The Inhibitive Effect Of Delphinidin-3-glucoside On The Oxidative Stress-induced Vascular Endothelial Dysfunction

Cadiovascular dieases induced by atherosclerosis (AS) has been demonstrated to bethe leading cause of death in the western countries, and the prevalence and incidence ratesincrease rapidly in China. Many researchers are agreed with the response-to-injuryhypothesis raised by Ross, in which it implies that endothelial impairment and dysfunctioninduced by the oxidative stress is the initiating step for AS. OxLDL induces endothelialdysfunction by increasing oxidative stress, thrombopoiesis, inflammation and suppressingvasodilatation. It was demonstrated that oxLDL could promote intracellular ROSgeneration and the increased ROS activates the downstream signaling pathway. P38mitogen-activated protein kinase (p38MAPK) is one of mitogen-activated protein kinase(MAPK) family member. It regulates cellular response to external stimulation through thetransmission of intracellular signals. Studies have shown ROS could promote the oxidativephosphorylation of p38MAPK, activate the nuclear transcription factor NF-κB, increasesecretion of ICAM-l, VCAM-1, MCP-1, P-selectin, NOX2and p22phox, and increaseneutrophils cells adhesion to endothelial cell. Therefore, ROS/p38MAPK/NF-κB signalingpathway plays an important role in oxLDL-induced endothelial dysfunction.Recent research have suggested that phytochemicals, which are widely present inmany kinds of plants, have the properties against chronic metabolic disease, such as AS.There are tens of thousands kinds of phytochemicals, and anthocyanins belong to thewidespread class of phenolic compounds collectively named flavonoids, which widelypresent in blue berry, mulberry, eggplant, black rice, purple potato and so on.Epidemiological studies have suggested that French people take in more satisfied fatty acidthan people in other countries in Europe, while the incidence of cardiovascular diseases islower. This inconsequent phenomenon is called "French paradox", which is closely relatedto the intake of red wine. Human intervention studies have suggested that the intake of600mg of anthocyanins increases the antioxidant of blood plasma, reduces the production ofinflammatory factors, and prevent AS progression. There are more than500kinds of anthocyanins found in the nature. In our previous works we investigated thestructure-activity relationship of21kinds of anthocyanins on endothelia injury and revealedthe structural requirements of anthocyanins for the protective potency againstoxLDL-induced endothelial injury. It was found that delphinidin-3-glucoside (DPg) showedprominent effects against oxLDL-induced endothelial injury. In our present study, we aimto explore the mechanism by which DPg inhibits oxLDL-induced endothelial dysfunction.We established an endothelial dysfunction model induced by oxLDL, measured by the cellviability, cell apoptosis, the level of MDA, LDH, SOD, NO and sICAM-1as well as theintracellular ROS level, respectively. And then the effects of different concentrations ofDPg on endothelial vitality, cell apoptosis, the level of MDA, LDH, SOD, NO andsICAM-1as well as monocyte adhesion and transmigration were measured respectively.Furthermore, the role of ROS/p38MAPK/NF-κB signaling pathway in the inhibition ofendothelial dysfunction by DPg were determined by qRT-pcr, western blotting analysis,dual luciferase reporter gene assays.The results and conclusions are summarized as follows:(1) OxLDL significantly induced endothelial dysfunction by decreasing the viability,secretory activity, antioxidant capacity and increasing cell apoptosis as well as promotinglipid peroxidation, inflammatory reaction and the intracellular ROS level in the endothelialcells.(2) DPg significantly inhibited oxLDL-induced endothelial dysfunction by increasingthe cell viability, secretory activity, antioxidant capacity and decreasing cell apoptosis aswell as decreasing lipid peroxidation, inflammatory reaction, monocyte adhesion andtransmigration.(3) ROS/p38MAPK/NF-κB signaling pathway played an important role in theinhibition of endothelial dysfunction by DPg. It was found that DPg significantly inhibitedoxLDL induced ROS generation, expression of Nox2and p22phox, phosphorylation ofp38MAPK, activity and expression of NF-κB p65.In summary, DPg significantly suppressed oxLDL-induced endothelial dysfunction,which might be mediated through the ROS/p38MAPK/NF-κB signaling pathway.Phytochemicals have been the hot spot in the research field, and might become leadcompounds in drug design. The present study might provide some evidence for AS prevention and a basis for the design of potent anti-atherosclerotic agents that will havetherapeutic potential in the prevention of AS.