cells from high-glucose triggered oxidative stress and apoptosis. Therefore, cathepsin K may represent a potential target in treating diabetes-associated cardiac dysfunction.
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DOI：
10.1161/circheartfailure.114.001540
发表时间：
2015-01
期刊：
Circulation. Heart failure
影响因子：
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作者：
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DOI：
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发表时间：
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影响因子：
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