Cytosolic DNA sensor cGAS plays an essential pathogenetic role in pressure overload-induced heart failure
Cytosolic DNA sensor cGAS plays an essential pathogenetic role in pressure overload-induced heart failure
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胞浆 DNA 传感器 cGAS 在压力超负荷诱发的心力衰竭中发挥重要的致病作用
DOI：
10.1152/ajpheart.00097.2020
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发表时间：
2020-06-01
影响因子：
4.8
通讯作者：
Chen, Hong
中科院分区：
文献类型：
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作者：
Hu, Dan;Cui, Yu-Xia;Chen, Hong
越来越多的证据表明，心脏中炎症的激活引起患有心力衰竭（HF）的人类和实验动物的左心室（LV）重构和功能障碍。此外，最近的研究发现，环GMP-AMP合酶（cGAS），作为一个细胞溶质DNA传感器，是必不可少的激活先天免疫对感染和细胞损伤，通过启动STING-IRFs-I型IFN信号级联，这在调节炎症反应中发挥重要作用。然而，cGAS在压力超负荷诱导的HF中的病理生理作用尚不清楚。对野生型C57 BL/6 J小鼠和cGAS抑制小鼠进行横向主动脉缩窄（TAC）以诱导HF或假手术。使用腺相关病毒9（AAV 9）进行鼠心脏中cGAS的抑制。通过qPCR和蛋白质印迹检查cGAS/STING途径的改变。通过超声心动图以及组织学和分子表型评估心脏重构。与假手术小鼠相比，TAC小鼠的LV组织中cGAS/STING通路被激活。尽管TAC小鼠表现出显著的病理性心脏重塑和LV功能障碍，但抑制cGAS改善了TAC后的早期存活率，保留了LV收缩功能，并减弱了病理性重塑，包括心脏肥大、纤维化和细胞凋亡。此外，cGAS的下调减少了响应于TAC的早期炎性细胞浸润和炎性细胞因子表达。这些结果表明，cGAS在压力超负荷诱导的HF中发挥重要的致病作用，以促进病理性心脏重塑和功能障碍。我们的研究结果表明，抑制cGAS可能是一种新的治疗方法HF。新&值得注意的是在这项研究中，我们首次揭示了cGAS在压力超负荷时病理性心脏重塑和功能障碍的调节中的新作用。我们发现cGAS/STING通路在压力过载期间被激活。此外，我们还证明了cGAS/STING通路的抑制减轻了病理性心脏重塑，并下调了压力超负荷诱导的HF期间的早期炎症反应。总之，这些发现将为HF提供新的治疗靶点。
Growing evidence shows that activation of inflammation in the heart provokes left ventricular (LV) remodeling and dysfunction in humans and experimental animals with heart failure (HF). Moreover, recent studies found that cyclic GMP-AMP synthase (cGAS), serving as a cytosolic DNA sensor, was essential for activating innate immunity against infection and cellular damage by initiating the STING-IRFs-type I IFN signaling cascade, which played important roles in regulating the inflammatory response. However, the pathophysiological role of cGAS in pressure overload-induced HF is unclear. Wild-type C57BL/6J mice and cGAS inhibition mice were subjected to transverse aortic constriction (TAC) to induce HF or sham operation. Inhibition of cGAS in the murine heart was performed using adeno-associated virus 9 (AAV9). Alterations of the cGAS/STING pathway were examined by qPCR and Western blotting. Cardiac remodeling was assessed by echocardiography as well as histological and molecular phenotyping. Compared with sham-operated mice, the cGAS/STING pathway was activated in LV tissues in TAC mice. Whereas TAC mice exhibited significant pathological cardiac remodeling and LV dysfunction, inhibition of cGAS improved early survival rates after TAC, preserved LV contractile function, and blunted pathological remodeling, including cardiac hypertrophy, fibrosis, and apoptosis. Furthermore, downregulation of cGAS diminished early inflammatory cell infiltration and inflammatory cytokine expression in response to TAC. These results demonstrated that cGAS played an essential pathogenetic role in pressure overload-induced HF to promote pathological cardiac remodeling and dysfunction. Our results suggest that inhibition of cGAS may be a novel therapeutic approach for HF.NEW & NOTEWORTHY In this study, we first revealed a novel role of cGAS in the regulation of pathological cardiac remodeling and dysfunction upon pressure overload. We found that the cGAS/STING pathway was activated during pressure overload. Moreover, we also demonstrated that inhibition of the cGAS/STING pathway alleviated pathological cardiac remodeling and downregulated the early inflammatory response during pressure overload-induced HF. Together, these findings will provide a new therapeutic target for HF.