STING is an essential regulator of heart inflammation and fibrosis in mice with pathological cardiac hypertrophy via endoplasmic reticulum (ER) stress
STING is an essential regulator of heart inflammation and fibrosis in mice with pathological cardiac hypertrophy via endoplasmic reticulum (ER) stress
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DOI：
10.1016/j.biopha.2020.110022
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发表时间：
2020-05-01
影响因子：
7.5
通讯作者：
Wang, Yan
中科院分区：
文献类型：
--
作者：
Zhang, Yan;Chen, Wenzhong;Wang, Yan
病理性心肌肥大的特征是心肌细胞增大和心功能不全。然而，这种疾病的发病机制仍然知之甚少。干扰素基因刺激因子（Stimulator of interferon genes，STING）可调节多种疾病的炎症反应和免疫反应。在这项工作中，我们证明了STING对压力超负荷诱导的心脏肥大至关重要。结果显示STING表达在人类和小鼠肥大心脏中上调。STING敲除减弱了由主动脉缩窄（AB）诱导的心脏肥大。STING缺乏对心肌肥厚和功能障碍的改善作用与抑制巨噬细胞浸润、炎症反应和纤维化有关。此外，在AB手术小鼠的心脏中检测到ER应激，如通过磷酸蛋白激酶RNA样内质网激酶（PERK）、磷酸真核起始因子2 α（eIF 2 α）和磷酸肌醇需要激酶（IRE）-1 α的表达增加所证明的。重要的是，这些蛋白质在AB手术后STING敲除的小鼠中受到抑制。此外，血管紧张素II（Ang II）诱导的STING可被ER应激激活剂加速，而被ER应激抑制剂显著消除。然后，我们发现，无论用或不用转化生长因子-β 1（TGF-β 1）共处理，在条件培养基（CM）中培养的来自Ang II孵育的具有STING敲低的心肌细胞的心脏成纤维细胞表现出显著减少的纤维化，如通过α-SMA、I型胶原（Col I）和III型胶原（Col III）的明显下调表达所显示的。因此，我们将STING定义为导致与ER应激密切相关的心脏肥大的重要信号。
Pathological cardiac hypertrophy is characterized by myocyte enlargement and cardiac dysfunction. However, the pathogenesis for this disease is still poorly understood. Stimulator of interferon genes (STING) could meditate inflammation and immune response in various kinds of diseases. In this work, we demonstrated that STING was critical for pressure overload-induced cardiac hypertrophy. Results showed that STING expression was upregulated in human and mouse hypertrophic hearts. STING knockout attenuated cardiac hypertrophy induced by aortic banding (AB). The effects of STING deficiency on the improvement of cardiac hypertrophy and dysfunction were associated with the restrained macrophage infiltration, inflammatory response and fibrosis. Moreover, ER stress was detected in hearts of AB-operated mice, as evidenced by the increased expression of phospho-protein kinase RNA-like endoplasmic reticulum kinase (PERK), phospho-eukaryotic initiation factor 2 alpha (eIF2 alpha) and phospho-inositol-requiring kinase (IRE)-1 alpha. Importantly, these proteins were restrained in mice with STING knockout after AB surgery. What's more, angiotensin II (Ang II)-induced STING could be accelerated by ER stress activator, while being markedly abolished by the ER stress inhibitor. We then found that whether co-treated with or without transforming growth factor-beta 1 (TGF-beta 1), cardiac fibroblasts cultured in the conditional medium (CM) from Ang II-incubated cardiomyocytes with STING knockdown exhibited significantly reduced fibrosis, as displayed by the clearly down-regulated expression of alpha-SMA, Collagen type I (Col I) and Collagen type III (Col III). Therefore, we defined STING as an important signal contributing to cardiac hypertrophy closely associated with ER stress.