Ligustrazine alleviates pulmonary arterial hypertension in rats by promoting the formation of myocardin transcription complex in the nucleus of pulmonary artery smooth muscle cells
Abstract Pulmonary arterial hypertension (PAH) is a pathophysiological state of abnormally elevated pulmonary arterial pressure caused by drugs, inflammation, toxins, viruses, hypoxia, and other risk factors. We studied the therapeutic effect and target of tetramethylpyrazine (tetramethylpyrazine [T...
| Main Authors: | , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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Wiley
2023-08-01
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| Series: | Clinical and Translational Science |
| Online Access: | https://doi.org/10.1111/cts.13534 |
| _version_ | 1828717975704698880 |
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| author | Xichao Yu Mingjie Wu Qinhai Meng Weijie Zhu Chenyan Zhang Bowen Liu Yuewen Qi Shuqun Gu Xinyu Wang Jingli Wen Yu Li Xu Qi |
| author_facet | Xichao Yu Mingjie Wu Qinhai Meng Weijie Zhu Chenyan Zhang Bowen Liu Yuewen Qi Shuqun Gu Xinyu Wang Jingli Wen Yu Li Xu Qi |
| author_sort | Xichao Yu |
| collection | DOAJ |
| description | Abstract Pulmonary arterial hypertension (PAH) is a pathophysiological state of abnormally elevated pulmonary arterial pressure caused by drugs, inflammation, toxins, viruses, hypoxia, and other risk factors. We studied the therapeutic effect and target of tetramethylpyrazine (tetramethylpyrazine [TMP]; ligustrazine) in the treatment of PAH and we speculated that dramatic changes in myocardin levels can significantly affect the progression of PAH. In vivo, the results showed that administration of TMP significantly prolonged the survival of PAH rats by reducing the proliferative lesions, right ventricular systolic pressure (RVSP), mean pulmonary arterial pressure (mPAP), and the Fulton index in the heart and lung of PAH rats. In vitro, TMP can regulate the levels of smooth muscle protein 22‐alpha (SM22‐α), and myocardin as well as intracellular cytokines such as NO, transforming growth factor beta (TGF‐β), and connective tissue growth factor (CTGF) in a dose‐dependent manner (25, 50, or 100 μM). Transfection of myocardin small interfering RNA (siRNA) aggravated the proliferation of pulmonary artery smooth muscle cells (PSMCs), and the regulatory effect of TMP on α‐smooth muscle actin (α‐SMA) and osteopontin (OPN) disappeared. The application of 10 nM estrogen receptor alpha (ERα) inhibitor MPP promoted the proliferation of PSMCs, but it does not affect the inhibition of TMP on PSMCs proliferation. Finally, we found that TMP promoted the nucleation of myocardin‐related transcription factor‐A (MRTF‐A) and combined it with myocardin. In conclusion, TMP can inhibit the transformation of PSMCs from the contractile phenotype to the proliferative phenotype by promoting the formation of the nuclear (MRTF‐A/myocardin) transcription complex to treat PAH. |
| first_indexed | 2024-03-12T14:36:11Z |
| format | Article |
| id | doaj.art-68132918f5b84996bf5be14843a7fb7e |
| institution | Directory Open Access Journal |
| issn | 1752-8054 1752-8062 |
| language | English |
| last_indexed | 2024-03-12T14:36:11Z |
| publishDate | 2023-08-01 |
| publisher | Wiley |
| record_format | Article |
| series | Clinical and Translational Science |
| spelling | doaj.art-68132918f5b84996bf5be14843a7fb7e2023-08-17T06:29:48ZengWileyClinical and Translational Science1752-80541752-80622023-08-011681369138010.1111/cts.13534Ligustrazine alleviates pulmonary arterial hypertension in rats by promoting the formation of myocardin transcription complex in the nucleus of pulmonary artery smooth muscle cellsXichao Yu0Mingjie Wu1Qinhai Meng2Weijie Zhu3Chenyan Zhang4Bowen Liu5Yuewen Qi6Shuqun Gu7Xinyu Wang8Jingli Wen9Yu Li10Xu Qi11School of Medicine & Holistic Integrative Medicine Nanjing University of Chinese Medicine Nanjing ChinaThe Third Clinical Medical College Nanjing University of Chinese Medicine Nanjing ChinaSchool of Medicine & Holistic Integrative Medicine Nanjing University of Chinese Medicine Nanjing ChinaSchool of Medicine & Holistic Integrative Medicine Nanjing University of Chinese Medicine Nanjing