scholarly journals Nitrite Potently Inhibits Hypoxic and Inflammatory Pulmonary Arterial Hypertension and Smooth Muscle Proliferation via Xanthine Oxidoreductase–Dependent Nitric Oxide Generation

Circulation ◽  
2010 ◽  
Vol 121 (1) ◽  
pp. 98-109 ◽  
Author(s):  
Brian S. Zuckerbraun ◽  
Sruti Shiva ◽  
Emeka Ifedigbo ◽  
Michael A. Mathier ◽  
Kevin P. Mollen ◽  
...  
Keyword(s):  
Nitric Oxide ◽  
Smooth Muscle ◽  
Pulmonary Arterial Hypertension ◽  
Arterial Hypertension ◽  
Xanthine Oxidoreductase ◽  
Smooth Muscle Proliferation ◽  
Pulmonary Arterial

scholarly journals Dependence of Golgi apparatus integrity on nitric oxide in vascular cells: implications in pulmonary arterial hypertension

2011 ◽  
Vol 300 (4) ◽  
pp. H1141-H1158 ◽  
Author(s):  
Jason E. Lee ◽  
Kirit Patel ◽  
Sharilyn Almodóvar ◽  
Rubin M. Tuder ◽  
Sonia C. Flores ◽  
...  
Keyword(s):  
Nitric Oxide ◽  
Smooth Muscle ◽  
Pulmonary Arterial Hypertension ◽  
Golgi Apparatus ◽  
Arterial Hypertension ◽  
Vascular Cells ◽  
Immunodeficiency Virus ◽  
Pulmonary Arterial ◽  
Golgi Fragmentation ◽  
In Cells

Although reduced bioavailability of nitric oxide (NO) has been implicated in the pathogenesis of pulmonary arterial hypertension (PAH), its consequences on organellar structure and function within vascular cells is largely unexplored. We investigated the effect of reduced NO on the structure of the Golgi apparatus as assayed by giantin or GM130 immunofluorescence in human pulmonary arterial endothelial (HPAECs) and smooth muscle (HPASMCs) cells, bovine PAECs, and human EA.hy926 endothelial cells. Golgi structure was also investigated in cells in tissue sections of pulmonary vascular lesions in idiopathic PAH (IPAH) and in macaques infected with a chimeric simian immunodeficiency virus containing the human immunodeficiency virus (HIV)- nef gene (SHIV- nef) with subcellular three-dimensional (3D) immunoimaging. Compounds with NO scavenging activity including 2-(4-carboxyphenyl)-4,4,5,5-tetramethylimidazoline-1-oxyl-3-oxide (c-PTIO), methylene blue, N-acetylcysteine, and hemoglobin markedly fragmented the Golgi in all cell types evaluated as did monocrotaline pyrrole, while LY-83583, sildenafil, fasudil, Y-27632, Tiron, Tempol, or H2O2did not. Golgi fragmentation by NO scavengers was inhibited by diethylamine NONOate, was evident in HPAECs after selective knockdown of endothelial nitric oxide synthase using small interfering RNA (siRNA), was independent of microtubule organization, required the GTPase dynamin 2, and was accompanied by depletion of α-soluble N-ethylmaleimide-sensitive factor (NSF) acceptor protein (α-SNAP) from Golgi membranes and codispersal of the SNAP receptor (SNARE) Vti1a with giantin. Golgi fragmentation was confirmed in endothelial and smooth muscle cells in pulmonary arterial lesions in IPAH and the SHIV- nef-infected macaque with subcellular 3D immunoimaging. In SHIV- nef-infected macaques Golgi fragmentation was observed in cells containing HIV-nef-bearing endosomes. The observed Golgi fragmentation suggests that NO plays a significant role in modulating global protein trafficking patterns that contribute to changes in the cell surface landscape and functional signaling in vascular cells.

scholarly journals Hyperuricemia impaired nitric oxide bioavailablity and deteriorated pulmonary arterial hypertension via a uric acid transporter, URATv1 in xanthine oxidoreductase (XOR)-independent manner

