The reversal of pulmonary vascular remodeling through inhibition of p38 MAPK-alpha: a potential novel anti-inflammatory strategy in pulmonary hypertension

The p38 mitogen-activated protein kinase (MAPK) system is increasingly recognized as an important inflammatory pathway in systemic vascular disease but its role in pulmonary vascular disease is unclear. Previous in vitro studies suggest p38 MAPKα is critical in the proliferation of pulmonary artery fibroblasts, an important step in the pathogenesis of pulmonary vascular remodeling (PVremod). In this study the role of the p38 MAPK pathway was investigated in both in vitro and in vivo models of pulmonary hypertension and human disease. Pharmacological inhibition of p38 MAPKα in both chronic hypoxic and monocrotaline rodent models of pulmonary hypertension prevented and reversed the pulmonary hypertensive phenotype. Furthermore, with the use of a novel and clinically available p38 MAPKα antagonist, reversal of pulmonary hypertension was obtained in both experimental models. Increased expression of phosphorylated p38 MAPK and p38 MAPKα was observed in the pulmonary vasculature from patients with idiopathic pulmonary arterial hypertension, suggesting a role for activation of this pathway in the PVremod A reduction of IL-6 levels in serum and lung tissue was found in the drug-treated animals, suggesting a potential mechanism for this reversal in PVremod. This study suggests that the p38 MAPK and the α-isoform plays a pathogenic role in both human disease and rodent models of pulmonary hypertension potentially mediated through IL-6. Selective inhibition of this pathway may provide a novel therapeutic approach that targets both remodeling and inflammatory pathways in pulmonary vascular disease.

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NPS2143 Modulates the Phenotypic Switching of PASMCs by Inhibiting Autophagy in Hypoxia-Induced Pulmonary Hypertension

Journal of Stem Cell Research and Transplantation ◽

10.26420/jstemcellrestransplant.2021.1038 ◽

2021 ◽

Vol 8 (2) ◽

Author(s):

Wang L ◽

◽

Shao H ◽

Che B ◽

Wang N ◽

...

Keyword(s):

Cell Proliferation ◽

Pulmonary Hypertension ◽

Pulmonary Artery ◽

Western Blot ◽

Vascular Remodeling ◽

Pulmonary Artery Hypertension ◽

Phenotypic Switching ◽

Pulmonary Vascular Remodeling

Background and Objectives: Pulmonary Artery Hypertension (PAH) is considered as a malignant tumor in cardiovascular disease. Our previous study found that Calcium-Sensing Receptor (CaSR) is involved in pulmonary vascular remodeling in hypoxic pulmonary hypertension (HPH). However, the relationship of Pulmonary Artery Smooth Muscle Cell (PASMC) phenotypic switching, proliferation, and autophagy in CaSR-related HPH remain unclear. The purpose of this study was to detect the role of a CaSR antagonist, NPS2143, on the vascular remodeling by autophagy modulation under hypoxia. Methods: Hypoxic rat PAH model were simulated in vivo. Meanwhile, mean Pulmonary Artery Pressure (mPAP) was measured while RVI, WT%, and WA% indices were calculated. Immunohistochemistry and Western blot were used to detect phenotypic switching and cell proliferation in pulmonary arteriole. Cell viability was determined in vitro by CCK8 and cell cycle. Cell proliferation, phenotypic switching, autophagy level and PI3K/Akt/mTOR pathways were investigated in human PASMCs through mRNA or Western blot methods. Results: Rats with hypoxic-induced PAH had an increased mPAP, RVI, WT% and WA%. Moreover, expression of CaSR was significantly increased, followed by activation of autophagy (increased LC3b and decreased p62), phenotypic switching of PASMCs (reduced calponin, SMA-a and increased OPN) and pulmonary vascular remodeling. However, NPS2143 weakened these hypoxic effects. The results using hypoxic-induced human PASMCs confirmed that NPS2143 suppressed autophagy and reversed phenotypic switching in vitro by inhibiting PI3K/Akt/mTOR pathways. Conclusions: Our study demonstrates that NPS2143 was conducive to inhibit the proliferation and reverse phenotypic switching of PASMCs by regulating autophagy levels in HPH and vascular remodeling.

