Caffeic Acid attenuates high glucose-induced oxidative stress and endothelial dysfunction in human endothelial cells via modulating NF-kB pathway

Oxidative stress plays a pivotal role in the development of diabetes complications, both microvascular and cardiovascular. The metabolic abnormalities of diabetes, mainly hyperglycemia, cause reactive oxygen species (ROS) overproduction in endothelial cells leading to endothelial dysfunction. It has been demonstrated that the transcription factor NF-κB, functionally dependent on cellular redox status, plays a key role in endothelial activation triggering adhesion molecules gene expression and then leukocyte adhesion to the endothelium. Several studies have shown that natural antioxidants ameliorate a number of altered physiological and metabolic parameters that occur as a result of type 2 diabetes. Recent review reported that these compounds are able to induce Nuclear factor erythroid 2-related factor 2 (Nrf2) that in turn upregulates the expression of antioxidant genes involved in the protection of the cells from oxidative damage (Speciale et al, 2011). Among various phenolic compounds, caffeic acid, found in many types of fruit and coffee in high concentrations, has exhibited pharmacological antioxidant activity and is known to have an antidiabetic effect in streptozotocin-induced diabetic rats (Jung et al., 2006). In this study we investigated if physiological concentrations of CA (10 nM) were able to protect human endothelial cells against alterations induced by high glucose levels (HG) in Human Umbilical Vein Endothelial Cells (HUVECs). Exposure of HUVECs to HG 25 mM for 24h up-regulated NF-kB nuclear translocation and reduced GSH, SOD and total antioxidant power (TAS) levels. Interestingly, CA cotreatment restored antioxidant levels and prevented NF-κB activation. Furthermore, physiological concentration of CA was able to induce Nrf2 nuclear translocation and HO-1 gene expression in HUVECs exposed or not to HG. These data support the involvement of the cellular adaptive response, activated by CA, able to counteract the damage induced by HG. The findings might be of clinical significance as endothelial dysfunction, that could lead to cardiovascular disease, is reversed by caffeic acid consumption, as well as other dietary plant polyphenols, suggesting that this approach could be applied to the prevention of diseases associated with inflammation and oxidative stress, including atherosclerosis.