Notch3/VEGF-A axis is involved in TAT-mediated proliferation of pulmonary artery smooth muscle cells: Implications for HIV-associated PAH

Guo, Ming‐Lei; Kook, Yeon Hee; Shannon, Callen E.; Buch, Shilpa

doi:10.1038/s41420-018-0087-9

Cited by 13 publications

(10 citation statements)

References 48 publications

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“…Notch signaling participates in multiple physiological vascular processes, such as proliferation and apoptosis ( 56 ). Notch-1 is associated with PA-EC proliferation ( 57 ), while Notch-3 is highly expressed in PA-SMCs and promotes PA-SMC proliferation via vascular endothelial growth factor ( 58 ). As miR-30d-5p was associated with PA-SMC proliferation and apoptosis, we hypothesized an association between miR-30d-5p and Notch-3.…”

Section: Discussionmentioning

confidence: 99%

Expression of the microRNA‑30 family in pulmonary arterial hypertension and the role of microRNA‑30d‑5p in the regulation of pulmonary arterial smooth muscle cell toxicity and apoptosis

Liu

et al. 2021

Exp Ther Med

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The biological processes of pulmonary artery vascular smooth muscle cells (PA-SMCs) and pulmonary artery endothelial cells in pulmonary arterial hypertension (PAH) are generally abnormal, with increased levels of proliferation and reduced levels of apoptosis. Although microRNAs (miRNAs/miRs) participate in a number of biological processes in a variety of diseases, such as tumors and infections, studies on the association between miRNAs and PAH are limited. In the present study, blood samples were collected from 6 patients with patent ductus arteriosus. The experimental group included 3 patients with severe PAH, while the control group included 3 patients without PAH. Microarray technology was used to detect the presence of any associated miRNAs. Moreover, a rat PAH model was established via left lung resection followed by monocrotaline injection, involving a total of 8 rats in the PAH group and 8 untreated rat in the control group. Reverse transcription-quantitative PCR was performed to verify the expression levels of the miR-30 family in the animal model. miR-30d-5p mimics and anti-miR-30d-5p were transfected into primary cultured PA-SMCs. Levels of cytotoxicity and cell apoptosis were examined, and Notch-3 expression levels were studied using western blotting. The results of the present study demonstrated that miR-30d-5p expression was downregulated in both patient blood and animal models of the PAH group compared with control groups. In primary cultured PA-SMCs, overexpression of miR-30d-5p attenuated the platelet-derived growth factor-induced toxicity of PA-SMCs, while knockdown of miR-30d-5p resulted in the increased toxicity of PA-SMCs compared with control group.The apoptosis rate of PA-SMCs increased with the overexpression of miR-30d-5p compared with control group. Moreover, the expression levels of Notch-3 in the miR-30d-5p group were significantly reduced compared with the anti-miR-30d-5p and miR-NC groups. In total, 10 circulating miRNAs that may be associated with PAH were discovered in the present study. Moreover, the expression of the miR-30 family was verified in animal models in vivo, and seven miRNAs in this family were discovered that may be associated with PAH. Additionally, miR-30d-5p was downregulated in both patients with PAH and animal models compared with control groups. Thus, the results of the present study demonstrated that the regulatory mechanism underlying PA-SMCs may be via the Notch-3 signaling pathway.

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Section: Discussionmentioning

confidence: 99%

Expression of the microRNA‑30 family in pulmonary arterial hypertension and the role of microRNA‑30d‑5p in the regulation of pulmonary arterial smooth muscle cell toxicity and apoptosis

Liu

et al. 2021

Exp Ther Med

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“…Extracellular HIV-Tat can bind integrins and vascular endothelial growth factor receptors via the c-terminal domain, containing an Arg-Gly-Asp (RGD) sequence and/or a basic domain 127 , 128 . Tat, on binding to these receptors, triggers signaling pathways that affect diverse processes, culminating in the pathogenesis of several HIV-associated co-morbidities – ranging from pulmonary hypertension to cognitive abnormalities 129 , 130 . Previous studies suggest that Tat acts as a proto-cytokine, which modulates the key functions of various cell types, including endothelial cells (ECs) as well as smooth muscle cells (SMC) 76 .…”

Section: Risk Factors That Complicate Hiv-phmentioning

confidence: 99%

Impact of human immunodeficiency virus on pulmonary vascular disease

Kumar

Mahajan

Salazar

et al. 2021

gcsp

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With the advent of anti-retroviral therapy, non-AIDS-related comorbidities have increased in people living with HIV. Among these comorbidities, pulmonary hypertension (PH) is one of the most common causes of morbidity and mortality. Although chronic HIV-1 infection is independently associated with the development of pulmonary arterial hypertension, PH in people living with HIV may also be the outcome of various co-morbidities commonly observed in these individuals including chronic obstructive pulmonary disease, left heart disease and co-infections. In addition, the association of these co-morbidities and other risk factors, such as illicit drug use, can exacerbate the development of pulmonary vascular disease. This review will focus on these complex interactions contributing to PH development and exacerbation in HIV patients. We also examine the interactions of HIV proteins, including Nef, Tat, and gp120 in the pulmonary vasculature and how these proteins alter the endothelial and smooth muscle function by transforming them into susceptible PH phenotype. The review also discusses the available infectious and non-infectious animal models to study HIV- associated PAH, highlighting the advantages and disadvantages of each model, along with their ability to mimic the clinical manifestations of HIV-PAH.

