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Article

O-GlcNAc Transferase Regulates Angiogenesis in Idiopathic Pulmonary Arterial Hypertension

1
Division of Pulmonary, Allergy and Critical Care Medicine, Department of Medicine, The University of Alabama at Birmingham, THT 422, 1720 2nd Ave S, Birmingham, AL 35294-0006, USA
2
Department of Inflammation & Immunity, Cleveland Clinic, 9500 Euclid Ave, Cleveland, OH 44195, USA
3
Respiratory Institute, Cleveland Clinic, 9500 Euclid Ave, Cleveland, OH 44195, USA
*
Author to whom correspondence should be addressed.
Int. J. Mol. Sci. 2019, 20(24), 6299; https://doi.org/10.3390/ijms20246299
Received: 20 November 2019 / Revised: 9 December 2019 / Accepted: 10 December 2019 / Published: 13 December 2019
(This article belongs to the Special Issue Metabolic Reprogramming in Health and Disease)
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. View Full-Text
Keywords: O-GlcNAc; IPAH; angiogenesis; OGT; VEGF O-GlcNAc; IPAH; angiogenesis; OGT; VEGF
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MDPI and ACS Style

Barnes, J.W.; Tian, L.; Krick, S.; Helton, E.S.; Denson, R.S.; Comhair, S.A.A.; Dweik, R.A. O-GlcNAc Transferase Regulates Angiogenesis in Idiopathic Pulmonary Arterial Hypertension. Int. J. Mol. Sci. 2019, 20, 6299. https://doi.org/10.3390/ijms20246299

AMA Style

Barnes JW, Tian L, Krick S, Helton ES, Denson RS, Comhair SAA, Dweik RA. O-GlcNAc Transferase Regulates Angiogenesis in Idiopathic Pulmonary Arterial Hypertension. International Journal of Molecular Sciences. 2019; 20(24):6299. https://doi.org/10.3390/ijms20246299

Chicago/Turabian Style

Barnes, Jarrod W., Liping Tian, Stefanie Krick, E. S. Helton, Rebecca S. Denson, Suzy A.A. Comhair, and Raed A. Dweik 2019. "O-GlcNAc Transferase Regulates Angiogenesis in Idiopathic Pulmonary Arterial Hypertension" International Journal of Molecular Sciences 20, no. 24: 6299. https://doi.org/10.3390/ijms20246299

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