Abstract
Hyperuricemia is an important risk factor for cardiovascular and renal diseases. Phloretin had shown antioxidant and anti‐inflammatory properties, but its role in endothelial injury is rarely reported. In this study, we aimed to investigate the protective effect of phloretin on UA‐induced injury in human umbilical vein endothelial cells. The effects of UA and phloretin on cell viability, inflammation, THP‐1 monocyte adhesion, endothelial cell tube formation, GLUT9 expression and UA uptake in human umbilical vein endothelial cells were evaluated. The changes of nuclear factor‐kappa B/extracellular regulated protein kinases signalling were also analysed. Our results showed that UA reduced cell viability and tube formation, and increased inflammation and monocytes adhesion in human umbilical vein endothelial cells in a dose‐dependent manner. In contrast, phloretin significantly attenuated pro‐inflammatory factors expression and endothelial injury induced by UA. Phloretin inhibited the activation of extracellular regulated protein kinases/nuclear factor‐kappa B pathway, and reduced GLUT9 and it mediated UA uptake in human umbilical vein endothelial cells. These results indicated that phloretin attenuated UA‐induced endothelial injury via a synergic mechanism including direct anti‐inflammatory effect and lowering cellular UA uptake. Our study suggested that phloretin might be a promising therapy for hyperuricemia‐related cardiovascular diseases.
Highlights
Uric acid (UA) is the end product of purine degradation in human and non-human primate, while it is further converted to allantoin by enzyme uricase in other mammals
We evaluated the effects of phloretin on GLUT9 expression, UA uptake and endothelial cell injury in HUVECs, and explored the potential protective mechanism of phloretin on UA-induced endothelial injury
Our results showed that GLUT9 Small interfering RNA (siRNA) significantly decreased inflammatory factors expression and NF-jB/ERK activation induced by UA, which was similar to the effect of phloretin on UA-treated HUVECs
Summary
Uric acid (UA) is the end product of purine degradation in human and non-human primate, while it is further converted to allantoin by enzyme uricase in other mammals. The normal level of UA may provide antioxidant defence in the human body, abnormal high level of blood UA (hyperuricemia) is often associated with gout, metabolic syndrome, insulin resistance, hypertension, T2DM and chronic renal diseases (CKD) [1,2,3,4]. Epidemiological evidences suggest that hyperuricemia and cardiovascular diseases are highly related [3, 4]. Endothelial dysfunction is an initial and essential factor in the progression of cardiovascular diseases [5], and UA could directly induce endothelial cells injury via multiple mechanisms such as oxidative stress and inflammation [6]. Increased evidences showed that some natural products such as polyphenols had beneficial effects on cardiovascular health. Phloretin was found to induce apoptosis in cancer cells [Correction added on 26 April 2017, after first online publication: The order of the author was corrected and this has been amended in this version.]
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