Andrographolide Attenuates Established Pulmonary Hypertension via Rescue of Vascular Remodeling
| Autor: | Dai You'ai, Xusheng Yang, Wei Wang, Zhi-Yuan Wu, Xiaowei Nie, Chenyou Shen, Haijian Sun, Chen Jingyu, Jianxin Tan |
|---|---|
| Jazyk: | angličtina |
| Rok vydání: | 2021 |
| Předmět: |
MAPK/ERK pathway
Male andrographolide pulmonary hypertension vascular remodeling pulmonary artery smooth muscle cells Indoles Cell Survival Hypertension Pulmonary Primary Cell Culture Anti-Inflammatory Agents Pharmacology medicine.disease_cause Microbiology Biochemistry Article Mice Cell Movement medicine Animals Humans Pyrroles Molecular Biology Cells Cultured Cell Proliferation chemistry.chemical_classification Reactive oxygen species NADPH oxidase biology Hypoxia (medical) medicine.disease Pulmonary hypertension QR1-502 BMPR2 Disease Models Animal chemistry Gene Expression Regulation Apoptosis biology.protein Female medicine.symptom Diterpenes Oxidative stress Signal Transduction |
| Zdroj: | Biomolecules Biomolecules; Volume 11; Issue 12; Pages: 1801 Biomolecules, Vol 11, Iss 1801, p 1801 (2021) |
| ISSN: | 2218-273X |
| Popis: | Pulmonary hypertension (PH) is characterized by vascular remodeling caused by marked proliferation of pulmonary artery smooth muscle cells (PASMCs). Andrographolide (ANDRO) is a potent anti-inflammatory agent which possesses antioxidant, and has anticarcinogenic activity. The present study examined potential therapeutic effects of ANDRO on PH in both chronic hypoxia and Sugen5416/hypoxia mouse PH models. Effects of ANDRO were also studied in cultured human PASMCs isolated from either healthy donors or PH patients. In vivo, ANDRO decreased distal pulmonary arteries (PAs) remodeling, mean PA pressure and right ventricular hypertrophy in chronic hypoxia- and Sugen/hypoxia-induced PH in mice. ANDRO reduced cell viability, proliferation and migration, but increased cell apoptosis in the PASMCs isolated from PH patients. ANDRO also reversed the dysfunctional bone morphogenetic protein receptor type-2 (BMPR2) signaling, suppressed [Ca2+]i elevation, reactive oxygen species (ROS) generation, and the upregulated expression of IL-6 and IL-8, ET-1 and VEGF in PASMCs from PH patients. Moreover, ANDRO significantly attenuated the activation of TLR4/NF-κB, ERK- and JNK-MAPK signaling pathways and reversed the inhibition of p38-MAPK in PASMCs of PH patients. Further, ANDRO blocked hypoxia-triggered ROS generation by suppressing NADPH oxidase (NOX) activation and augmenting nuclear factor erythroid 2-related factor 2 (Nrf2) expression both in vitro and in vivo. Conventional pulmonary vasodilators have limited efficacy for the treatment of severe PH. We demonstrated that ANDRO may reverse pulmonary vascular remodeling through modulation of NOX/Nrf2-mediated oxidative stress and NF-κB-mediated inflammation. Our findings suggest that ANDRO may have therapeutic value in the treatment of PH. |
| Databáze: | OpenAIRE |
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