Berberine attenuates hypoxia‐induced pulmonary arterial hypertension via bone morphogenetic protein and transforming growth factor‐β signaling

Abstract

Hypoxia‐induced excessive pulmonary artery smooth muscle cell (PASMC) proliferation plays an important role in the pathology of pulmonary arterial hypertension (PAH). Berberine (BBR) is reported as an effective antiproliferative properties applied in clinical. However, the effect of BBR on PAH remains unclear. In the present study, we elucidated the protective effects of BBR against abnormal PASMC proliferation and vascular remodeling in chronic hypoxia‐induced hearts. Furthermore, the potential mechanisms of BBR were investigated. For this purpose, C57/BL6 mice were exposed to chronic hypoxia for 4 weeks to mimic severe PAH. Hemodynamic and pulmonary pathomorphology data showed that chronic hypoxia significantly increased the right ventricular systolic pressure (RVSP), the right ventricle/left ventricle plus septum RV/(LV + S) weight ratio, and the median width of pulmonary arterioles. BBR attenuated the elevations in RVSP and RV/(LV + S) and mitigated pulmonary vascular structure remodeling. BBR also suppressed the hypoxia‐induced increases in the expression of proliferating cell nuclear antigen (PCNA) and of α‐smooth muscle actin. Furthermore, administration of BBR significantly increased the expression of bone morphogenetic protein type II receptor (BMPR‐II) and its downstream molecules P‐smad1/5 and decreased the expression of transforming growth factor‐β (TGF‐β) and its downstream molecules P‐smad2/3. Moreover, peroxisome proliferator‐activated receptor γ expression was significantly decreased in the hypoxia group, and this decrease was reversed by BBR treatment. Our study demonstrated that the protective effect of BBR against hypoxia‐induced PAH in a mouse model may be achieved through altered BMPR‐II and TGF‐β signaling.

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

“…MCT can lead to the decreased expression of BMPR2 protein and mRNA in rats (Price et al, 2011; Yang, Li, Al‐Lamki, et al, 2013). TNF‐α not only induced the proliferation of PASMCs but also reduced the expression of BMPR2 in PASMCs (Chen, Shen, et al, 2019; Chen, Wang, et al, 2019; Hurst et al, 2017). TNF‐α, a key inflammatory cytokine, participated in the pathological processes of PAH and induced the excessive proliferation of PASMCs (Cheng et al, 2017).…”

“…In addition, pulmonary artery remodeling, including wall thickening, muscularization, and fibrosis of the outer membrane in pulmonary artery, eventually leading to right heart failure, was also an important pathological feature of PAH (Cajigas & Awdish, 2016; Hoette, Jardim, & Souza, 2010; Stenmark, Fagan, & Frid, 2006). In previous researches, the indexes of WT%, WA%, and infiltration of inflammatory were used to assess pulmonary artery remodeling (Cheng et al, 2018; Davies et al, 2012; Pickworth et al, 2017; Wu, Hao, et al, 2017; Zhang, Chang, Zhao, et al, 2019), and CSA of cardiomyocyte was used to assess right ventricular hypertrophy (Chen, Shen, et al, 2019; Chen, Wang, et al, 2019). In the current study, H&E staining results revealed that isorhamnetin not only reduced the abnormal increase of MCT‐induced WT% and WA% and CSA but also improved MCT‐induced pulmonary arterial wall thickness, increased luminal stenosis wall, and infiltration of inflammatory cells in rats.…”

“…Given the in‐depth studies on PAH in the past few years, BMP signaling pathway may be an ideal drug target for PAH treatment (Chen, Shen, et al, 2019; Chen, Wang, et al, 2019; Orriols et al, 2017; Yang, Li, Al‐Lamki, et al, 2013; Zhang, Dong, et al, 2018; Zhang, Peng, & Han, 2018). BMP is a very important cytokine in the transforming growth factor superfamily, which can be synthesized and secreted by various cells, including smooth muscle cells and endothelial cells.…”

“…Many clinical researches showed that BMP receptor type 2 (BMPR2) had a central role in the BMP signaling pathway, and BMPR2 mutations were present in patients with heritable and idiopathic PAH (Girerd et al, 2010; West, Austin, Fessel, Loyd, & Hamid, 2014; Yang et al, 2013; Yang, Li, Al‐Lamki, et al, 2013). In addition, BMPR2 mutations led to abnormal proliferation of PASMCs, and BMPR2 deficiency led to chronic hypoxia and monocrotaline (MCT)‐induced pulmonary vascular remodeling (Chen et al, 2019, 2019; Yang et al, 2010; Yang, Li, Li, et al, 2013). Inflammation is an important pathological mechanism of PAH.…”

“…Dysfunction in the BMPR2 signaling pathway can aggravate inflammation. Previous studies have shown that inflammatory response in turn aggravates PAH because of BMP/BMPR2 signal deficiency (Chen, Shen, et al, 2019; Chen, Wang, et al, 2019; Davies et al, 2012; Pickworth et al, 2017). Thus, the BMP signaling pathway is a potential therapeutic target for PAH treatment.…”