Premium
Critical role of VGLL4 in the regulation of chronic normobaric hypoxia‐induced pulmonary hypertension in mice
Author(s) -
Tian Qiuyun,
Fan Xiaofang,
Ma Jianshe,
Li Dantong,
Han Yujiao,
Yin Xianghong,
Wang Hui,
Huang Tingting,
Wang Zhenglu,
Shentu Yangping,
Xue Feng,
Du Congkuo,
Wang Yongyu,
Mao Sunzhong,
Fan Junming,
Gong Yongsheng
Publication year - 2021
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fj.202002650rr
Subject(s) - pulmonary hypertension , hypoxia (environmental) , medicine , cardiology , chemistry , oxygen , organic chemistry
Pulmonary hypertension (PH), a rare but deadly cardiopulmonary disorder, is characterized by extensive remodeling of pulmonary arteries resulting from enhancement of pulmonary artery smooth muscle cell proliferation and suppressed apoptosis; however, the underlying pathophysiological mechanisms remain largely unknown. Recently, epigenetics has gained increasing prominence in the development of PH. We aimed to investigate the role of vestigial‐like family member 4 (VGLL4) in chronic normobaric hypoxia (CNH)‐induced PH and to address whether it is associated with epigenetic regulation. The rodent model of PH was established by CNH treatment (10% O 2 , 23 hours/day). Western blot, quantitative reverse transcription polymerase chain reaction, immunofluorescence, immunoprecipitation, and adeno‐associated virus tests were performed to explore the potential mechanisms involved in CNH‐induced PH in mice. VGLL4 expression was upregulated and correlated with CNH in PH mouse lung tissues in a time‐dependent manner. VGLL4 colocalized with α‐smooth muscle actin in cultured pulmonary arterial smooth muscle cells (PASMCs), and VGLL4 immunoactivity was increased in PASMCs following hypoxia exposure in vitro. VGLL4 knockdown attenuated CNH‐induced PH and pulmonary artery remodeling by blunting signal transducer and activator of transcription 3 (STAT3) signaling; conversely, VGLL4 overexpression exacerbated the development of PH. CNH enhanced the acetylation of VGLL4 and increased the interaction of ac‐H3K9/VGLL4 and ac‐H3K9/STAT3 in the lung tissues, and levels of ac‐H3K9, p‐STAT3/STAT3, and proliferation‐associated protein levels were markedly up‐regulated, whereas apoptosis‐related protein levels were significantly downregulated, in the lung tissues of mice with CNH‐induced PH. Notably, abrogation of VGLL4 acetylation reversed CNH‐induced PH and pulmonary artery remodeling and suppressed STAT3 signaling. Finally, STAT3 knockdown alleviated CNH‐induced PH. In conclusion, VGLL4 acetylation upregulation could contribute to CNH‐induced PH and pulmonary artery remodeling via STAT3 signaling, and abrogation of VGLL4 acetylation reversed CNH‐induced PH. Pharmacological or genetic deletion of VGLL4 might be a potential target for therapeutic interventions in CNH‐induced PH.