Abstract 133: Hemodynamic Environment-dependent Effects of Human HDL and oxHDL on Vessel Wall Inflammation
High density lipoprotein (HDL) concentration is inversely correlated with cardiovascular disease and exerts atheroprotective effects on endothelial (EC) and smooth muscle cells (SMC). Oxidation of LDL (oxLDL) is a well-appreciated driver of atherosclerosis. What is less well known is that HDL can become oxidized (oxHDL) by myeloperoxidase, which may negate its beneficial effects. Further, previous mechanistic studies of HDL were performed on static culture ECs or SMCs that do not take into consideration in vivo hemodynamics; a critical regulator of vascular phenotype. Regional hemodynamics prime EC/SMCs towards either an atheroprotective phenotype or, in regions such as bifurcations, towards an atheroprone, pro-inflammatory phenotype. We assessed the role of the hemodynamic environment in modulating the differential response of vascular cells to human HDL or oxHDL from normal donors. To test this, HDL was added to EC/SMC cocultures primed by atheroprotective or atheroprone shear stresses derived from the human carotid bifurcation or an “Advanced Inflammatory” condition that combines atheroprone shear stress with additional atherogenic factors such as oxLDL and TNFα. In the presence of HDL, ECs under Advanced Inflammatory conditions reduced pro-inflammatory (NFkB Activity, IL6, COX2), and oxidative stress (SOD2), but did not have an effect in baseline atheroprotective and atheroprone conditions. Many of the anti-inflammatory responses of endothelial cells were retained when HDL was oxidized. Conversely, while HDL had minimal effect on SMC gene expression, oxHDL was found to reduced the atheroprotective phenotype by potently inducing oxidative and inflammatory cytokine genes/secreted proteins (IL1B, IL6). Overall, this study illustrates the importance of reproducing relevant in vivo environments in order to understand HDL-mediated mechanisms in vascular biology in vitro. This study supports that oxidation dysfunctionally transforms HDL from an atheroprotective to an inflammatory and intrinsically oxidative particle and might damage otherwise healthy regions of the vasculature. Thus, measurement of circulating HDL without consideration of HDL composition and oxidation may limit its predictive value for cardiovascular risk.
- © 2013 by American Heart Association, Inc.