Critical role of VGLL4 in the regulation of chronic normobaric hypoxia‐induced pulmonary hypertension in mice

Abstract

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 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, 2 of 18 | TIAN eT Al.

Hypoxia‐sensing VGLL4 promotes LDHA‐driven lactate production to ameliorate neuronal dysfunction in a cellular model relevant to Alzheimer's disease

“…Notably, our previous study found that VGLL4 protein expression increases time-dependently with hypoxia in C57BL/6 mice and is upregulated in systemic (e.g., heart, liver, lung, kidney, and brain) expression distribution all in response to hypoxia. 21 The response of VGLL4 to hypoxia exists as a coordination among various tissues that work together to improve hypoxic metabolism. Brain tissues are extremely sensitive to hypoxia for several reasons, 39 including low glucose and oxygen reserves in the brain.…”

“…Our previous research 21 and Wang et al 22 found that VGLL4 is a key factor in the regulation of hypoxia-sensitive pathways. We then explored the hypoxia sensitivity of VGLL4 by treating SH-SY5Y and SAS cells with hypoxia for 0, 2, 4, 8, and 12 h. The results showed that the protein expression of VGLL4 and LDHA in SH-SY5Y cells increased with hypoxia in a time-dependent manner (Figure 4A-C), indicating that VGLL4 and LDHA can be sensitively regulated by hypoxic concentrations.…”

“…Notably, our recent research has reported that VGLL4 promotes the proliferation and inhibits the apoptosis of pulmonary artery vascular smooth muscle cells in hypoxic-induced pulmonary hypertension (PH). 21 As a key factor in the regulation of hypoxia-sensitive pathways, VGLL4 can be sensitively regulated by hypoxia concentration and together improve hypoxia metabolism. 22 A growing body of evidence indicates that hypoxia is closely related to the increased risk of AD.…”

RNA Modifications and Epigenetics in Modulation of Lung Cancer and Pulmonary Diseases

“…This downregulation of MEIS1 was dependent on METTL14 m6A writer, which was highly upregulated under hypoxic conditions [139]. Additionally, PASMC proliferation can also occur via the STAT3 pathway [140]. This occurs when chronic normobaric hypoxia upregulates the expression of VGLL4, activating the SIRT1-mediated histone acetylation to contribute to pulmonary artery remodelling and the development of PH.…”

Yes-Associated Protein and Transcriptional Coactivator with PDZ-Binding Motif in Cardiovascular Diseases

“…VGLL4 can also target the Hippo-YAP/TEAD1 signaling pathway by inducing the degradation of TEAD1 to attenuate oxidative stress, inflammation, and dysfunction in HUVECs induced by ox-LDL [ 157 ]. In addition, VGLL4 promotes pulmonary hypertension and pulmonary arterial remodeling through a signal transducer and the activation of transcription 3 (STAT3) signaling [ 158 ]; alternatively, the specific knockout of VGLL4 in ECs increases the YAP expression and heart valve malformation [ 159 ].…”