The potential of asiaticoside for TGF-β1/Smad signaling inhibition in prevention and progression of hypoxia-induced pulmonary hypertension

Wang, Xiaobing; Wu, Wei; Zhu, Xiongzhao; Ye, Wen-Jing; Cai, Hui; Wu, Peiliang; Huang, Xiaoying; Wang, Liangxing

doi:10.1016/j.lfs.2015.07.016

Cited by 31 publications

(22 citation statements)

References 29 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…For example, BMP2 promoted SMC phenotypic modulation and germline BMP9 mutation caused idiopathic PAH . In particular, TGF‐β1 is an important cytokine regulating cell differentiation and development, and recent reports have shown that hypoxia can significantly enhance the expression and activity of TGF‐β1 . In our study, it is revealed the level of TGF‐β1 protein to increase higher in hypoxia‐induced HPAECs and transdifferentiating SM‐like cells than BMP2 and BMP9, indicating that hypoxia may promote HPAECs differentiation by triggering TGF‐β1.…”

Section: Discussionsupporting

confidence: 48%

ITE promotes hypoxia‐induced transdifferentiation of human pulmonary arterial endothelial cells possibly by activating transforming growth factor‐β/Smads and MAPK/ERK pathways

Wang

Yan

Guo

et al. 2019

J of Cellular Biochemistry

View full text Add to dashboard Cite

This study aimed to investigate the transdifferentiation of human pulmonary arterial endothelial cells (HPAECs) into smooth muscle like (SM-like) cells under hypoxic conditions and reveal the role of endogenous small molecular compound 2-(1′H-indole-3′-carbonyl)-thiazole-4-carboxylicacid methyl ester (ITE) in this process. HPAECs were treated by hypoxia and hypoxia + ITE with different durations. The endothelial markers (CD31 and VE-cad) and smooth muscle markers (α-SMA, SM22α, and OPN) were investigated by immunofluorescence double staining, and their expressions, along with the differentiation regulators transforming growth factor-β (TGF-β) ligands and downstream signals including TGF-β1, bone morphogenetic protein (BMP2), BMP9, Samd2/3, ERK, and p38 MAPK, were determined by Western blot analysis. The viability and proliferation of HPAECs were detected by Cell Counting Kit-8 (CCK-8) method and bromodeoxyuridine (BrdU) assays. As a result, hypoxia induced HPAECs transdifferentiation from paving-stone-like into polygonal or spindle cells, whose number increased greatly after additional ITE stimulation for 7 days. Compared with the normoxic HPAECs, the expression of endothelial markers reduced and smooth muscle markers were enhanced with the extension of hypoxia + ITE treatment, and meanwhile the cell viability increased significantly. Hypoxia could promote expression of TGF-β1 protein rather than BMP2 and BMP9, and regulate phosphorylation levels of Samd2/3, ERK and p38 MAPK in different manners. In conclusion, ITE can promote the hypoxia-induced transdifferentiation of HPAECs into SM-like cells via TGF-β/Smads and MAPK/ERK pathways. K E Y W O R D S endothelial cells, hypoxia, ITE, pulmonary vascular remodeling, smooth muscle-like cells Jinxia Wang and Guosen Yan contributed equally to this work.

show abstract

Section: Discussionsupporting

confidence: 48%

ITE promotes hypoxia‐induced transdifferentiation of human pulmonary arterial endothelial cells possibly by activating transforming growth factor‐β/Smads and MAPK/ERK pathways

Wang

Yan

Guo

et al. 2019

J of Cellular Biochemistry

View full text Add to dashboard Cite

show abstract

“…It is possible that Smurf-1 is regulated by glucose uptake/metabolism by mechanisms similar to those of Gremlin-1, in which transforming growth factor b-1 (TGFb-1) signaling pathways are amplified (60,62). Indeed, dysregulated TGFb-1 signaling has been documented in pulmonary hypertension (63,64), has opposing effects on BMP signaling (65,66), and can up-regulate the expression of Smurf proteins (67,68). More research is required to determine the links among glucose dysregulation, TGFb-1 signaling, and Smurf-1 expression in IPAH.…”

Section: Original Researchmentioning

confidence: 99%

Bone Morphogenic Protein Type 2 Receptor Mutation-Independent Mechanisms of Disrupted Bone Morphogenetic Protein Signaling in Idiopathic Pulmonary Arterial Hypertension

