Ligustrazine alleviates pulmonary arterial hypertension in rats by promoting the formation of myocardin transcription complex in the nucleus of pulmonary artery smooth muscle cells

Author:

Yu Xichao1ORCID,Wu Mingjie2,Meng Qinhai1,Zhu Weijie1,Zhang Chenyan1,Liu Bowen1,Qi Yuewen3,Gu Shuqun4,Wang Xinyu4,Wen Jingli4,Li Yu1,Qi Xu45

Affiliation:

1. School of Medicine & Holistic Integrative Medicine Nanjing University of Chinese Medicine Nanjing China

2. The Third Clinical Medical College Nanjing University of Chinese Medicine Nanjing China

3. Craig High School Janesville Wisconsin USA

4. Department of Respiratory Medicine The First Affiliated Hospital of Nanjing Medical University Nanjing China

5. The Affiliated Jiangsu Shengze Hospital of Nanjing Medical University Suzhou China

Abstract

AbstractPulmonary 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.

Publisher

Wiley

Subject

General Pharmacology, Toxicology and Pharmaceutics,General Biochemistry, Genetics and Molecular Biology,General Medicine,General Neuroscience

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