Effect of vitamin D on ROS, ICAM‐1, and monocyte adhesion in human umbilical vein endothelial cells treated with high glucose and acetoacetate (828.10)

Abstract

Monocyte adhesion to the endothelium plays a central role in the progression of endothelial dysfunction and cardiovascular disease (CVD). This study examines whether VD supplementation is beneficial in preventing endothelial dysfunction in diabetes. HUVEC were treated with 1, 25‐(OH)2‐D3 (0‐25nM, 24h) and later exposed to the ketone body acetoacetate (AA, 4mM) or high glucose (HG, 25mM) for 24h. There was an increase in ROS, ICAM‐1 expression, and monocyte adhesion in HUVEC treated with AA or HG. VD (25nM) supplementation significantly lowered ROS (41%, p<0.05), ICAM‐1 (73%, p=0.05) and p‐NFκB expression (50%, p<0.05), and IL‐8 (16%, p=0.05) and MCP‐1 (41.2%, p<0.001) secretion along with monocyte adhesion (37.5%, p=0.05) in AA treated HUVEC. VD had a similar beneficial effect on HG treated HUVEC. Interestingly, we also saw an upregulation in GSH and GCLC with VD. We hypothesize that the beneficial effect of VD is mediated by the upregulation of GCLC and GSH, a potential antioxidant. To explore this idea, we knocked down GCLC using siRNA. Results show that beneficial effect of VD was abolished on ketone‐ or HG‐induced ICAM‐1 in GCLC knockdown cells. This suggests that VD mediates its beneficial effects via the upregulation of GCLC. This study provides the biochemical mechanism through which VD can lower ROS, ICAM‐1 expression, monocyte‐endothelial adhesion, and thereby lower the risk of CVD in diabetes.Grant Funding Source: Supported by NIH and Malcolm Feist Chair in Diabetes