Critical role of VGLL4 in the regulation of chronic normobaric hypoxia‐induced pulmonary hypertension in mice
Qiuyun TianXiaofang FanJianshe MaDantong LiYujiao HanXianghong YinHui WangTingting HuangZhenglu WangYangping ShentuXue FengCongkuo DuYongyu WangSun‐Zhong MaoJunming FanYongsheng Gong
7
Citation
52
Reference
10
Related Paper
Citation Trend
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% O2 , 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.Keywords:
Hypoxia
Signal transducer and activator of transcription 3 (STAT3) take part in cell proliferation, differentiation, survival, apoptosis, transformation, cellular immunity and some other important physiological and pathological processes. Among STAT3 signaling pathways, the JAK-STAT signaling pathway has been comprehensively studied. Abnormal activation of STAT3 is frequently detected in various tumors, and the abnormal activation is closely related with the tumorigenesis. Recent studies have found that mutations and several specific genotypes of single nucleotide polymorphisms in STAT3 gene may be involved in tumor formation, also suggesting the important role of STAT3 in tumor biology. In this review, the role of STAT3 in the development of tumors is briefly summarized.
Transcription
STAT1
Cite
Citations (1)
Transcription
Cite
Citations (0)
Objective:To study the effect of Feixinping on endothelin level in pulmonary artery,NOSmRNA expression in rats with pulmonary hypertension in pulmonary heart disease,and probe in to the action mechanism of Feixinping in treating pulmonary hypertension in pulmonary heart disease.Methods:Rat model of pulmonary hypertension in pulmonary heart disease was duplicated by injection of 2% monocrotaline at dosage of 60mg/Kg peritonially at one time.ET and nitrogen monoxide synthase(NOSmRNA) were determined with RTPCR.Results:Compared to normal group,in model group ETmRNA expression in pulmonary artery increases while NOSmRNA expression decreases;Compared to model group,in Feixingping and Catopril group pulmonary artery ETmRNA expression decrease,increase NOSmRNA expression in pulmonary artery.Conclusion:Feixinping is of good therapeutic effect in treating pulmonary hypertension in pulmonary heart disease.The action of mechanism might be Feixinping can decrease ETmRNA expression in pulmonary artery,increase NOSmRNA expression in pulmonary artery in rats with pulmonary hypertension in pulmonary heart disease.
Pulmonary heart disease
Cite
Citations (0)
Signal transducer and activator of transcription 3(STAT3) is constitutively activated in many human cancers which has been recognized as one of the common pathways. Numerous cytokines,growth factors,and oncogenic proteins activate STAT3. STAT3 signaling affects the expression and function of a variety of genes that are critical to cell survival,cell proliferation,invasion,angiogenesis. So,regulating the STAT3 signaling pathway constitutes a potential preventive and therapeutic target for cancer metastasis.
Cite
Citations (0)
STAT6
Gene targeting
Cite
Citations (21)
Signal transducer and activator of transcription 3 (STAT3), a member of the STAT protein family, can be phosphorylated by receptor-associated Janus kinases (JAKs) in response to stimulation by cytokines and growth factors. It forms homo- or heterodimers that can translocate to the cell nucleus where they act as transcription activators. Constitutive activation of STAT3 has been found to be associated with initiation and progression of various cancers. It can exert proliferative as well as anti-apoptotic effects. This review focuses on the role of STAT3 in pathogenesis i.e., proliferation, differentiation, migration, and apoptosis of hematological malignancies viz. leukemia, lymphoma and myeloma, and briefly highlights the potential therapeutic approaches developed against STAT3 activation pathway.
Janus kinase 2
Cite
Citations (112)
The signal transducer and activator of transcription–3 (Stat3) protein is activated by the interleukin 6 (IL-6) family of cytokines, epidermal growth factor, and leptin. A protein named PIAS3 (protein inhibitor of activated STAT) that binds to Stat3 was isolated and characterized. The association of PIAS3 with Stat3 in vivo was only observed in cells stimulated with ligands that cause the activation of Stat3. PIAS3 blocked the DNA-binding activity of Stat3 and inhibited Stat3-mediated gene activation. Although Stat1 is also phosphorylated in response to IL-6, PIAS3 did not interact with Stat1 or affect its DNA-binding or transcriptional activity. The results indicate that PIAS3 is a specific inhibitor of Stat3.
STAT1
Transcription
Cite
Citations (973)
Cutaneous squamous cell carcinoma (CSCC) is the second most common malignant skin tumor and significantly affects patients' quality of life and health. The Janus kinase/signal transducer and activator of transcription 3 (JAK/STAT3) pathway activation is involved in CSCC development. Radix Tetrastigma hemsleyani flavone (RTHF) is an active Radix Tetrastigma extract (RTE), which was recently reported to have promising inhibitory effects on CSCC. However, the underlying functional mechanisms of this inhibition remain unknown. In the present study, A431 cells or SCL-1 cells were incubated with 1, 5, and 10 mg/mL RTHF for 48 h, respectively. A significantly increased wound closure rate, decreased number of migrated and invaded cells, decreased colony number, and elevated apoptotic rate were observed after treatment with 1, 5, and 10 mg/mL RTHF. Furthermore, after incubation with RTHF, p-JAK1/JAK1, p-JAK2/JAK2, and p-STAT3/STAT3 levels were drastically reduced. An A431 xenograft model was constructed, followed by oral administration of 15, 30, or 60 mg/kg RTHF for 21 consecutive days. A significantly lower increase in tumor volume and reduced tumor weight were observed in all RTHF-treated groups. In addition, JAK/STAT3 signaling was drastically repressed in tumor tissues. Collectively, RTHF inhibited CSCC progression, which may be associated with JAK/STAT3 pathway inactivation.
Janus kinase 2
Cite
Citations (0)
Signal transducer and activator of transcription 3(STAT3),as an important nuclear transcription factor,can inhibit cell apoptosis,promote cell proliferation and participate in such cell biological processes as survival,transformation and migration.STAT3 plays an important role in skin diseases with the characteristics of over proliferation and abnormal differentiation of the epidermis,such as psoriasis.STAT3 is an important signal transducer and transcription activator in the pathogenesis of psoriasis.Blocking the signaling pathway of STAT3 could become a novel and effective method for the treatment of psoriasis.
Pathogenesis
Transcription
Cite
Citations (0)
STAT3 is an important member of the signal transducer and activator of transcription(STAT) family of transcription factors.It is a key signal transduction protein activated by numerous cytokines, growth factors and oncoproteins that controls cell proliferation, differention, development, survival and inflammation.Constitutive activation of STAT3 has been found frequently in a wide variety of human tumors and celluar transformation and tumor formation.In this article, the effects of STAT3 on the tumorigenesis were reviewed.For instance, the mechanism of constitutive activation of STAT3 in tumor cells, the mechanism of STAT3's regulation to tumor cells as a transcription factor and so on.
Transcription
Cite
Citations (0)