Nitro-Oleic Acid Prevents Hypoxia- and Asymmetric Dimethylarginine-Induced Pulmonary Endothelial Dysfunction

Abstract

Rationale Pulmonary hypertension (PH) represents a serious health complication accompanied with hypoxic conditions, elevated levels of asymmetric dimethylarginine (ADMA), and overall dysfunction of pulmonary vascular endothelium. Since the prevention strategies for treatment of PH remain largely unknown, our study aimed to explore the effect of nitro-oleic acid (OA-NO2), an exemplary nitro-fatty acid (NO2-FA), in human pulmonary artery endothelial cells (HPAEC) under the influence of hypoxia or ADMA. Methods HPAEC were treated with OA-NO2 in the absence or presence of hypoxia and ADMA. The production of nitric oxide (NO) and interleukin-6 (IL-6) was monitored using the Griess method and ELISA, respectively. The expression or activation of different proteins (signal transducer and activator of transcription 3, STAT3; hypoxia inducible factor 1α, HIF-1α; endothelial nitric oxide synthase, eNOS; intercellular adhesion molecule-1, ICAM-1) was assessed by the Western blot technique. Results We discovered that OA-NO2 prevents development of endothelial dysfunction induced by either hypoxia or ADMA. OA-NO2 preserves normal cellular functions in HPAEC by increasing NO production and eNOS expression. Additionally, OA-NO2 inhibits IL-6 production as well as ICAM-1 expression, elevated by hypoxia and ADMA. Importantly, the effect of OA-NO2 is accompanied by prevention of STAT3 activation and HIF-1α stabilization. Conclusion In summary, OA-NO2 eliminates the manifestation of hypoxia- and ADMA-mediated endothelial dysfunction in HPAEC via the STAT3/HIF-1α cascade. Importantly, our study is bringing a new perspective on molecular mechanisms of NO2-FAs action in pulmonary endothelial dysfunction, which represents a causal link in progression of PH.

Profile of Arachidonic Acid-Derived Inflammatory Markers and Its Modulation by Nitro-Oleic Acid in an Inherited Model of Amyotrophic Lateral Sclerosis

“…Several work in the literature demonstrate the pluripotent activity of NO 2 -FA, some of them related to NO 2 -OA ( Kelley et al, 2008 ; Liu et al, 2008 , 2013 ; Kansanen et al, 2009 ; Wang et al, 2010a , b ; Sculptoreanu et al, 2010 ; Artim et al, 2011 ; Klinke et al, 2014 ; Zhang et al, 2014 ; Ambrozova et al, 2016 ; Koudelka et al, 2016 ). It has been demonstrated their capacity to modulate inflammatory processes, e.g., induction of HO-1 ( Ferreira et al, 2009 ; Kansanen et al, 2011 , 2012 ; Diaz-Amarilla et al, 2016 ) or reduction of pro-inflammatory mediators by inhibiting enzyme activities, e.g., inhibition of 5-LOX in neutrophils ( Awwad et al, 2014 ).…”

Novel gene regulatory networks identified in response to nitro-conjugated linoleic acid in human endothelial cells

“…4, C and D), especially the pathways related to the response to hypoxia, fluid shear stress, and to atherosclerosis. In ECs, NO 2 -FAs enhance NO bioavailability (29,31), inhibit inflammation (21,57) and oxidative inflammatory reactions (19,25,27,29,67), enhance the heat shock response (25), and promote angiogenesis (45). NO 2 -OA and NO 2 -LA inhibit NF-B activation and TNF-␣-stimulated proinflamma-tory cytokine expression (10,21).…”

miR-190a-5p participates in the regulation of hypoxia-induced pulmonary hypertension by targeting KLF15 and can serve as a biomarker of diagnosis and prognosis in chronic obstructive pulmonary disease complicated with pulmonary hypertension

“… 35 , 36 Hypoxia leads to a decrease in the expression of eNOS in vascular ECs. 37 , 38 However, several studies have indicated that the gene expression, protein content, and activity of lung eNOS are high in mice with chronic hypoxic PH. 39 – 41 These findings are consistent with our observations.…”