Abstract
Statins exert pleiotropic effects on endothelial cells in addition to lowering cholesterol. 15-Lipoxygenase-1 (ALOX15) has been implicated in vascular inflammation and disease. The relationship between atorvastatin and ALOX15 was investigated using a rat carotid artery balloon-injury model. Hematoxylin and eosin (HE) staining showed that ALOX15 overexpression increased the thickness of the intima-media (IMT). Immunohistochemistry and western blotting showed that atorvastatin increased the expression of cellular adhesion molecules (CAMs) but decreased the expression of endothelial nitric oxide synthase (eNOS); these effects of atorvastatin were blocked by ALOX15 overexpression. In human umbilical venous endothelial cells (HUVECs), silencing of ALOX15 enhanced the effects of atorvastatin on endothelial function. Expression levels of CAMs and Akt/eNOS/NO under oxidized low-density lipoprotein (ox-LDL) stimulation were modulated by ALOX15 inhibitor and ALOX15 small interfering RNA (siRNA). Atorvastatin abolished the activation of nuclear factor-kappa B (NF-κB) induced by ox-LDL. Exposure to ox-LDL induced upregulation of ALOX15 in HUVECs, but this effect was partially abolished by atorvastatin or the NF-κB inhibitor pyrrolidine dithiocarbamate (PDTC). These results demonstrate that regulation of ALOX15 expression might be involved in the effects of atorvastatin on endothelial dysfunction.
Highlights
Statins are widely used to treat hyperlipidemia and prevent coronary heart disease
Atorvastatin treatment suppressed upregulation of adhesion molecules and downregulation of endothelial nitric oxide synthase (eNOS) induced by balloon injury, whereas overexpression of ALOX15 partially eliminated these effects
Atorvastatin suppressed upregulation of adhesion molecules and downregulation of p-Aktser473 and p-eNOSser1177 induced by oxidized low-density lipoprotein (ox-LDL) stimulation in vitro
Summary
Statins are widely used to treat hyperlipidemia and prevent coronary heart disease. In addition to their lipidlowering effects, statins produce an antiatherogenic effect by improving endothelial function, stabilizing atherosclerotic plaques, and reducing oxidative stress and endothelial inflammation [1,2,3]. Statins enhance expression of growth factors, activate the phosphatidylinositol 3-kinase (PI3K)/Akt-mediated signaling pathway, and postpone the initiation of atherosclerosis through decreased regulation of nitric oxide (NO) synthesis by upregulating endothelial nitric oxide synthase (eNOS) mRNA expression and decreasing superoxide anion O2-production in endothelial cells [4, 5]. Activation of the PI3K/Akt/eNOS pathway and downregulation of adhesion molecule expression might be involved in the beneficial effects of statins, but the mechanism by which statins improve endothelial function has not been fully elucidated.
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