scholarly journals O-GlcNAc Transferase Regulates Angiogenesis in Idiopathic Pulmonary Arterial Hypertension

2019 ◽  
Vol 20 (24) ◽  
pp. 6299 ◽  
Author(s):  
Jarrod W. Barnes ◽  
Liping Tian ◽  
Stefanie Krick ◽  
E. Scott Helton ◽  
Rebecca S. Denson ◽  
...  
Keyword(s):  
Pulmonary Arterial Hypertension ◽  
Arterial Hypertension ◽  
De Novo ◽  
Idiopathic Pulmonary Arterial Hypertension ◽  
Tube Length ◽  
Vegf Expression ◽  
Plexiform Lesions ◽  
Pulmonary Arterial ◽  
Glcnac Transferase

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.

scholarly journals High levels of hyaluronan in idiopathic pulmonary arterial hypertension

2008 ◽  
Vol 295 (5) ◽  
pp. L789-L799 ◽  
Author(s):  
Metin Aytekin ◽  
Suzy A. A. Comhair ◽  
Carol de la Motte ◽  
Sudip K. Bandyopadhyay ◽  
Carol F. Farver ◽  
...  
Keyword(s):  
Pulmonary Arterial Hypertension ◽  
Arterial Hypertension ◽  
Mononuclear Cells ◽  
Specific Binding ◽  
Idiopathic Pulmonary Arterial Hypertension ◽  
Relative Expression ◽  
Pulmonary Arterial ◽  
Ha Synthase ◽  
Hyaluronidase 2

Hyaluronan (HA), a large glycosaminoglycan found in the ECM, has major roles in lung and vascular biology and disease. However, its role in idiopathic pulmonary arterial hypertension (IPAH) is unknown. We hypothesized that HA metabolism is abnormal in IPAH. We measured the plasma levels of HA in IPAH and healthy individuals. We also evaluated HA synthesis and the expression of HA synthases and hyaluronidases in pulmonary artery smooth muscle cells (PASMCs) from explanted lungs. Plasma HA levels were markedly elevated in IPAH compared with controls [HA (ng/ml, mean ± SD): IPAH 325 ± 80, control 28 ± 9; P = 0.02]. In vitro, unstimulated IPAH PASMCs produced high levels of HA compared with control cells [HA in supernatant (μg/ml, mean ± SD): IPAH 12 ± 2, controls 6 ± 0.9; P = 0.04]. HA levels were also higher in IPAH PASMC lysates. The increased HA was biologically relevant as shown by tissue staining and increased HA-specific binding of mononuclear cells to IPAH compared with control PASMCs [number of bound cells × 104 (mean ± SD): IPAH 9.5 ± 3, control 3.0 ± 1; P = 0.01]. This binding was abrogated by the addition of hyaluronidase. HA synthase-2 and hyaluronidase-2 were predominant in control and IPAH PASMCs. Interestingly, the expressions of HA synthase-2 and hyaluronidase-2 were ∼2-fold lower in IPAH compared with controls [HA synthase-2 (relative expression mean ± SE): IPAH 4.3 ± 0.02, control 7.8 ± 0.1; P = 0.0004; hyaluronidase-2 (relative expression mean ± SE): IPAH 4.2 ± 0.06, control 7.6 ± 0.07; P = 0.008]. Thus patients with IPAH have higher circulating levels of HA, and PASMCs derived from IPAH lungs produce more HA compared with controls. This is associated with increased tissue levels and increased binding of inflammatory cells suggesting a role for HA in remodeling and inflammation in IPAH.

scholarly journals Skeletal muscle mitochondrial oxidative phosphorylation function in idiopathic pulmonary arterial hypertension: in vivo and in vitro study

2018 ◽  
Vol 8 (2) ◽  
pp. 204589401876829 ◽  
Author(s):  
Sasiharan Sithamparanathan ◽  
Mariana C. Rocha ◽  
Jehill D. Parikh ◽  
Karolina A. Rygiel ◽  
Gavin Falkous ◽  
...  
Keyword(s):  
Skeletal Muscle ◽  
Pulmonary Arterial Hypertension ◽  
Oxidative Phosphorylation ◽  
Arterial Hypertension ◽  
Idiopathic Pulmonary Arterial Hypertension ◽  
Mitochondrial Oxidative Phosphorylation ◽  
Pulmonary Vessels ◽  
Pulmonary Arterial

Mitochondrial dysfunction within the pulmonary vessels has been shown to contribute to the pathology of idiopathic pulmonary arterial hypertension (IPAH). We investigated the hypothesis of whether impaired exercise capacity observed in IPAH patients is in part due to primary mitochondrial oxidative phosphorylation (OXPHOS) dysfunction in skeletal muscle. This could lead to potentially new avenues of treatment beyond targeting the pulmonary vessels. Nine clinically stable participants with IPAH underwent cardiopulmonary exercise testing, in vivo and in vitro assessment of mitochondrial function by 31P-magnetic resonance spectroscopy (31P-MRS) and laboratory muscle biopsy analysis. 31P-MRS showed abnormal skeletal muscle bioenergetics with prolonged recovery times of phosphocreatine and abnormal muscle pH handling. Histochemistry and quadruple immunofluorescence performed on muscle biopsies showed normal function and subunit protein abundance of the complexes within the OXPHOS system. Our findings suggest that there is no primary mitochondrial OXPHOS dysfunction but raises the possibility of impaired oxygen delivery to the mitochondria affecting skeletal muscle bioenergetics during exercise.

