Abstract
Remnant-like lipoprotein particles (RLPs) have been implicated as potentially atherogenic lipoproteins. Endothelial dysfunction is known to be an early event in atherosclerosis and an important contributor to the pathogenesis of coronary artery disease. Moreover, there is considerable evidence linking increased RLP cholesterol levels with endothelial dysfunction, reflected by impaired endothelial vasodilatation and abnormal endothelial secretion. The underlying mechanisms by which RLPs may contribute to endothelial dysfunction are complex and have not been completely elucidated. Because the expression and activation of endothelial nitric oxide synthase (eNOS) are vital to endothelial function, and recent data have implied an association between RLPs and eNOS, this manuscript proposes the hypothesis that RLPs could impair endothelial function via direct and indirect effects on eNOS: RLPs may affect the autophosphorylation of focal adhesion kinase and its downstream phosphatidylinositol kinase/Akt (protein kinase B) signaling pathway, resulting in eNOS inactivation through induction of intracellular oxidative stress in endothelial cells; and RLPs could affect the expression or activation of eNOS indirectly by stimulating secretion of various inflammatory factors from multiple origins. The practical applications of this manuscript provide new insights for the future investigation of RLPs.
Highlights
Remnant-like lipoprotein particles (RLPs) have been implicated as potentially atherogenic lipoproteins
Twickler et al [50] reported that plasma levels of IL-6 and tumor necrosis factor-a (TNF-a) increased during the postprandial period and were related to the elevated levels of RLP-C in patients with the adult-onset growth hormone deficiency syndrome, indicating a pronounced postprandial inflammatory response associated with the postprandial RLP-C response
One major mechanism for inhibition of Endotheliumdependent vasorelaxation (EDR) by RLPs is decreasing nitric oxide (NO) production from endothelium
Summary
In the inflammatory and proliferative responses of the endothelium, some adhesion molecules, including vascular cell adhesion molecule-1 (VCAM-1), intercellular adhesion molecule-1 (ICAM-1), and E-selectin, are expressed by the activated endothelial cells in the atherosclerotic lesions [21], and chemokines such as monocyte chemoattractant protein-1 and cytokines such as interleukin-1 (IL-1) and tumor necrosis factor-a (TNF-a) are secreted by the endothelial cells [22]. Upon incubation of human umbilical vein endothelial cells (HUVECs) with RLPs (50 mg/ml), adherent monocytes significantly increased by 3.3-fold, with increased cell surface expression of VCAM-1, ICAM-1, E-selectin, and monocyte chemoattractant protein-1 [23]. Shin et al [25] have emphasized the importance of RLPs in increasing the expression of LOX-1 receptor protein in NADPH oxidase-dependent superoxide production associated with DNA fragmentation and apoptotic cell death in HUVECs. Isolated RLPs were found to be oxidized or to be susceptible to oxidation in plasma. It is conjectured that RLPs, not Ox-LDL in plasma, are the major ligand for the LOX-1 receptor in endothelial cells, causing endothelial dysfunction and the initiation of atherosclerosis [29]
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