2020 ◽  
Vol 41 (Supplement_2) ◽  
Author(s):  
T Watanabe ◽  
K Abe ◽  
M Ishikawa ◽  
T Ishikawa ◽  
S Imakiire ◽  
...  
Keyword(s):  
Nitric Oxide ◽  
Uric Acid ◽  
Pulmonary Arterial Hypertension ◽  
Arterial Hypertension ◽  
Isometric Tension ◽  
Xanthine Oxidoreductase ◽  
Independent Manner ◽  
Perfused Lung ◽  
Pulmonary Arterial

Abstract Background Hyperuricemia occurs in approximately 80% in patients with pulmonary arterial hypertension (PAH) and is positively correlated with pulmonary arterial pressure (PAP). It has been reported that uric acid (UA) reduced endothelium derived nitric oxide (NO) production in porcine pulmonary arterial endothelial cells (PAEC). However, the effects of UA and xanthine oxidoreductase (XOR), catalytic enzyme of UA, on the development of PAH have not been fully elucidated. Purpose We examined the followings; (1) the effects of hyperuricemia on the endothelial function and the development of PAH in rats (2) the therapeutic effects of UA transporter inhibitor on PAH in rats, and (3) the role of XOR in PAH in mice. Methods We used normal and 5-wk Sugen5416/Hypoxia/Normoxia-exposed (SU/Hx/Nx) rats. Gene expression levels of URATv1, a UA transporter, were measured by RT-PCR. We determined the isometric tension of PA rings isolated from normal rats. The study with the isolated perfused lung preparation was performed in SU/HX/Nx rats. To investigate the chronic effect of UA on the development of PAH, hyperuricemia was induced by the administration of 2% oxonic acid (OA) in diet for 6-wk. Benzbromarone (BBR, 10mg/kg/day, diet, from weeks 0 to 5), a URATv1 transporter inhibitor, was administered in the SU/Hx/Nx-rats with or without 2%OA. To examine the role of XOR in PAH, XOR+/− and wild type (WT) mice were exposed to 3-wk Nx or Hx (10% O2). Results The mRNA of URATv1 was detected in the normal lungs. Isometric tension study showed that UA (8 mg/dl) inhibited acetylcholine-induced vasorelaxation. In perfused lung preparations, UA acutely increased estimated PVR in a dose-dependent manner (1.6–16.0mg/dl) with reducing cGMP levels in the lungs. BBR significantly attenuated the pressor response to UA. UA levels in the plasma and the lung tissues were significantly elevated in SU/Hx/Nx-rats with 2%OA (normal vs. vehicle vs. 2%OA, plasma: 0.24±0.01 vs. 0.80±0.14 and 1.44±0.17 mg/dl; lung tissues: 68±3 vs. 142±3 and 377±46 pmol/g tissue). They exhibited further elevation of right ventricle systolic pressure (RVSP) (31±2 vs. 72±6 vs. 101±3 mmHg) and Ea (a marker of RV afterload) (0.24±0.04 vs. 0.97±0.15 vs. 2.36±0.49 mmHg/μL) with the exacerbation of occlusive lesions of PAs. BBR had no changes in the UA levels in the plasma (1.93±0.30 mg/dL), but significantly reduced the UA levels in the lung tissues (101±10 pmol/g tissue) and attenuated the increase in RVSP (53±8mmHg) and Ea (0.21±0.05 mmHg/mL) in the SU/Hx/Nx-rats with 2%OA. On the other hand, BBR had no effects on RVSP (76±7 mmHg) and Ea (0.91±0.15 mmHg/mL) in the SU/Hx/Nx-rats without 2%OA. There were no significant differences in RVSP between XOR+/− mice with Hx and WT with Hx (26±2 vs. 26±2 mmHg). Conclusions Hyperuricemia itself impairs endothelial function and deteriorates PAH via URATv1 in a XOR-independent manner. UA can be a novel therapeutic target for PAH. Funding Acknowledgement Type of funding source: None

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