An Aberrant Resurgence of Endogenous Retroviruses Prompts Myocarditis and Heart Failure
Abstract
BACKGROUND: Endogenous retroviruses (ERVs) occupy >8% of the human genome. Aberrant resurgence of ERVs has been implicated recently in several critical pathologies. However, the possible incidence and role of ERV resurgence in heart failure (HF), a leading cause of global morbidity and mortality, remain unexplored. METHODS: We established a total RNA sequencing analyzing pipeline to assess the ERV occurrence in human and murine HF models. We generated 2 myocardium-specific mouse lines by crossing Myh6 -MerCreMer ( Myosin heavy chain 6 promoter driving MerCreMer recombinase) with TRIM28 f/f and SETDB1 f/f mice to identify the molecular regulators of ERV resurgence and the downstream pathways in the heart. We evaluated ERV expression by total RNA sequencing, reverse transcription-quantitative polymerase chain reaction and RNA fluorescence in situ hybridization. We restrained ERV activation by overexpressing TRIM28 (tripartite motif–containing 28) using adeno-associated virus serotype 9. The therapeutic potential of the ERV-mediated inflammatory pathway was tested in a myocardial ischemia/reperfusion model. RESULTS: ERVs, particularly class I ERVs, were prominently activated in multiple cross-species models of HF. Depletion of TRIM28, an epigenetic repressor, attenuated the epigenetic surveillance of trimethylation at lysine 9 of histone H3 and N 6 -methyladenosine, leading to the activation of ERVs in the failing heart. This ERV activation stimulated the antiviral innate immune pathways of TLR7/9 (Toll-like receptor 7/9) and NF-κB and lead to myocarditis and acute HF. Furthermore, restraining ERV activation and ERV-mediated innate immune responses by either adeno-associated virus serotype 9–mediated TRIM28 expression or a small-molecule TLR7/9 inhibitor improved heart function and alleviated HF in an ischemia/reperfusion model. CONCLUSIONS: ERV resurgence is a specific molecular trait of HF, driven by TRIM28 depletion in cardiomyocytes. ERV resurgence activates the innate immune TLR7/9–NF-κB pathway and induces myocarditis and HF. Inception of ERVs and the ERV-mediated immune pathway confers cardiac protection. These results identify TRIM28–ERV–TLR7/9–NF-κB as a target for therapeutic management of myocarditis and HF.
Article Details
Authors (28)
Junhao Xiong
Key Laboratory of Systems Biomedicine, Shanghai Center for Systems Biomedicine, Department of Cardiovascular Surgery, Shanghai Chest Hospital, Engineering Research Center of Techniques and Instruments for Diagnosis and Treatment of Congenital Heart Disease, Institute of Developmental and Regenerative Medicine, Xin Hua Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China.
Shasha Zhang
Zilong Geng
Juntao Lin
Key Laboratory of Systems Biomedicine, Shanghai Center for Systems Biomedicine, Department of Cardiovascular Surgery, Shanghai Chest Hospital, Engineering Research Center of Techniques and Instruments for Diagnosis and Treatment of Congenital Heart Disease, Institute of Developmental and Regenerative Medicine, Xin Hua Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China (J.X., S.Z., Z.G., J.L., K.C., H.H., Y.W., Y.S., P.Y., Yige Li, S.W., X.C., A.F.C., X.H., R.L., D.Z., K.S., B.Z.).
Kang Cheng
Huan Hu
Yuze Wang
Shanghai Engineering Research Center of Molecular Therapeutics and New Drug Development, School of Chemistry and Molecular Engineering, East China Normal University, Dongchuan Road 500, Shanghai 200241, China
Xing Liu
Yuanzhe Sheng
Key Laboratory of Systems Biomedicine, Shanghai Center for Systems Biomedicine, Department of Cardiovascular Surgery, Shanghai Chest Hospital, Engineering Research Center of Techniques and Instruments for Diagnosis and Treatment of Congenital Heart Disease, Institute of Developmental and Regenerative Medicine, Xin Hua Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China (J.X., S.Z., Z.G., J.L., K.C., H.H., Y.W., Y.S., P.Y., Yige Li, S.W., X.C., A.F.C., X.H., R.L., D.Z., K.S., B.Z.).
Ping Yang
Yige Li
Shuo Wu
Department of Chemistry
Xiao Cheng
Department of Biomedical Engineering, Columbia University
Yelan Li
Department of Pharmacology, School of Medicine, Southern University of Science and Technology, Shenzhen, China (Yelan Li, Y.F.).
Aijun Sun
Alex F. Chen
Key Laboratory of Systems Biomedicine, Shanghai Center for Systems Biomedicine, Department of Cardiovascular Surgery, Shanghai Chest Hospital, Engineering Research Center of Techniques and Instruments for Diagnosis and Treatment of Congenital Heart Disease, Institute of Developmental and Regenerative Medicine, Xin Hua Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China (J.X., S.Z., Z.G., J.L., K.C., H.H., Y.W., Y.S., P.Y., Yige Li, S.W., X.C., A.F.C., X.H., R.L., D.Z., K.S., B.Z.).
Daowen Wang
Chen Chen
Yan Zhang
Gengze Wu
Department of Cardiology, Chongqing Institute of Cardiology, Chongqing Cardiovascular Clinical Research Center, Daping Hospital (G.W., C.Z.).
Chunyu Zeng
Xiaoling Guo
Xumin Hou
Shanghai Chest Hospital Shanghai Jiao Tong University School of Medicine, Shanghai, China
Ruogu Li
Key Laboratory of Systems Biomedicine, Shanghai Center for Systems Biomedicine, Department of Cardiovascular Surgery, Shanghai Chest Hospital, Engineering Research Center of Techniques and Instruments for Diagnosis and Treatment of Congenital Heart Disease, Institute of Developmental and Regenerative Medicine, Xin Hua Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China (J.X., S.Z., Z.G., J.L., K.C., H.H., Y.W., Y.S., P.Y., Yige Li, S.W., X.C., A.F.C., X.H., R.L., D.Z., K.S., B.Z.).
Yuliang Feng
Dan Zhu
Kun Sun
Bing Zhang