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

Barnes, Jarrod W.; Kucera, Elif T.; Tian, Li; Mellor, Noël E.; Dvorina, Nina; Baldwin, W W; Aldred, Micheala A.; Farver, Carol; Comhair, Suzy; Aytekin, Metin; Dweik, Raed A.

doi:10.1165/rcmb.2015-0402oc

Cited by 22 publications

(22 citation statements)

References 73 publications

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“…In line with this, blocking OGT activity reduced de novo vasculogenesis in PAEC-embedded collagen implants within the dermis and peritoneum of humanized NODSCID mice. Altogether, these data, combined with our previous studies [26,28], suggest that increased OGT activity, through SP1/VEGF, may contribute to the vascular dysregulation in IPAH.…”

Section: Discussionsupporting

confidence: 73%

“…We and others have reported on the dysregulated glucose uptake/metabolism in PAH patients [19,23], animal models [25,55], and primary isolated cell cultures [23,26,28]. In our IPAH 3D culture models, the vascular spheroids had more spontaneous sprouts and increased sprout length compared to controls (Figure 3A,B).…”

Section: Discussionmentioning

confidence: 57%

“…We previously showed that increased glucose uptake facilitates pathways involved in the augmentation of glycosylation and cell proliferation [28] as well as cell migration [26] in IPAH PASMCs. To determine the role of dysregulated cellular glucose uptake on VEGF-A expression in these cells, we analyzed VEGF-A by Western blot under physiological and high glucose concentrations.…”

Section: The Ogt/o-glcnac Axis Regulates Vegf-a Expression By the O-gmentioning

confidence: 99%

“…Metabolic dysregulation has emerged as a major area of research in the pathobiology of IPAH [7,[18][19][20][21][22]. In particular, altered metabolic functions, including increased glucose uptake/metabolism, have been characterized in IPAH, including higher glycolytic rates than healthy individuals [19,[22][23][24][25][26][27][28]. Altered glucose metabolic flux into cells may result in glucose intolerance in IPAH patients.…”

Section: Introductionmentioning

confidence: 99%

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O-GlcNAc Transferase Regulates Angiogenesis in Idiopathic Pulmonary Arterial Hypertension

Barnes

Tian

Krick

et al. 2019

IJMS

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Idiopathic pulmonary arterial hypertension (IPAH) is considered a vasculopathy characterized by elevated pulmonary vascular resistance due to vasoconstriction and/or lung remodeling such as plexiform lesions, the hallmark of the PAH, as well as cell proliferation and vascular and angiogenic dysfunction. The serine/threonine hydroxyl-linked N-Acetylglucosamine (O-GlcNAc) transferase (OGT) has been shown to drive pulmonary arterial smooth muscle cell (PASMC) proliferation in IPAH. OGT is a cellular nutrient sensor that is essential in maintaining proper cell function through the regulation of cell signaling, proliferation, and metabolism. The aim of this study was to determine the role of OGT and O-GlcNAc in vascular and angiogenic dysfunction in IPAH. Primary isolated human control and IPAH patient PASMCs and pulmonary arterial endothelial cells (PAECs) were grown in the presence or absence of OGT inhibitors and subjected to biochemical assessments in monolayer cultures and tube formation assays, in vitro vascular sprouting 3D spheroid co-culture models, and de novo vascularization models in NODSCID mice. We showed that knockdown of OGT resulted in reduced vascular endothelial growth factor (VEGF) expression in IPAH primary isolated vascular cells. In addition, specificity protein 1 (SP1), a known stimulator of VEGF expression, was shown to have higher O-GlcNAc levels in IPAH compared to control at physiological (5 mM) and high (25 mM) glucose concentrations, and knockdown resulted in decreased VEGF protein levels. Furthermore, human IPAH PAECs demonstrated a significantly higher degree of capillary tube-like structures and increased length compared to control PAECs. Addition of an OGT inhibitor, OSMI-1, significantly reduced the number of tube-like structures and tube length similar to control levels. Assessment of vascular sprouting from an in vitro 3D spheroid co-culture model using IPAH and control PAEC/PASMCs and an in vivo vascularization model using control and PAEC-embedded collagen implants demonstrated higher vascularization in IPAH compared to control. Blocking OGT activity in these experiments, however, altered the vascular sprouting and de novo vascularization in IPAH similar to control levels when compared to controls. Our findings in this report are the first to describe a role for the OGT/O-GlcNAc axis in modulating VEGF expression and vascularization in IPAH. These findings provide greater insight into the potential role that altered glucose uptake and metabolism may have on the angiogenic process and the development of plexiform lesions. Therefore, we believe that the OGT/O-GlcNAc axis may be a potential therapeutic target for treating the angiogenic dysregulation that is present in IPAH.

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Section: Discussionsupporting

confidence: 73%

Section: Discussionmentioning

confidence: 57%

Section: The Ogt/o-glcnac Axis Regulates Vegf-a Expression By the O-gmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

O-GlcNAc Transferase Regulates Angiogenesis in Idiopathic Pulmonary Arterial Hypertension

Barnes

Tian

Krick

et al. 2019

IJMS

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“…Multiple phenotypes (other than vasoconstriction), such as dysregulated pulmonary vascular cell proliferation and remodeling, increased angiogenesis, and inflammation, contribute to the PAH disease process. 15 In addition, altered metabolism, including altered glucose uptake/metabolism, dyslipidemia, leptin dysregulation, and deficits in NO production, have been established in IPAH 13,[16][17][18][19] and may affect the disease processes. IPAH is remarkable because of its phenotypic and metabolic similarities to cancer.…”

Section: Introductionmentioning

confidence: 99%

Novel Methods in Pulmonary Hypertension Phenotyping in the Age of Precision Medicine (2015 Grover Conference Series)

et al. 2016

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Among pulmonary vascular diseases, pulmonary hypertension (PH) is the best studied and has been the focus of our work. The current classification of PH is based on a relatively simple combination of patient characteristics and hemodynamics. This leads to inherent limitations, including the inability to customize treatment and the lack of clarity from a more granular identification based on individual patient phenotypes. Accurate phenotyping of PH can be used in the clinic to select therapies and determine prognosis and in research to increase the homogeneity of study cohorts. Rapid advances in the mechanistic understanding of the disease, improved imaging methods, and innovative biomarkers now provide an opportunity to define novel PH phenotypes. We have recently shown that altered metabolism may affect nitric oxide levels and protein glycosylation, the peripheral circulation (which may provide insights into the response to therapy), and exhaled-breath analysis (which may be useful in disease evaluation). This review is based on a talk presented during the 2015 Grover Conference and highlights the relevant literature describing novel methods to phenotype pulmonary arterial hypertension patients by using approaches that involve the pulmonary and systemic (peripheral) vasculature. In particular, abnormalities in metabolism, the pulmonary and peripheral circulation, and exhaled breath in PH may help identify phenotypes that can be the basis for a precision-medicine approach to PH management. These approaches may also have a broader scope and may contribute to a better understanding of other diseases, such as asthma, diabetes, and cancer.

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

Chen

Shen

Zhu

et al. 2019

Journal Cellular Physiology

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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.

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

Cited by 22 publications

References 73 publications

O-GlcNAc Transferase Regulates Angiogenesis in Idiopathic Pulmonary Arterial Hypertension

O-GlcNAc Transferase Regulates Angiogenesis in Idiopathic Pulmonary Arterial Hypertension

Novel Methods in Pulmonary Hypertension Phenotyping in the Age of Precision Medicine (2015 Grover Conference Series)

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

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