Overexpression of steroidogenic acute regulatory protein in rat aortic endothelial cells attenuates palmitic acid-induced inflammation and reduction in nitric oxide bioavailability

Abstract

BackgroundEndothelial dysfunction is a well documented evidence for the onset of atherosclerosis and other cardiovascular diseases. Lipids disorder is among the main risk factors for endothelial dysfunction in these diseases. Steroidogenic acute regulatory protein (StAR), one of the cholesterol transporters, plays an important role in the maintenance of intracellular lipid homeostasis. However, the effect of StAR on endothelial dysfunction is not well understood. Palmitic acid (PA) has been shown to decrease eNOS activity and induce inflammation, both are the causes of endothelial dysfunction, in an endothelial cell culture model.MethodsStAR gene was introduced into primary rat aortic endothelial cells by adenovirus infection. Real-time PCR and Western blotting were performed to determine the relative genes and proteins expression level to elucidate the underlying mechanism. The free fatty acid and cholesterol quantification kits were used to detect total cellular free fatty acid and cholesterol. The levels of inflammatory factors and nitric oxide were determined by ELISA and classic Griess reagent methods respectively.ResultsWe successfully overexpressed StAR in primary rat aortic endothelial cells. Following StAR overexpression, mRNA levels of IL-1β, TNFα, IL6 and VCAM-1 and protein levels of IL-1β, , TNFα and IL-6 in culture supernatant were significantly decreased, which duing to blocke NFκB nuclear translocation and activation. Moreover, StAR overexpression attenuated the PA-induced reduction of nitric oxide bioavailability by protecting the bioactivity of pAkt/peNOS/NO pathway. Furthermore, the key genes involved in lipid metabolism were greatly reduced following StAR overexpression. In order to investigate the underlying mechanism, cerulenin and lovastatin, the inhibitor of fatty acid and cholesterol synthase, were added prior to PA treatment. The results showed that both cerulenin and lovastatin had a similar effect as StAR overexpression. On the other hand, the role of StAR was inhibited when siRNA was introduced to reduce StAR expression.ConclusionsOur results showed that StAR attenuated lipid synthesis and uptake as well as PA-induced inflammation and reduction in NO bioavailability in aortic endothelial cells. StAR can ameliorate endothelial dysfunction induced by PA via reducing the intracellular lipid levels.

Palmitic Acid Induces Production of Proinflammatory Cytokines Interleukin-6, Interleukin-1β, and Tumor Necrosis Factor-αvia a NF-

“…This is in agreement with several studies that suggest a link between these three proinflammatory cytokines and PA-induced inflammation [26, 27]. For example, Staiger et al reported palmitate-induced interleukin-6 expression in human coronary artery endothelial cells and suggested a potential contribution of palmitate to vascular inflammation [27].…”

Steroidogenic Acute Regulatory Protein (StAR) Overexpression Reduces Inflammation and Insulin Resistance in Obese Mice

“…Augmented levels of serum inflammatory cytokines and macrophages infiltration in adipose tissue have been proven as the most common appearances of obesity-linked inflammation [Weisberg et al, 2003;Gregor and Hotamisligil, 2011]. We have previously reported that overexpression of StAR in rat aortic endothelial cells attenuated PA-induced reduction in nitric oxide bioavailability [Tian et al, 2012]. We have previously reported that overexpression of StAR in rat aortic endothelial cells attenuated PA-induced reduction in nitric oxide bioavailability [Tian et al, 2012].…”

Identification of early transcriptome-based biomarkers related to lipid metabolism in peripheral blood mononuclear cells of rats nutritionally programmed for improved metabolic health

“…In macrophages, Star overexpression impacts positively on the lipid-related phenotype of these cells, since it represses a number of genes involved in cholesterol biosynthesis and LDL uptake and markedly increases the expression of ABCA1, strongly suggesting that Star increases sterol efflux to apoAI (Taylor et al 2010). This protein has also been shown to be a protective molecule for endothelial dysfunctions in aortic endothelium (Tian et al 2012). Interestingly, presence of STAR protein has also been described in human liver cells, where it appears to be involved in cellular cholesterol homeostasis, representing a potential therapeutic target in the management of hyperlipidemia (Hall et al 2005).…”