PMID- 32383996 OWN - NLM STAT- MEDLINE DCOM- 20200713 LR - 20201124 IS - 1522-1539 (Electronic) IS - 0363-6135 (Linking) VI - 318 IP - 6 DP - 2020 Jun 1 TI - Cytosolic DNA sensor cGAS plays an essential pathogenetic role in pressure overload-induced heart failure. PG - H1525-H1537 LID - 10.1152/ajpheart.00097.2020 [doi] AB - 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. FAU - Hu, Dan AU - Hu D AD - Department of Cardiology, Beijing Key Laboratory of Early Prediction and Intervention of Acute Myocardial Infarction, Center for Cardiovascular Translational Research, Peking University People's Hospital, Beijing, China. FAU - Cui, Yu-Xia AU - Cui YX AD - Department of Cardiology, Beijing Key Laboratory of Early Prediction and Intervention of Acute Myocardial Infarction, Center for Cardiovascular Translational Research, Peking University People's Hospital, Beijing, China. FAU - Wu, Man-Yan AU - Wu MY AD - Department of Cardiology, Beijing Key Laboratory of Early Prediction and Intervention of Acute Myocardial Infarction, Center for Cardiovascular Translational Research, Peking University People's Hospital, Beijing, China. FAU - Li, Long AU - Li L AD - Department of Cardiology, Beijing Key Laboratory of Early Prediction and Intervention of Acute Myocardial Infarction, Center for Cardiovascular Translational Research, Peking University People's Hospital, Beijing, China. FAU - Su, Li-Na AU - Su LN AD - Department of Cardiology, Beijing Key Laboratory of Early Prediction and Intervention of Acute Myocardial Infarction, Center for Cardiovascular Translational Research, Peking University People's Hospital, Beijing, China. FAU - Lian, Zheng AU - Lian Z AD - Department of Cardiology, Beijing Key Laboratory of Early Prediction and Intervention of Acute Myocardial Infarction, Center for Cardiovascular Translational Research, Peking University People's Hospital, Beijing, China. FAU - Chen, Hong AU - Chen H AD - Department of Cardiology, Beijing Key Laboratory of Early Prediction and Intervention of Acute Myocardial Infarction, Center for Cardiovascular Translational Research, Peking University People's Hospital, Beijing, China. LA - eng PT - Journal Article PT - Research Support, Non-U.S. Gov't DEP - 20200508 PL - United States TA - Am J Physiol Heart Circ Physiol JT - American journal of physiology. Heart and circulatory physiology JID - 100901228 RN - 0 (Membrane Proteins) RN - 0 (Sting1 protein, mouse) RN - EC 2.7.7.- (Nucleotidyltransferases) RN - EC 2.7.7.- (cGAS protein, mouse) SB - IM MH - Animals MH - Blood Pressure/*physiology MH - Heart/physiopathology MH - Heart Failure/genetics/*metabolism/physiopathology MH - Male MH - Membrane Proteins/genetics/*metabolism MH - Mice MH - Mice, Transgenic MH - Nucleotidyltransferases/genetics/*metabolism MH - Signal Transduction MH - Ventricular Remodeling/*physiology OTO - NOTNLM OT - cGAS OT - cytosolic DNA OT - heart failure OT - inflammation OT - pathological cardiac remodeling EDAT- 2020/05/10 06:00 MHDA- 2020/07/14 06:00 CRDT- 2020/05/09 06:00 PHST- 2020/05/10 06:00 [pubmed] PHST- 2020/07/14 06:00 [medline] PHST- 2020/05/09 06:00 [entrez] AID - 10.1152/ajpheart.00097.2020 [doi] PST - ppublish SO - Am J Physiol Heart Circ Physiol. 2020 Jun 1;318(6):H1525-H1537. doi: 10.1152/ajpheart.00097.2020. Epub 2020 May 8.