ChinaSchool of Medicine & Holistic Integrative Medicine Nanjing University of Chinese Medicine Nanjing ChinaSchool of Medicine & Holistic Integrative Medicine Nanjing University of Chinese Medicine Nanjing ChinaCraig High School Janesville Wisconsin USADepartment of Respiratory Medicine The First Affiliated Hospital of Nanjing Medical University Nanjing ChinaDepartment of Respiratory Medicine The First Affiliated Hospital of Nanjing Medical University Nanjing ChinaDepartment of Respiratory Medicine The First Affiliated Hospital of Nanjing Medical University Nanjing ChinaSchool of Medicine & Holistic Integrative Medicine Nanjing University of Chinese Medicine Nanjing ChinaDepartment of Respiratory Medicine The First Affiliated Hospital of Nanjing Medical University Nanjing ChinaAbstract Pulmonary arterial hypertension (PAH) is a pathophysiological state of abnormally elevated pulmonary arterial pressure caused by drugs, inflammation, toxins, viruses, hypoxia, and other risk factors. We studied the therapeutic effect and target of tetramethylpyrazine (tetramethylpyrazine [TMP]; ligustrazine) in the treatment of PAH and we speculated that dramatic changes in myocardin levels can significantly affect the progression of PAH. In vivo, the results showed that administration of TMP significantly prolonged the survival of PAH rats by reducing the proliferative lesions, right ventricular systolic pressure (RVSP), mean pulmonary arterial pressure (mPAP), and the Fulton index in the heart and lung of PAH rats. In vitro, TMP can regulate the levels of smooth muscle protein 22‐alpha (SM22‐α), and myocardin as well as intracellular cytokines such as NO, transforming growth factor beta (TGF‐β), and connective tissue growth factor (CTGF) in a dose‐dependent manner (25, 50, or 100 μM). Transfection of myocardin small interfering RNA (siRNA) aggravated the proliferation of pulmonary artery smooth muscle cells (PSMCs), and the regulatory effect of TMP on α‐smooth muscle actin (α‐SMA) and osteopontin (OPN) disappeared. The application of 10 nM estrogen receptor alpha (ERα) inhibitor MPP promoted the proliferation of PSMCs, but it does not affect the inhibition of TMP on PSMCs proliferation. Finally, we found that TMP promoted the nucleation of myocardin‐related transcription factor‐A (MRTF‐A) and combined it with myocardin. In conclusion, TMP can inhibit the transformation of PSMCs from the contractile phenotype to the proliferative phenotype by promoting the formation of the nuclear (MRTF‐A/myocardin) transcription complex to treat PAH.https://doi.org/10.1111/cts.13534 |
| spellingShingle | Xichao Yu Mingjie Wu Qinhai Meng Weijie Zhu Chenyan Zhang Bowen Liu Yuewen Qi Shuqun Gu Xinyu Wang Jingli Wen Yu Li Xu Qi Ligustrazine alleviates pulmonary arterial hypertension in rats by promoting the formation of myocardin transcription complex in the nucleus of pulmonary artery smooth muscle cells Clinical and Translational Science |
| title | Ligustrazine alleviates pulmonary arterial hypertension in rats by promoting the formation of myocardin transcription complex in the nucleus of pulmonary artery smooth muscle cells |
| title_full | Ligustrazine alleviates pulmonary arterial hypertension in rats by promoting the formation of myocardin transcription complex in the nucleus of pulmonary artery smooth muscle cells |
| title_fullStr | Ligustrazine alleviates pulmonary arterial hypertension in rats by promoting the formation of myocardin transcription complex in the nucleus of pulmonary artery smooth muscle cells |
| title_full_unstemmed | Ligustrazine alleviates pulmonary arterial hypertension in rats by promoting the formation of myocardin transcription complex in the nucleus of pulmonary artery smooth muscle cells |
| title_short | Ligustrazine alleviates pulmonary arterial hypertension in rats by promoting the formation of myocardin transcription complex in the nucleus of pulmonary artery smooth muscle cells |
| title_sort | ligustrazine alleviates pulmonary arterial hypertension in rats by promoting the formation of myocardin transcription complex in the nucleus of pulmonary artery smooth muscle cells |
| url | https://doi.org/10.1111/cts.13534 |
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