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Notch4 mediates vascular remodeling via ERK/JNK/P38 MAPK signaling pathways in hypoxic pulmonary hypertension

Respiratory Research ◽

10.1186/s12931-022-01927-9 ◽

2022 ◽

Vol 23 (1) ◽

Author(s):

Mingzhou Guo ◽

Mengzhe Zhang ◽

Xiaopei Cao ◽

Xiaoyu Fang ◽

Ke Li ◽

...

Keyword(s):

Pulmonary Hypertension ◽

Right Ventricular ◽

Signaling Pathways ◽

P38 Mapk ◽

Vascular Remodeling ◽

Cell Surface Receptor ◽

Cell Counting ◽

Pulmonary Vascular Remodeling ◽

Hypoxic Pulmonary Hypertension ◽

And Migration

Abstract Background Hypoxic pulmonary hypertension (HPH) is a chronic progressive advanced disorder pathologically characterized by pulmonary vascular remodeling. Notch4 as a cell surface receptor is critical for vascular development. However, little is known about the role and mechanism of Notch4 in the development of hypoxic vascular remodeling. Methods Lung tissue samples were collected to detect the expression of Notch4 from patients with HPH and matched controls. Human pulmonary artery smooth muscle cells (HPASMCs) were cultured in hypoxic and normoxic conditions. Real-time quantitative PCR and western blotting were used to examine the mRNA and protein levels of Notch4. HPASMCs were transfected with small interference RNA (siRNA) against Notch4 or Notch4 overexpression plasmid, respectively. Cell viability, cell proliferation, apoptosis, and migration were assessed using Cell Counting Kit-8, Edu, Annexin-V/PI, and Transwell assay. The interaction between Notch4 and ERK, JNK, P38 MAPK were analyzed by co-immunoprecipitation. Adeno-associated virus 1-mediated siRNA against Notch4 (AAV1-si-Notch4) was injected into the airways of hypoxic rats. Right ventricular systolic pressure (RVSP), right ventricular hypertrophy and pulmonary vascular remodeling were evaluated. Results In this study, we demonstrate that Notch4 is highly expressed in the media of pulmonary vascular and is upregulated in lung tissues from patients with HPH and HPH rats compared with control groups. In vitro, hypoxia induces the high expression of Delta-4 and Notch4 in HPASMCs. The increased expression of Notch4 promotes HPASMCs proliferation and migration and inhibits cells apoptosis via ERK, JNK, P38 signaling pathways. Furthermore, co-immunoprecipitation result elucidates the interaction between Notch4 and ERK/JNK/P38. In vivo, silencing Notch4 partly abolished the increase in RVSP and pulmonary vascular remodeling caused by hypoxia in HPH rats. Conclusions These findings reveal an important role of the Notch4-ERK/JNK/P38 MAPK axis in hypoxic pulmonary remodeling and provide a potential therapeutic target for patients with HPH.

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Fluorofenidone attenuates vascular remodeling in hypoxia-induced pulmonary hypertension of rats

Canadian Journal of Physiology and Pharmacology ◽

10.1139/cjpp-2013-0056 ◽

2014 ◽

Vol 92 (1) ◽

pp. 58-69 ◽

Cited By ~ 4

Author(s):

Xian-Wei Li ◽

Jie Du ◽

Gao-Yun Hu ◽

Chang-Ping Hu ◽

Dai Li ◽

...

Keyword(s):

Pulmonary Hypertension ◽

Vascular Remodeling ◽

Transforming Growth Factor ◽

Transforming Growth Factor Β ◽

Brdu Incorporation ◽

Pulmonary Vascular Remodeling ◽

Collagen Iii ◽

Pulmonary Arterial

Fluorofenidone (AKF-PD) is a novel pyridone derivate that targets transforming growth factor-β1 (TGF-β1) signaling. Previous studies have proven that AKF-PD functions as an antifibrotic agent in pulmonary fibrosis and renal fibrosis models. Activated TGF-β1 signaling is thought to be a major feature of pulmonary hypertension (PH). TGF-β1 exerts powerful pro-proliferation effects on pulmonary arterial smooth muscle cells (PASMCs), and hence, prompts vascular remodeling. This study is designed to investigate the effect of AKF-PD on vascular remodeling in a rat model of hypoxia-induced PH. PH was induced in rats by 4 weeks of hypoxia. The expression of TGF-β1, collagen I, and collagen III was analyzed by ELISA, immunohistochemistry, real-time PCR, or Western blot. Proliferation of cultured PASMCs was determined by the BrdU incorporation method and flow cytometry. The results showed that AKF-PD treatment (0.5 or 1.0 g·(kg body mass)·d−1) for 4 weeks attenuated pulmonary vascular remodeling and improved homodynamic parameters. TGF-β1 level was significantly down-regulated by AKF-PD both in vivo and in vitro. Furthermore, hypoxia- and TGF-β1-induced PASMC proliferation and collagen expression were both significantly suppressed by AKF-PD. These results suggest that AKF-PD ameliorates the progression of PH induced by hypoxia in rats through its regulation of TGF-β1 expression, PASMC proliferation, and the extracellular matrix.