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“…By binding its receptor VEGFR2, VEGFA regulates angiogenesis and vascular permeability through promoting the proliferation and survival of ECs, where the downstream signaling pathways include phosphoinositide 3 kinase (PI3K)/Akt, focal adhesion kinase (FAK), Rho family GTPases, nitric oxide (NO), and p38 mitogen−activated protein kinase (MAPK) (Claesson-Welsh and Welsh, 2013). Moreover, a recent study showed HIV protein transactivator of transcription (TAT) stimulated the proliferation of pulmonary artery SMCs (PASMCs) through increasing the expression VEGFA, and may be a potential therapeutic target for the treatment of HIV-associated PAH (Guo et al, 2018). SIRT1 is a NAD + -dependent deacetylase shown to play important roles in angiogenesis signaling both in vitro and in mice through controlling the acetylation of the forkhead transcription factor, Foxo1, which is highly expressed in ECs and mediates the expression of angiopoietin 2 (Ang2) (Potente et al, 2005(Potente et al, , 2007.…”

Section: Discussionmentioning

confidence: 99%

Hypoxia-Inducible Factor 2-Alpha Mediated Gene Sets Differentiate Pulmonary Arterial Hypertension

Zhu

Zhao

et al. 2021

Front. Cell Dev. Biol.

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ObjectivesHIF2α is of vital importance in the regulation of endothelial dysfunction, cell proliferation, migration, and pulmonary vascular remodeling in pulmonary hypertension. Our previous studies demonstrated that conditional and inducible deletion of HIF2α in mouse lung endothelial cells, dramatically protected the mice against vascular remodeling and the development of pulmonary arterial hypertension (PAH). Here, we provide a novel transcriptome insight into the impact of HIF2α in PAH pathogenesis and the potential to use HIF2α-mediated gene sets to differentiate PAH human subjects.MethodsUsing transcriptome data, we first tapped the value of the difference in gene expression profile between wild type (WT) and Hif2a knockdown (KD) cell lines. We considered the deregulated genes between WT and Hif2a-KD cells as HIF2α influenced genes. By examining the lung tissue transcriptome data set with nine controls and eight PAH patients, we evaluated the HIF2α regulatory network in PAH pathogenesis to further determine the identification ability of HIF2α-mediated gene sets in human PAH subjects. On the other hand, using peripheral blood mononuclear cells (PBMCs) transcriptome data from PAH patients and healthy controls, we further validated the potential of the HIF2α-mediated PBMC gene sets as a possible diagnostic tool for PAH. To verify the ability of HIF2α-mediated gene sets for the identification of PAH, endothelial cell-specific Phd2 knockout mice with spontaneous pulmonary hypertension were used for reverse validation experiments.Results19 identified GO biological process terms were significantly correlated with the genes down-regulated in Hif2a-KD cells, all of which are strongly related to the PAH pathogenesis. We further assessed the discriminative power of these HIF2α-mediated gene sets in PAH human subjects. We found that the expression profile of the HIF2α-mediated gene sets in lung tissues and PBMCs were differentiated both between controls and PAH patients. Further, a significant positive correlation was observed between hypoxia and Phd2 deficiency mediated gene set expression profiles. As expected, 7 of the 19 significantly down-regulated GO terms in Hif2a-KD cells were found to overlap with the up-regulated GO gene sets in Phd2EC–/– mice compared to WT controls, suggesting opposing effects of HIF2α and PHD2 on PAH pathogenesis.ConclusionHIF2α-mediated gene sets may be used to differentiate pulmonary arterial hypertension.

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Notch3/VEGF-A axis is involved in TAT-mediated proliferation of pulmonary artery smooth muscle cells: Implications for HIV-associated PAH

Cited by 13 publications

References 48 publications

Expression of the microRNA‑30 family in pulmonary arterial hypertension and the role of microRNA‑30d‑5p in the regulation of pulmonary arterial smooth muscle cell toxicity and apoptosis

Expression of the microRNA‑30 family in pulmonary arterial hypertension and the role of microRNA‑30d‑5p in the regulation of pulmonary arterial smooth muscle cell toxicity and apoptosis

Impact of human immunodeficiency virus on pulmonary vascular disease

Hypoxia-Inducible Factor 2-Alpha Mediated Gene Sets Differentiate Pulmonary Arterial Hypertension

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