LINC00599 Promotes Pulmonary Hypertension via Liquid-Liquid Phase Separation With G3BP1 and MYH9

作者：Y. Wang, Lulu Yin, Shuang Zheng, Aijing Liu, Chunmiao Liu, Zhitu Bao, He Zhu, Xiaoxu Zhao, Ziru Zhao, Yu Pan, Daling Zhu, Hang Yu · 发表于：Hypertension · 年份：2025 · DOI：10.1161/hypertensionaha.124.24511 · 被引用次数：4 · 研究领域：RNA modifications and cancer、Cancer-related molecular mechanisms research、Pulmonary Hypertension Research and Treatments

BACKGROUND: Pulmonary hypertension (PH) represents a significant cardiovascular disorder marked by both functional and structural alterations within the pulmonary vasculature. Long noncoding RNAs have been closely associated with PH pathogenesis and progression, particularly in vascular remodeling and cell proliferation. Nonetheless, how long noncoding RNAs interact with downstream targets to modulate PH remains unclear. METHODS: The expression levels of LINC00599 were quantified in the mouse lung tissues and pulmonary arterial smooth muscle cells (PASMCs) under hypoxic conditions. The involvement of LINC00599 in PH progression and vascular remodeling was evaluated through in vivo studies. To investigate its role in human PASMC proliferation, small interfering RNA and overexpression plasmids were used. RESULTS: The expression of LINC00599 is upregulated in the medial layer of pulmonary arteries in experimental PH models and hypoxic PASMCs. Administration of lentivirus-mediated shRNA targeting LINC00599 reverses hypoxic PH in murine models. Mechanistically, LINC00599 promotes PASMC proliferation by modulating stress granule formation through m6A (N6-methyladenosine) modification and facilitating liquid-liquid phase separation with MYH9 (myosin heavy chain 9), a process previously implicated in cell-cycle regulation. Furthermore, its expression is driven by a super-enhancer mediated by the transcription factor ZNF263. CONCLUSIONS: This study demonstrates that LINC00599 promotes...