Baicalin attenuates transforming growth factor-β1-induced human pulmonary artery smooth muscle cell proliferation and phenotypic switch by inhibiting hypoxia inducible factor-1α and aryl hydrocarbon receptor expression

Huang, Shian; Chen, Puwen; Shui, Xiaorong; He, Yuan; Wang, Heyong; Zheng, Jing; Zhang, Liangqing; Li, Jianwen; Xue, Yiqiang; Chen, Can; Lei, Wei

doi:10.1111/jphp.12273

Cited by 45 publications

(36 citation statements)

References 38 publications

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“…Our current finding that the extensive expression of AhR protein in human lung tissues is consistent with our previous reports showing the presence of AhR in pulmonary arterial smooth muscle cells in vitro [11] and in human fetal lung tissues. [22] This broad distribution (endothelium, vascular smooth muscle cells, bronchial epithelium, alveolar sac epithelium, and stromal cells) of AhR in human lung tissues implies the overall importance of AhR in mediating function of different types of human lung cells.…”

Section: Discussionsupporting

confidence: 93%

“…AhR has been reported to express in human pulmonary artery smooth muscle cells (HPASMCs) in vitro [11] and in human fetal lung tissues, [22] and is associated with Baicalin-inhibited proliferation of HPASMCs. [11] However, it is unknown if the ITE/AhR pathway regulates growth of HPAECs.…”

Section: Introductionmentioning

confidence: 99%

“…[11] However, it is unknown if the ITE/AhR pathway regulates growth of HPAECs. Herein, we determined AhR expression in human lung tissues.…”

Section: Introductionmentioning

confidence: 99%

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ITE inhibits growth of human pulmonary artery endothelial cells

Pang

Zou

et al. 2017

Experimental Lung Research

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Aim Pulmonary arterial hypertension (PAH), a deadly disorder is associated with excessive growth of human pulmonary artery endothelial (HPAECs) and smooth muscle (HPASMCs) cells. Current therapies primarily aim at promoting vasodilation, which only ameliorates clinical symptoms without a cure. 2-(1′H-indole-3′-carbonyl)-thiazole-4-carboxylic acid methyl ester (ITE) is an endogenous aryl hydrocarbon receptor (AhR) ligand, and mediates many cellular function including cell growth. However, the roles of ITE in human lung endothelial cells remain elusive. Herein, we tested a hypothesis that ITE inhibits growth of human pulmonary artery endothelial cells via AhR. Materials and Methods Immunohistochemistry was performed to localize AhR expression in human lung tissues. The crystal violet method and MTT assay were used to determine ITE’s effects on growth of HPAECs. The AhR activation in HPAECs was confirmed using Western blotting and RT-qPCR. The role of AhR in ITE-affected proliferation of HPAECs was assessed using siRNA knockdown method followed by the crystal violet method. Results Immunohistochemistry revealed that AhR was present in human lung tissues, primarily in endothelial and smooth muscle cells of pulmonary veins and arteries, as well as in bronchial and alveolar sac epithelia. We also found that ITE dose- and time-dependently inhibited proliferation of HPAECs with a maximum inhibition of 83% at 20 µM after 6 days of treatment. ITE rapidly decreased AhR protein levels, while it increased mRNA levels of cytochrome P450 (CYP), family 1, member A1 (CYP1A1) and B1 (CYP1B1), indicating activation of the AhR/CYP1A1 and AhR/CYP1B1 pathways in HPAECs. The AhR siRNA significantly suppressed AhR protein expression, whereas it did not significantly alter ITE-inhibited growth of HPAECs. Conclusions ITE suppresses growth of HPAECs independent of AhR, suggesting that ITE may play an important role in preventing excessive growth of lung endothelial cells.

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Section: Discussionsupporting

confidence: 93%

Section: Introductionmentioning

confidence: 99%

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ITE inhibits growth of human pulmonary artery endothelial cells

Pang

Zou

et al. 2017

Experimental Lung Research

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“…39,40 To the best of our knowledge, only 1 study has reported a role for AhR in PH, whereby inhibition of TGF-β1 using baicalin led to a decrease in hPASMC proliferation through a decrease in AhR. 19 AhR antagonism is considered a promising mode of treatment and preventive target for diseases, such as gastric and breast cancer and nitric oxidedependent vasculature diseases. 41,42 We found elevated expression of AhR in vehicle SuHx rats, particularly in occluded lesions, and this was reversed by metformin.…”

mentioning

confidence: 99%

“…18 One transcription factor for CYP1B1 is the aryl hydrocarbon receptor (AhR), suppression of which has been shown to be antiproliferative (protective) in PH. 19 Metformin is a well-established drug for use in type 2 diabetes mellitus 20,21 and has been demonstrated to activate AMP-activated protein kinase (AMPK) in many tissues, although AMPK does not underlie the hypoglycemic actions of metformin. 22 AMPK is a ubiquitously expressed serine/threonine protein kinase, which plays a critical role in cellular and organ metabolism.…”

