Transgelin as a therapeutic target to prevent hypoxic pulmonary hypertension
| العنوان: | Transgelin as a therapeutic target to prevent hypoxic pulmonary hypertension |
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| المؤلفون: | Xiaohong Wu, Ruifeng Zhang, Lin Zhou, Guofeng Ma, Fangchun Shao, Gensheng Zhang, Kejing Ying, Liuhong Shi |
| المصدر: | American Journal of Physiology-Lung Cellular and Molecular Physiology. 306:L574-L583 |
| بيانات النشر: | American Physiological Society, 2014. |
| سنة النشر: | 2014 |
| مصطلحات موضوعية: | Male, Pulmonary and Respiratory Medicine, Chromatin Immunoprecipitation, medicine.medical_specialty, Physiology, Hypertension, Pulmonary, Transgelin, Myocytes, Smooth Muscle, Muscle Proteins, Blood Pressure, Pulmonary Artery, Biology, Rats, Sprague-Dawley, Transforming Growth Factor beta1, Downregulation and upregulation, Physiology (medical), Internal medicine, Basic Helix-Loop-Helix Transcription Factors, medicine, Animals, Humans, Smad3 Protein, RNA, Small Interfering, Promoter Regions, Genetic, Cells, Cultured, Cell Proliferation, Arterial smooth muscle cells, Microfilament Proteins, Cell Biology, Hypoxia (medical), medicine.disease, Pulmonary hypertension, Cell Hypoxia, Rats, DNA-Binding Proteins, Endocrinology, Pulmonary Veins, Cancer research, RNA Interference, medicine.symptom, Protein Binding |
| الوصف: | We previously observed that transgelin was preferentially expressed in human pulmonary arterial smooth muscle cells (PAMSCs) under hypoxia and that the upregulation of transgelin was independent of hypoxia-inducible factor 1α (HIF-1α). Reduced transgelin expression was accompanied by significantly impaired migration ability in vitro. However, the regulation mechanism of transgelin and its function in preventing hypoxic pulmonary hypertension (HPH) was unclear. In the present study, RNA interference with hypoxia-inducible factor 2α (HIF-2α) was employed in human PASMCs. Transgelin expression was diminished in HIF-2α-siRNA-treated cells at both the mRNA and protein levels under hypoxia. However, HIF-2α did not transactivate the transgelin promoter directly. TGF-β1 concentration in human PASMCs culture medium was higher under hypoxia, and the accumulated TGF-β1 under hypoxia was regulated by HIF-2α. Furthermore, luciferase and chromatin immunoprecipitation assays indicated that TGF-β1/Smad3 could bind to the transgelin promoter, resulting in increased transgelin expression. In addition to nonintact cellular migration, inhibition of transgelin expression resulted in impaired proliferation in vitro under hypoxia. A lentiviral vector used to inhibit transgelin expression was constructed and intratracheally instilled in rats 3 wk prior to hypoxia treatment. Our final results indicated that inhibition of transgelin expression locally could attenuate increased right ventricular systolic pressure and its associated cardiac and pulmonary vessel remodeling under hypoxia. Our findings indicate that HIF-2α upregulates transgelin indirectly and that accumulated TGF-β1 is a mediator in the upregulation of transgelin by HIF-2α under hypoxia. Inhibition of transgelin expression locally could prevent HPH and pulmonary vascular remodeling in vivo. |
| تدمد: | 1522-1504 1040-0605 |
| DOI: | 10.1152/ajplung.00327.2013 |
| URL الوصول: | https://explore.openaire.eu/search/publication?articleId=doi_dedup___::7f67a44b59085ad8dd6eea0fa9a76be2 https://doi.org/10.1152/ajplung.00327.2013 |
| رقم الانضمام: | edsair.doi.dedup.....7f67a44b59085ad8dd6eea0fa9a76be2 |
| قاعدة البيانات: | OpenAIRE |
| تدمد: | 15221504 10400605 |
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| DOI: | 10.1152/ajplung.00327.2013 |