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Cyanidin‑3‑O‑β‑glucoside protects against pulmonary artery hypertension induced by monocrotaline via the TGF‑β1/p38 MAPK/CREB signaling pathway.

ABSTRACT: Pulmonary artery hypertension (PAH) is a disease with high morbidity and mortality. Cyanidin‑3‑O‑β‑glucoside (Cy‑3‑g), a classical anthocyanin, has a variety of biological effects. The present study evaluated whether Cy‑3‑g attenuated PAH, and explored the potential mechanism of action. Rats were injected with monocrotaline (MCT; 60 mg per kg of body weight) and then treated with Cy‑3‑g (200 or 400 mg per kg of body weight) for 4 weeks. Protein expression was determined in vitro in transforming growth factor‑β1 (TGF‑β1)‑mediated human pulmonary arterial smooth muscle cells (SMCs). The results indicated that Cy‑3‑g significantly inhibited the mean pulmonary artery pressure, right ventricular systolic pressure and right ventricular hypertrophy index, as well as vascular remodeling induced by MCT in PAH rats. Further experiments showed that Cy‑3‑g suppressed the expression of pro‑-inflammatory factors and enhanced the levels of anti‑inflammatory factors. Cy‑3‑g blocked oxidative stress and improved vascular endothelial injury. Cy‑3‑g also reduced the proliferation of SMCs. Furthermore, the MCT‑ and TGF‑β1‑induced increase in TGF‑β1, phosphorylated (p)‑p38 mitogen‑activated protein kinase (MAPK) and p‑cAMP‑response element binding protein (CREB) expression was blocked by Cy‑3‑g treatment in vivo and in vitro. These results indicated that Cy‑3‑g could prevent vascular remodeling in PAH via inhibition of the TGF‑β1/p38 MAPK/CREB axis.

SUBMITTER: Ouyang S

PROVIDER: S-EPMC7974420 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:Preeclampsia, a hypertensive disorder occurring during pregnancy, is characterized by excessive oxidative stress and trophoblast dysfunction with dysregulation of soluble Fms-like tyrosine kinase 1 (sFlt-1) and placental growth factor (PlGF) production. Nicotinamide Adenine Dinucleotide Phosphate (NADPH) oxidase (Nox) is the major source of placental superoxide in early pregnancy and its activation with the subsequent formation of superoxide has been demonstrated for various agents including Transforming Growth Factor beta-1 (TGF-β1), a well-known p38 MAPK pathway activator. However, the bridge between Nox and sFlt-1 remains unknown. The purpose of this study was to explore the possible signaling pathway of TGF-β1/Nox/p38 induced sFlt-1 production in human chorionic villi (CV). Human chorionic villi from first trimester placenta (7-9 Gestational Weeks (GW)) were treated with TGF-β1 or preincubated with p38 inhibitor, SB203580. For NADPH oxidase inhibition, CV were treated with diphenyleneiodonium (DPI). The protein levels of phospho-p38, p38, phospho-Mothers Against Decapentaplegic homolog 2 (SMAD2), and SMAD2 were detected by Western blot. The secretion of sFlt-1 and PlGF by chorionic villi were measured with Electrochemiluminescence Immunologic Assays, and NADPH oxidase activity was monitored by lucigenin method. We demonstrate for the first time that NADPH oxidase is involved in sFlt-1 and PlGF secretion in first trimester chorionic villi. Indeed, the inhibition of Nox by DPI decreases sFlt-1, and increases PlGF secretions. We also demonstrate the involvement of p38 MAPK in sFlt-1 secretion and Nox activation as blocking the p38 MAPK phosphorylation decreases both sFlt-1 secretion and superoxide production. Nevertheless, TGF-β1-mediated p38 activation do not seem to be involved in regulation of the first trimester placental angiogenic balance and no crosstalk was found between SMAD2 and p38 MAPK pathways. Thus, the placental NADPH oxidase play a major role in mediating the signal transduction cascade of sFlt-1 production. Furthermore, we highlight for the first time the involvement of p38 activation in first trimester placental Nox activity.

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Cyanidin‑3‑O‑β‑glucoside protects against pulmonary artery hypertension induced by monocrotaline via the TGF‑β1/p38 MAPK/CREB signaling pathway.

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