Abstract
Hypoxia plays a crucial role in the pathogenesis of cardiovascular diseases. Mitochondrial enzyme arginase type II (Arg-II) is reported to lead to endothelial dysfunction and enhance the expression of endothelial inflammatory adhesion molecules such as intercellular adhesion molecule-1 (ICAM-1) and vascular cell adhesion molecule-1 (VCAM-1). In this study, we investigate the role of Arg-II in hypoxia-induced endothelial activation and the potential underlying mechanisms. Exposure of the human endothelial cells to hypoxia induced a time-dependent increase in Arg-II, HIF1α, HIF2α, and ICAM-1 protein level, whereas no change in the protein level of VCAM-1 and E-selectin was observed. Similar effects were obtained in cells treated with a hypoxia mimetic Dimethyloxaloylglycine (DMOG). Silencing HIF1α, but not HIF2α, reversed hypoxia-induced upregulation of Arg-II. Moreover, silencing Arg-II prevented the ICAM-1 upregulation induced by hypoxia or DMOG. Furthermore, the endothelial cells incubated under hypoxic condition or treated with DMOG or hypoxia enhanced monocyte adhesion, which was inhibited by silencing Arg-II. Lastly, silencing Arg-II prevented hypoxia-induced mitochondrial superoxide production in endothelial cells, and hypoxia-induced ICAM-1 upregulation was reversed by mitochondrial electron transport inhibitor rotenone. These data demonstrate that hypoxia enhances ICAM-1 protein level and monocyte-endothelial interaction through HIF1α-mediated increase in Arg-II protein level on leading to increased mitochondrial reactive oxygen species production. These effects of hypoxia on endothelial cells may play a key role in cardiovascular diseases. Our results suggest that Arg-II could be a promising therapeutic target to prevent hypoxia-induced vascular damage/dysfunction.
Highlights
Chronic hypoxia plays a key role in the pathophysiology of cardiovascular diseases including hypertension, atherosclerosis, and heart failure (Hulten and Levin, 2009; Bosc et al, 2010; Abe et al, 2017)
Missouri, USA); antiVCAM-1 (12367S) was from Cell Signaling Technology (Danvers, USA); mouse antibody against HIF1α (610958) was from BD Biosciences (New Jersey, USA); rabbit antibody against HIF2α (PAB12124) was from Abnova (Taipei, Taiwan); Alexa fluor 680 conjugated anti-mouse IgG (A21057), MitoSox, and Hoechst 33342 were from Invitrogen/Thermo Fisher Scientific (Waltham, MA USA); IRDye 800-conjugated anti-rabbit IgG (926-32211) was from LI-COR Bioconcept (Lincoln, USA); endothelial cell growth supplement (ECGS) pack was from PromoCell GmbH (Heidelberg, Germany); and all cell culture media and materials were from Gibco/Thermo Fisher Scientific (Waltham, MA USA)
The results suggest a role of Hypoxia-inducible factors (HIFs) in upregulation of Arg-II protein level in the endothelial cells under hypoxic condition
Summary
Chronic hypoxia plays a key role in the pathophysiology of cardiovascular diseases including hypertension, atherosclerosis, and heart failure (Hulten and Levin, 2009; Bosc et al, 2010; Abe et al, 2017). Studies show that Arg-II is upregulated in response to hypoxia in endothelial cells, which contributes to hypoxia-triggered reduction in NO generation and hypertension (Krotova et al, 2010; Prieto et al, 2011; Cowburn et al, 2016; Pandey et al, 2018) This hypoxia-induced upregulation of Arg-II has been shown to be mediated through HIF2α (Krotova et al, 2010; Cowburn et al, 2016). Arg-II was reported to be upregulated by hypoxia in pulmonary artery VSMC resulting in proliferation of the cells (Xue et al, 2017) These provide compelling evidence that Arg-II is a HIF-inducible gene in regulating endothelial NO production and VSMC proliferation under hypoxic condition. A role of Arg-II in endothelial activation regulated by HIFs remains unknown
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