Abstract
Manganese superoxide dismutase (MnSOD), a foremost antioxidant enzyme, plays a key role in angiogenesis. Barley-derived (1.3) β-d-glucan (β-d-glucan) is a natural water-soluble polysaccharide with antioxidant properties. To explore the effects of β-d-glucan on MnSOD-related angiogenesis under oxidative stress, we tested epigenetic mechanisms underlying modulation of MnSOD level in human umbilical vein endothelial cells (HUVECs) and angiogenesis in vitro and in vivo. Long-term treatment of HUVECs with 3% w/v β-d-glucan significantly increased the level of MnSOD by 200% ± 2% compared to control and by 50% ± 4% compared to untreated H2O2-stressed cells. β-d-glucan-treated HUVECs displayed greater angiogenic ability. In vivo, 24 hrs-treatment with 3% w/v β-d-glucan rescued vasculogenesis in Tg (kdrl: EGFP) s843Tg zebrafish embryos exposed to oxidative microenvironment. HUVECs overexpressing MnSOD demonstrated an increased activity of endothelial nitric oxide synthase (eNOS), reduced load of superoxide anion (O2−) and an increased survival under oxidative stress. In addition, β-d-glucan prevented the rise of hypoxia inducible factor (HIF)1-α under oxidative stress. The level of histone H4 acetylation was significantly increased by β-d-glucan. Increasing histone acetylation by sodium butyrate, an inhibitor of class I histone deacetylases (HDACs I), did not activate MnSOD-related angiogenesis and did not impair β-d-glucan effects. In conclusion, 3% w/v β-d-glucan activates endothelial expression of MnSOD independent of histone acetylation level, thereby leading to adequate removal of O2−, cell survival and angiogenic response to oxidative stress. The identification of dietary β-d-glucan as activator of MnSOD-related angiogenesis might lead to the development of nutritional approaches for the prevention of ischemic remodelling and heart failure.
Highlights
In humans, the chronic exposure to reactive oxygen species (ROS) is a major risk factor for the impairment of endothelial function [1] and angiogenesis [2], which are both essential in self-repair ability of ischemic heart [3]
Even if ROS activates angiogenesis [2], compelling evidence indicates that the endothelial dysfunction because of superoxide anion (O2À) overload represents a mechanism for deregu
We used the combination of two gold standard angiogenic tests, such as the in vitro human umbilical vein endothelial cells (HUVECs) matrigel assay [12, 19, 20] and the in vivo zebrafish angiogenesis assay [21, 22]
Summary
The chronic exposure to reactive oxygen species (ROS) is a major risk factor for the impairment of endothelial function [1] and angiogenesis [2], which are both essential in self-repair ability of ischemic heart [3]. The daily intake of b-D-glucan (1.5–4%) induces the above-mentioned benefits in animal models and humans [16, 17] To date, it is unknown whether b-D-glucan promotes the MnSOD expression and the angiogenic ability of mature endothelial cells. Despite some controversial preliminary evidence [18], it has been suggested that long-term treatment with b-D-glucan enhances MnSOD-related angiogenesis under oxidative stress. For this purpose, we used the combination of two gold standard angiogenic tests, such as the in vitro human umbilical vein endothelial cells (HUVECs) matrigel assay [12, 19, 20] and the in vivo zebrafish angiogenesis assay [21, 22]
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