An Aberrant Resurgence of Endogenous Retroviruses Prompts Myocarditis and Heart Failure

作者：Junhao Xiong, Shasha Zhang, Zilong Geng, Jun‐Tao Lin, Kang Cheng, Huan Hu, Yuze Wang, Xing Liu, Yuanzhe Sheng, Ping Yang, Yige Li, Shuo Wu, Xiao Cheng, Yelan Li, Aijun Sun, Alex F. Chen, Dao Wen Wang, Chen Chen, Yan Zhang, Gengze Wu, Chunyu Zeng, Xiaoling Guo, Xumin Hou, Ruogu Li, Yuliang Feng, Dan Zhu, Kun Sun, Bing Zhang · 发表于：Circulation · 年份：2025 · DOI：10.1161/circulationaha.125.074845 · 被引用次数：5 · 研究领域：Chromosomal and Genetic Variations、Xenotransplantation and immune response、Herpesvirus Infections and Treatments

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 imm...