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Metformin Reverses Development of Pulmonary Hypertension via Aromatase Inhibition

et al. 2016

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H uman pulmonary arterial hypertension (PAH) is a progressive disease of the pulmonary vasculature, which often leads to right heart failure. PAH is characterized by elevated pulmonary pressure (>25 mm Hg at rest), vascular remodeling, and occlusive pulmonary vascular lesions. Although survival rates are improving slowly; there remains an unacceptably poor survival rate. 1 Females are more susceptible to PAH than males, as indicated in, for example, the REVEAL (Registry to Evaluate Early and Long-Term PAH Disease Management) registry where ≈80% of the patients registered were female.2,3 However, male patients have a poorer survival rate than females, implicating sex hormones in both PAH susceptibility and survival. 4 Consequently, the role of estrogens in PAH has been accumulating significant interest. [5][6][7][8] There is an estrogen paradox however as while exogenous estrogen may be protective against experimental pulmonary hypertension (PH) and right ventricular (RV) hypertrophy in rodent models, [9][10][11][12] endogenous estrogen is causative in female animal models. [13][14][15][16][17] Estrogen is synthesized from testosterone through the enzyme aromatase and inhibition of aromatase attenuates experimental PH but only in females. 17 Estrogen can be metabolized through the cytochrome p450 1B1 (CYP1B1) enzyme to form the mitogenic 16α-hydroxyestrone, a metabolite established to be pathogenic in PH. 16 Furthermore, single-nucleotide polymorphisms of CYP1B1 have been recently identified to be associated with PH and indicated to play a key role in sexual dimorphism in RV failure. 18 One transcription factor for CYP1B1 is the aryl hydrocarbon receptor (AhR), suppression of which has been shown to be antiproliferative (protective) in PH. 19 Metformin is a well-established drug for use in type 2 diabetes mellitus 20,21 and has been demonstrated to activate AMP-activated protein kinase (AMPK) in many tissues, although AMPK does not underlie the hypoglycemic actions of metformin. 22 AMPK is a ubiquitously expressed serine/threonine protein kinase, which plays a critical role in cellular and organ metabolism. 23,24 In breast cancer and polycystic ovarian syndrome, the therapeutic effects of metformin involves the enhancement of the AMPK pathway and inhibition of the nuclear translocation of cyclic AMPresponsive element binding protein-regulated transcription coactivator 2 (CRTC2). CRTC2 (a downstream target of AMPK) can bind to the PII promoter site of the aromatase Abstract-Females are more susceptible to pulmonary arterial hypertension than males, although the reasons remain unclear. The hypoglycemic drug, metformin, is reported to have multiple actions, including the inhibition of aromatase and stimulation of AMP-activated protein kinase. Inhibition of aromatase using anastrazole is protective in experimental pulmonary hypertension but whether metformin attenuates pulmonary hypertension through this mechanism remains unknown. We investigated whether metformin affected aromatase activity and if it could r...

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Overexpressed long noncoding RNA CPS1‐IT alleviates pulmonary arterial hypertension in obstructive sleep apnea by reducing interleukin‐1β expression via HIF1 transcriptional activity

Zhang

Wang

et al. 2019

Journal Cellular Physiology

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Pulmonary arterial hypertension (PAH) is characterized by pulmonary vascular remodeling of the precapillary pulmonary arteries, with excessive proliferation of vascular cells. This study was performed to examine the effects of long noncoding RNA CPS1 intronic transcript 1 (CPS1-IT) on PAH in rat models of obstructive sleep apnea (OSA) through regulating interleukin (IL)-1β expression. The OSA models were induced in rats, for determination of the CPS1-IT expression. The binding of CPS1-IT and hypoxia-inducible factor 1 (HIF1) was verified. To analyze the effects of CPS1-IT on PAH, the overexpression vector of CPS1-IT and HIF1, shRNA against IL-1β and pyrrolidine dithiocarbamate (PDTC, inhibitor of the NF-κB signaling pathway) were injected into rat models, respectively. The blood pressure and activity of biochemical indicators including nitric oxide (NO), nitric oxide synthase (NOS), superoxide dismutase (SOD), and lipid peroxide (LPO) were assessed. The expression of IL-1β, HIF1, α-smooth muscle actin (α-SMA), proliferating cell nuclear antigen (PCNA), and fibronectin (FN) was determined. The relationship of CPS1-IT to IL-1β and NF-κB was evaluated. CPS1-IT was downregulated in the OSA rat model. Overexpressed CPS1-IT increased the activity of NO, NOS, and SOD as well as α-SMA expression, whereas decreasing LPO activity and expression of PCNA and FN, whereby PAH was suppressed. Notably, overexpressed CPS1-IT reduced IL-1β expression through NF-κB signaling pathway via inhibiting the HIF1 transcriptional activity, suggesting a mechanism affecting PAH. To conclude, overexpressed CPS1-IT alleviated PAH in OSA by reducing IL-1β expression, the mechanism of which was involved with inhibited HIF1 transcriptional activity and the NF-κB signaling pathway. K E Y W O R D S hypoxia-inducible factor 1, interleukin-1β, long noncoding RNA CPS1 intronic transcript 1, nuclear factor-κB, obstructive sleep apnea, pulmonary arterial hypertension, transcriptional activity Overexpressed long noncoding RNA CPS1-IT alleviates pulmonary arterial hypertension in obstructive sleep apnea by reducing interleukin-1β expression via HIF1 transcriptional activity.

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Baicalin attenuates transforming growth factor-β1-induced human pulmonary artery smooth muscle cell proliferation and phenotypic switch by inhibiting hypoxia inducible factor-1α and aryl hydrocarbon receptor expression

Abstract: Our study shows that baicalin has the potential to be used as a novel drug in the treatment of pulmonary arterial hypertension pathology by antagonizing HIF-1α and AhR expression and subsequently decreasing HPASMC proliferation and the phenotypic switch.

Cited by 45 publications

References 38 publications

ITE inhibits growth of human pulmonary artery endothelial cells

ITE inhibits growth of human pulmonary artery endothelial cells

Metformin Reverses Development of Pulmonary Hypertension via Aromatase Inhibition

Overexpressed long noncoding RNA CPS1‐IT alleviates pulmonary arterial hypertension in obstructive sleep apnea by reducing interleukin‐1β expression via HIF1 transcriptional activity

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