Hyperproliferative apoptosis-resistant endothelial cells in idiopathic pulmonary arterial hypertension

2007 ◽  
Vol 293 (3) ◽  
pp. L548-L554 ◽  
Author(s):  
Fares A. Masri ◽  
Weiling Xu ◽  
Suzy A. A. Comhair ◽  
Kewal Asosingh ◽  
Michelle Koo ◽  
...  
Keyword(s):  
Endothelial Cells ◽  
Pulmonary Arterial Hypertension ◽  
Arterial Hypertension ◽  
Idiopathic Pulmonary Arterial Hypertension ◽  
Janus Kinase ◽  
Vascular Lesions ◽  
Nuclear Antigen ◽  
Pulmonary Arterial

Idiopathic pulmonary arterial hypertension (IPAH) is characterized by plexiform vascular lesions, which are hypothesized to arise from deregulated growth of pulmonary artery endothelial cells (PAEC). Here, functional and molecular differences among PAEC derived from IPAH and control human lungs were evaluated. Compared with control cells, IPAH PAEC had greater cell numbers in response to growth factors in culture due to increased proliferation as determined by bromodeoxyuridine incorporation and Ki67 nuclear antigen expression and decreased apoptosis as determined by caspase-3 activation and TdT-mediated dUTP nick end labeling assay. IPAH cells had greater migration than control cells but less organized tube formation in in vitro angiogenesis assay. Persistent activation of signal transducer and activator of transcription 3 (STAT3), a regulator of cell survival and angiogenesis, and increased expression of its downstream prosurvival target, Mcl-1, were identified in IPAH PAEC. A Janus kinase (JAK) selective inhibitor reduced STAT3 activation and blocked proliferation of IPAH cells. Phosphorylated STAT3 was detected in endothelial cells of IPAH lesions in vivo, suggesting that STAT3 activation plays a role in the proliferative pulmonary vascular lesions in IPAH lungs.

CD44 expression in plexiform lesions of idiopathic pulmonary arterial hypertension

2012 ◽  
Vol 62 (4) ◽  
pp. 219-225 ◽  
Author(s):  
Keiko Ohta-Ogo ◽  
Hiroyuki Hao ◽  
Hatsue Ishibashi-Ueda ◽  
Seiichi Hirota ◽  
Kazufumi Nakamura ◽  
...  
Keyword(s):  
Pulmonary Arterial Hypertension ◽  
Arterial Hypertension ◽  
Idiopathic Pulmonary Arterial Hypertension ◽  
Cd44 Expression ◽  
Plexiform Lesions ◽  
Pulmonary Arterial

scholarly journals Abnormal platelet aggregation in idiopathic pulmonary arterial hypertension: role of nitric oxide

2012 ◽  
Vol 302 (6) ◽  
pp. L512-L520 ◽  
Author(s):  
Metin Aytekin ◽  
Kulwant S. Aulak ◽  
Sarah Haserodt ◽  
Ritu Chakravarti ◽  
Joseph Cody ◽  
...  
Keyword(s):  
Nitric Oxide ◽  
Pulmonary Arterial Hypertension ◽  
Arterial Hypertension ◽  
Platelet Function ◽  
Cellular Proliferation ◽  
Idiopathic Pulmonary Arterial Hypertension ◽  
Original Research ◽  
No Production ◽  
Pulmonary Arterial

Idiopathic pulmonary arterial hypertension (IPAH) is a rare and progressive disease. Several processes are believed to lead to the fatal progressive pulmonary arterial narrowing seen in IPAH including vasoconstriction, cellular proliferation inflammation, vascular remodeling, abnormalities in the lung matrix, and in situ thrombosis. Nitric oxide (NO) produced by NO synthases (NOS) is a potent vasodilator and plays important roles in many other processes including platelet function. Reduced NO levels in patients with IPAH are known to contribute to the development of pulmonary hypertension and its complications. Platelet defects have been implied in IPAH, but original research supporting this hypothesis has been limited. Normal platelets are known to have NOS activity, but little is known about NOS expression and NO production by platelets in patients with IPAH. Here we characterized the phenotype of the platelets in IPAH and show a defect in their ability to be activated in vitro by thrombin receptor activating protein but not adenosine diphosphate. We also show that endothelial NOS (eNOS) levels in these platelets are reduced and demonstrate that NO is an important regulator of platelet function. Thus reduced levels of eNOS in platelets could impact their ability to regulate their own function appropriately.

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