Abstract
Olive leaf extract (OLE) is used in traditional medicine as a food supplement and as an over-the-counter drug for a variety of its effects, including anti-inflammatory and anti-atherosclerotic ones. Mechanisms through which OLE could modulate these pathways in human vasculature remain largely unknown. Serum amyloid A (SAA) plays a causal role in atherosclerosis and cardiovascular diseases and induces pro-inflammatory and pro-adhesive responses in human coronary artery endothelial cells (HCAEC). Within this study we explored whether OLE can attenuate SAA-driven responses in HCAEC. HCAEC were treated with SAA (1,000 nM) and/or OLE (0.5 and 1 mg/ml). The expression of adhesion molecules VCAM-1 and E-selectin, matrix metalloproteinases (MMP2 and MMP9) and microRNA 146a, let-7e, and let-7g (involved in the regulation of inflammation) was determined by qPCR. The amount of secreted IL-6, IL-8, MIF, and GRO-α in cell culture supernatants was quantified by ELISA. Phosphorylation of NF-κB was assessed by Western blot and DNA damage was measured using the COMET assay. OLE decreased significantly released protein levels of IL-6 and IL-8, as well as mRNA expression of E-selectin in SAA-stimulated HCAEC and reduced MMP2 levels in unstimulated cells. Phosphorylation of NF-κB (p65) was upregulated in the presence of SAA, with OLE significantly attenuating this SAA-induced effect. OLE stabilized SAA-induced upregulation of microRNA-146a and let-7e in HCAEC, suggesting that OLE could fine-tune the SAA-driven activity of NF-κB by changing the microRNA networks in HCAEC. SAA induced DNA damage and worsened the oxidative DNA damage in HCAEC, whereas OLE protected HCAEC from SAA- and H2O2-driven DNA damage. OLE significantly attenuated certain pro-inflammatory and pro-adhesive responses and decreased DNA damage in HCAEC upon stimulation with SAA. The reversal of SAA-driven endothelial activation by OLE might contribute to its anti-inflammatory and anti-atherogenic effects in HCAEC.
Highlights
Cardiovascular diseases, including coronary artery disease, are the leading cause of death globally, with atherosclerosis being the most common underlying reason for cardiovascular morbidity and mortality
Stimulation of human coronary artery endothelial cells (HCAEC) with Serum amyloid A (SAA) significantly increased the release of IL-6, IL-8, and MIF (Figures 1A,B)
While 1 mg/ml Olive leaf extract (OLE) significantly decreased the release of IL-6 into supernatants of the SAA-stimulated HCAEC, the release of IL-8 returned to baseline levels
Summary
Cardiovascular diseases, including coronary artery disease, are the leading cause of death globally, with atherosclerosis being the most common underlying reason for cardiovascular morbidity and mortality. Systemic inflammation (present in a number of chronic diseases, including metabolic syndrome and rheumatoid arthritis) drives accelerated atherosclerosis [1] and patients with these diseases are at risk for developing atherosclerosis and its complications. Serum amyloid A (SAA), a major acute phase protein, is increased in chronic inflammatory diseases and coronary artery disease [2, 3]. Serum levels of SAA have been reported to correlate with severity of atherosclerosis [6, 7] and have been utilized as a predictor of mortality following acute myocardial infarction [8, 9]. Ridker reported that even chronic low grade inflammation may lead to atherosclerosis and the development of cardiovascular diseases [11], emphasizing the importance of measuring systemic inflammatory markers, such as SAA
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