Protective effects of isorhamnetin on pulmonary arterial hypertension: in vivo and in vitro studies

• Published in: Phytotherapy research Vol. 34; no. 10; pp. 2730 - 2744
• Main Authors: Chang, Zhi, Wang, Jia‐ling, Jing, Zhi‐cheng, Ma, Ping, Xu, Qing‐bing, Na, Jian‐rong, Tian, Jie, Ma, Xuan, Zhou, Wei, Zhou, Ru
• Format: Journal Article
• Language: English
• Published: Chichester, UK John Wiley & Sons, Ltd 01.10.2020; Wiley Subscription Services, Inc
• Subjects: BMP signaling pathway; Bone morphogenetic protein receptor type II; Bone morphogenetic proteins; Cell proliferation; Flavonoids; Gene expression; Hemodynamics; human proliferation of pulmonary artery smooth muscle cells; Hypertension; Id1 protein; In vivo methods and tests; isorhamnetin; Monocrotaline; Muscles; Mutation; Oral administration; Protein expression; Proteins; pulmonary arterial hypertension; Pulmonary arteries; Pulmonary artery; Pulmonary hypertension; Signal transduction; Sildenafil; Smooth muscle; TNF‐α; BMP signaling pathway; TNF-α; human proliferation of pulmonary artery smooth muscle cells; isorhamnetin; pulmonary arterial hypertension; monocrotaline
• ISSN: 0951-418X; 1099-1573
• DOI: 10.1002/ptr.6714

Pulmonary arterial hypertension (PAH) is a malignant disease with high mortality and closely involves the bone morphogenetic protein (BMP) pathway. Mutations in BMPR2 caused proliferation of pulmonary artery smooth muscle cells (PASMCs) leading to PAH. Isorhamnetin, one of the main naturally occurring flavonoids extracted from Hippophae rhamnoides L, shows antiinflammatory and anti‐proliferative properties. Nevertheless, the effects of isorhamnetin on PAH remain unclear. This study aimed to investigate whether isorhamnetin has protective effects against PAH and explore possible mechanisms. An in vivo model of PAH induced by monocrotaline (MCT) was employed, and sildenafil and isorhamnetin were orally administered for 21 consecutive days. An in vitro model induced by TNF‐α was employed, and cell proliferation of HPASMCs was detected. Results indicated that isorhamnetin significantly improved hemodynamic, histopathological, and echocardiographic changes in MCT‐induced PAH in rats. In vitro, isorhamnetin suppressed TNF‐α‐induced HPASMCs proliferation. Furthermore, isorhamnetin improved protein expression of BMPR2 and suppressed protein expression of TNF‐α and IL‐6 in rat lungs. Isorhamnetin improved protein expression of BMPR2 and p‐smad1/5 and mRNA expression of Id1 and Id3 in HPASMCs. Isorhamnetin ameliorated MCT‐induced PAH in rats and inhibited TNF‐α‐induced HPASMCs proliferation by a mechanism likely involving the regulation of the BMP signaling pathway.