11β-HSD1 inhibition ameliorates diabetes-induced cardiomyocyte hypertrophy and cardiac fibrosis through modulation of EGFR activity.
11β-HSD1 inhibition ameliorates diabetes-induced cardiomyocyte hypertrophy and cardiac fibrosis through modulation of EGFR activity.
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11 beta-HSD1 抑制通过调节 EGFR 活性改善糖尿病诱导的心肌细胞肥大和心脏纤维化
DOI：
10.18632/oncotarget.22015
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发表时间：
2017-11-10
期刊：
影响因子：
--
通讯作者：
Zhao Y
中科院分区：
文献类型：
--
作者：
Zou C;Li W;Pan Y;Khan ZA;Li J;Wu X;Wang Y;Deng L;Liang G;Zhao Y
11β-HSD1已被认为是2型糖尿病的潜在治疗靶点。最近的研究表明，高血糖导致11β-HSD1的激活，增加细胞内糖皮质激素水平。过量的糖皮质激素可导致心脏损伤的临床表现。因此，本研究的目的是探讨11β-HSD1激活是否与糖尿病性心肌病的发生发展有关。为了研究11β-HSD1的作用，我们在1型和2型糖尿病小鼠模型和培养的心肌细胞中施用了一种选择性11β-HSD1抑制剂。我们的研究结果表明，糖尿病会增加心脏组织中的可的松水平。11β-HSD1抑制剂可降低可的松水平，改善糖尿病心肌病的所有结构和功能特征，包括纤维化和肥厚。我们还表明，高水平的葡萄糖引起心肌细胞肥大和增加基质蛋白沉积在培养。重要的是，抑制11β-HSD1可减弱这些变化。此外，我们发现11β-HSD1激活通过调节EGFR的磷酸化和活性来介导这些变化。我们的研究结果表明，11β-HSD1通过激活糖皮质激素和EGFR信号通路参与糖尿病性心肌病的发展。这些结果表明，抑制11β-HSD1可能是糖尿病心肌病的一种治疗策略，而这种治疗策略独立于其对葡萄糖稳态的影响。
11β-HSD1 has been recognized as a potential therapeutic target for type 2 diabetes. Recent studies have shown that hyperglycemia leads to activation of 11β-HSD1, increasing the intracellular glucocorticoid levels. Excess glucocorticoids may lead to the clinical manifestations of cardiac injury. Therefore, the aim of this study is to investigate whether 11β-HSD1 activation contributes to the development of diabetic cardiomyopathy. To investigate the role of 11β-HSD1, we administered a selective 11β-HSD1 inhibitor in type 1 and type 2 murine models of diabetes and in cultured cardiomyocytes. Our results show that diabetes increases cortisone levels in heart tissues. 11β-HSD1 inhibitor decreased cortisone levels and ameliorated all structural and functional features of diabetic cardiomyopathy including fibrosis and hypertrophy. We also show that high levels of glucose caused cardiomyocyte hypertrophy and increased matrix protein deposition in culture. Importantly, inhibition of 11β-HSD1 attenuated these changes. Moreover, we show that 11β-HSD1 activation mediates these changes through modulating EGFR phosphorylation and activity. Our findings demonstrate that 11β-HSD1 contributes to the development of diabetic cardiomyopathy through activation of glucocorticoid and EGFR signaling pathway. These results suggest that inhibition of 11β-HSD1 might be a therapeutic strategy for diabetic cardiomyopathy, which is independent of its effects on glucose homeostasis.
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