Critical role of VGLL4 in the regulation of chronic normobaric hypoxia-induced pulmonary hypertension in mice
Critical role of VGLL4 in the regulation of chronic normobaric hypoxia-induced pulmonary hypertension in mice
复制标题
VGLL4 在调节小鼠慢性常压缺氧诱导的肺动脉高压中的关键作用
DOI：
10.1096/fj.202002650rr
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发表时间：
2021
期刊：
影响因子：
--
通讯作者：
Yongsheng Gong
中科院分区：
文献类型：
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作者：
Qiuyun Tian;Xiaofang Fan;Jianshe Ma;Dantong Li;Yujiao Han;Xianghong Yin;Hui Wang1;Tingting Huang;Zhenglu Wang;Yangping Shentu;Feng Xue;Congkuo Du;Yongyu Wang;Sunzhong Mao;Junming Fan;Yongsheng Gong
肺动脉高压（PH）是一种罕见但致命的心肺疾病，其特征是肺动脉平滑肌细胞增殖增强和凋亡抑制导致肺动脉广泛重构，但其病理生理机制尚不清楚。本研究旨在探讨VGLL 4在慢性常压缺氧（CNH）诱导的PH中的作用，并探讨其是否与表观遗传调控有关。用CNH处理（10%O_2，23小时/天）建立PH动物模型。采用Western blot、定量逆转录、聚合酶链反应、免疫荧光、免疫沉淀和腺相关病毒试验等方法，探讨CNH诱导小鼠PH的可能机制。PH小鼠肺组织中VGLL 4表达上调，并与CNH呈时间依赖性相关。在体外培养的肺动脉平滑肌细胞（PASMCs）中，VGLL 4与α-平滑肌肌动蛋白（α-smooth muscle actin）共定位，低氧暴露后PASMCs VGLL 4免疫活性增强。VGLL 4基因敲低通过钝化信号转导子和转录激活子3（STAT 3）信号通路减轻CNH诱导的PH和肺动脉重构; PH. CNH的发生增强了VGLL 4的乙酰化，增加了肺组织中ac-H3 K9/VGLL 4和ac-H3 K9/STAT 3的相互作用，增加了肺组织中ac-H3 K9，p-STAT 3/STAT 3，在CNH诱导的PH小鼠的肺组织中，VGLL 4和增殖相关蛋白水平显著上调，而凋亡相关蛋白水平显著下调。值得注意的是，VGLL 4乙酰化的废除逆转了CNH诱导的PH和肺动脉重塑，并抑制了STAT 3信号传导。总之，VGLL 4乙酰化上调可能通过STAT 3信号通路参与了CNH诱导的PH和肺动脉重构，VGLL 4乙酰化的消除逆转了CNH诱导的PH。VGLL 4的药理学或遗传学缺失可能是CNH诱导的PH治疗的潜在靶点。
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% O2, 23 hours/day). Western blot, quantitative reverse transcription .polymerase chain reaction, immunofluorescence, immunoprecipitation, and adenoassociated 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.