Barnes¹,

Kucera²,

Tian³

et al. 2016

Am J Respir Cell Mol Biol

View full text Add to dashboard Cite

Altered bone morphogenic protein (BMP) signaling, independent of BMPR2 mutations, can result in idiopathic pulmonary arterial hypertension (IPAH). Glucose dysregulation can regulate multiple processes in IPAH. However, the role of glucose in BMP antagonist expression in IPAH has not been characterized. We hypothesized that glucose uptake regulates BMP signaling through stimulation of BMP antagonist expression in IPAH. Using human plasma, lung tissue, and primary pulmonary arterial smooth muscle cells (PASMCs), we examined the protein expression of BMP2, BMP-regulated Smads, and Smurf-1 in patients with IPAH and control subjects. Gremlin-1 levels were elevated in patients with IPAH compared with control subjects, whereas expression of BMP2 was not different. We demonstrate increased Smad polyubiquitination in IPAH lung tissue and PASMCs that was further enhanced with proteasomal inhibition. Examination of the Smad ubiquitin-ligase, Smurf-1, showed increased protein expression in IPAH lung tissue and localization in the smooth muscle of the pulmonary artery. Glucose dose dependently increased Smurf-1 protein expression in control PASMCs, whereas Smurf-1 in IPAH PASMCs was increased and sustained. Conversely, phosphoSmad1/5/8 levels were reduced in IPAH compared with control PASMCs at physiological glucose concentrations. Interestingly, high glucose concentrations decreased phosphorylation of Smad1/5/8 in control PASMCs. Blocking glucose uptake had opposing effects in IPAH PASMCs, and inhibition of Smurf-1 activity resulted in partial rescue of Smad1/5/8 activation and cell migration rates. Collectively, these data suggest that BMP signaling can be regulated through BMPR2 mutation-independent mechanisms. Gremlin-1 (synonym: induced-in-high-glucose-2 protein) and Smurf-1 may function to inhibit BMP signaling as a consequence of the glucose dysregulation described in IPAH.

show abstract

“…(20,21). Elevated levels of TGF-β1 expression and Smad2/3 phosphorylation have been reported in rat models of experimental PH in response to hypoxia, as well as in patients with idiopathic PH (22). On a cellular level, TGF-β1 has been shown to promote the proliferation and migration of PASMCs from rats and patients with PH and to increase extracellular matrix and endothelin-1 expression in rat and human PASMCs (23).…”

Section: Discussionmentioning

confidence: 99%

Inactivated Pseudomonas aeruginosa inhibits hypoxia-induced pulmonary hypertension by preventing TGF-β1/Smad signaling

Chai

Liu

Dong

et al. 2016

Braz J Med Biol Res

View full text Add to dashboard Cite

Pseudomonas aeruginosa is one of the common colonizing bacteria of the human body and is an opportunistic pathogen frequently associated with respiratory infections. Inactivated P. aeruginosa (IPA) have a variety of biological effects against inflammation and allergy. Transforming growth factor-β (TGF-β) signaling plays a critical role in the regulation of cell growth, differentiation, and development in a wide range of biological systems. The present study was designed to investigate the effects of IPA on TGF-β/Smad signaling in vivo, using a hypoxia-induced pulmonary hypertension (PH) rat model. Sprague Dawley rats (n=40) were exposed to 10% oxygen for 21 days to induce PH. At the same time, IPA was administered intravenously from day 1 to day 14. Mean pulmonary artery pressure (mPAP) and the right ventricle (RV) to left ventricle plus the interventricular septum (LV+S) mass ratio were used to evaluate the development of PH. Vessel thickness and density were measured using immunohistochemistry. Primary arterial smooth muscle cells (PASMCs) were isolated and the proliferation of PASMCs was assayed by flow cytometry. The production of TGF-β1 in cultured supernatant of PASMCs was assayed by ELISA. The expression levels of α-smooth muscle actin (α-SMA), TGF-β1 and phospho-Smad 2/3 in PASMCs were assayed by western blot. Our data indicated that IPA attenuated PH, RV hypertrophy and pulmonary vascular remodeling in rats, which was probably mediated by restraining the hypoxia-induced overactive TGF-β1/Smad signaling. In conclusion, IPA is a promising protective treatment in PH due to the inhibiting effects on TGF-β1/Smad 2/3 signaling.

show abstract

The potential of asiaticoside for TGF-β1/Smad signaling inhibition in prevention and progression of hypoxia-induced pulmonary hypertension

Cited by 31 publications

References 29 publications

ITE promotes hypoxia‐induced transdifferentiation of human pulmonary arterial endothelial cells possibly by activating transforming growth factor‐β/Smads and MAPK/ERK pathways

ITE promotes hypoxia‐induced transdifferentiation of human pulmonary arterial endothelial cells possibly by activating transforming growth factor‐β/Smads and MAPK/ERK pathways

Bone Morphogenic Protein Type 2 Receptor Mutation-Independent Mechanisms of Disrupted Bone Morphogenetic Protein Signaling in Idiopathic Pulmonary Arterial Hypertension

Inactivated Pseudomonas aeruginosa inhibits hypoxia-induced pulmonary hypertension by preventing TGF-β1/Smad signaling

Contact Info

Product

Resources

About