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Adiponectin deficiency: a model of pulmonary hypertension associated with pulmonary vascular disease

AJP Lung Cellular and Molecular Physiology ◽

10.1152/ajplung.90599.2008 ◽

2009 ◽

Vol 297 (3) ◽

pp. L432-L438 ◽

Cited By ~ 76

Author(s):

Ross Summer ◽

Christopher A. Fiack ◽

Yasumasa Ikeda ◽

Kaori Sato ◽

Daniel Dwyer ◽

...

Keyword(s):

Pulmonary Hypertension ◽

Vascular Disease ◽

Pulmonary Vascular Disease ◽

Targeted Deletion ◽

Vascular Homeostasis ◽

Vascular Phenotype ◽

Luminal Side ◽

Pulmonary Arterial ◽

High Concentrations

Adiponectin (APN) is an adipocyte-derived factor that exists at high concentrations in serum and has anti-inflammatory and systemic vascular-protective properties. In this study, we investigated the role of APN in pulmonary vascular homeostasis. We found that APN localizes to the luminal side of blood vessels in lung and acts in vitro to block TNF-α-induced E-selectin upregulation in pulmonary artery endothelial cells. Targeted deletion of the APN gene in mice leads to a vascular phenotype in lung characterized by E-selectin upregulation and age-dependent increases in perivascular inflammatory cell infiltration and pulmonary arterial pressures. Taken together, these findings demonstrate an important role for APN in lung vascular homeostasis and suggest that APN-deficient states may contribute to the pathogenesis of inflammatory pulmonary vascular disease and to the development of pulmonary hypertension.

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Disrupted pulmonary vascular development and pulmonary hypertension in transgenic mice overexpressing transforming growth factor-α

AJP Lung Cellular and Molecular Physiology ◽

10.1152/ajplung.00045.2003 ◽

2003 ◽

Vol 285 (5) ◽

pp. L1046-L1054 ◽

Cited By ~ 46

Author(s):

Timothy D. Le Cras ◽

William D. Hardie ◽

Karen Fagan ◽

Jeffrey A. Whitsett ◽

Thomas R. Korfhagen

Keyword(s):

Pulmonary Hypertension ◽

Growth Factor ◽

Transgenic Mice ◽

Vascular Disease ◽

Vascular Remodeling ◽

Transforming Growth Factor ◽

Vascular Development ◽

Angiogenic Factor ◽

Pulmonary Vascular Disease ◽

Pulmonary Vascular Development

Pulmonary vascular disease plays a major role in morbidity and mortality in infant and adult lung diseases in which increased levels of transforming growth factor (TGF)-α and its receptor EGFR have been associated. The aim of this study was to determine whether overexpression of TGF-α disrupts pulmonary vascular development and causes pulmonary hypertension. Lung-specific expression of TGF-α in transgenic mice was driven with the human surfactant protein (SP)-C promoter. Pulmonary arteriograms and arterial counts show that pulmonary vascular development was severely disrupted in TGF-α mice. TGF-α mice developed severe pulmonary hypertension and vascular remodeling characterized by abnormally extensive muscularization of small pulmonary arteries. Pulmonary vascular development was significantly improved and pulmonary hypertension and vascular remodeling were prevented in bitransgenic mice expressing both TGF-α and a dominant-negative mutant EGF receptor under the control of the SP-C promoter. Vascular endothelial growth factor (VEGF-A), an important angiogenic factor produced by the distal epithelium, was decreased in the lungs of TGF-α adults and in the lungs of infant TGF-α mice before detectable abnormalities in pulmonary vascular development. Hence, overexpression of TGF-α caused severe pulmonary vascular disease, which was mediated through EGFR signaling in distal epithelial cells. Reductions in VEGF may contribute to the pathogenesis of pulmonary vascular disease in TGF-α mice.

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