Vascular endothelial dysfunction is the initiation and hallmark of various cardiovascular diseases, such as atherosclerosis, hypertension, coronary vascular disease and diabetes. Several therapeutic interventions, including changes in lifestyle and pharmacologic treatments, are used to ameliorate endothelial dysfunction under various risk factors. It is of great interest to explore new therapeutic strategies to improve endothelial function for protection and prevention of these diseases which cause significant number of deaths each year.
In the present study, we provided insight into the effect of StAR on rat aortic endothelium lipid metabolism and dysfunction. As shown in Figure 1, StAR mRNA and protein levels were significantly increased by infection with recombinant adenovirus. Following StAR overexpression, key genes involved in fatty acid synthesis (FAS, ACC-1), cholesterol synthesis (HMGR) and uptake (LDLR, SREBP-2) were greatly repressed. And, intracellular total cholesterol and FFAs were significantly reduced. Furthermore, StAR overexpression inhibited mRNA expression and secretion of inflammatory factors by blocking NFκB nuclear translocation. Finally, StAR overexpression attenuated the reduction of NO bioavailability induced by PA treatment via regulating the p-Akt/p-eNOS/NO pathway.
An elevation of circulating FFAs is supposed to be related to the onset and progression of endothelial dysfunction [39, 40], and associate with a number of cardiovascular risk factors, including hypertension, dyslipidemia, and abnormal fibrinolysis. It has been noted that FFAs may increase the production of multiple cytokines in mononuclear cells by generation of reactive oxygen species (ROS) and activation of the pro-inflammatory NFκB pathway in human endothelial cells [41, 42]. In the present study, we used PA as one of the major mediators to induce endothelial dysfunction by activating inflammation and reducing NO biovailability.
When the endothelium in vessels is affected by risk factors, such as pro-inflammatory factors or hyperlipidemia, it will be activated and secrete inflammatory factors. Cell adhesion molecules including intercellular adhesion molecule-1 (ICAM-1), vascular adhesion molecule-1 (VCAM-1) and E-selectin are the biomarkers of endothelial activation . As shown in our study, the mRNA expression and secretion of inflammatory factors were greatly increased after PA treatment in cultured rat aortic endothelial cells, while the mRNA expression of VCAM-1 was also upregulated significantly. However, the extent of increase is reduced when StAR is overexpressed by adenovirus infection. As shown by previous studies, the transcription factor NFκB regulates the expression of numerous genes including those related to pro-inflammatory responses, such as L-1β, IL-6, TNFα and VCAM-1, IL-1α [35, 44]. We found that NFκB translocation from cytosol to nucleus was blocked by StAR overexpression. Thus, StAR could attenuate inflammatory responses in endothelium via its blocking of NFκB translocation.
There is strong clinical evidence that endothelial dysfunction contributes to the pathogenesis of cardiovascular disease and insulin resistance [45, 46]. Endothelial cell dysfunction is defined by a decrease in the bioavailability of nitric oxide (NO), a critical regulator of vascular tone . Endothelial nitric oxide synthase (eNOS) serves as a critical enzyme in producing NO. As shown in previous studies, the pAkt/peNOS/NO pathway was inhibited by PA treatment [19, 20, 46]. Our observations in this study demonstrated that StAR overexpression in endothelial cells attenuated the reduction of phosphorylation of Akt and eNOS, as well as NO production. Previous studies have shown an inverse correlation between StAR and NO in the steiodogenic tissues [48, 49], in which NO was produced from activation of iNOS (also named NOS2). However, in our study, we observed a direct correlation between StAR and NO in vascular tissue, where NO is produced from eNOS (named NOS3). This suggests that StAR could take different roles in physiological process at different location. As shown in previous reports, NO production is regulated by a complicate network, including interactions among CaM, Cavelion-1, BH4 and ROS to regulate activation of eNOS (Ref). Each step in the network will affect the production of NO, and as a result, StAR overexpression ameliorates the reduction of NO production induced by PA treatment at a mild degree. Our results using siRNAs to inhibit StAR expression confirmed a positive role for StAR in endothelial dysfunction.
As already demonstrated in many investigations, lipids overload is a major risk factor for endothelial dysfunction. Our data obtained in the present study indicate that StAR inhibits lipid synthesis and uptake, PA-induced inflammation, and reduction in NO bioavailability in aortic endothelial cells. The inhibitor of FAS and HMGR could also ameliorate the inflammatory response induced by PA in RAECs. Taken together, the role of StAR overexpression in inhibiting inflammatory response and NO bioavailability in the cellular model of endothelial dysfunction might result from decreased lipid levels in RAECs.