A rise in postprandial serum triglycerides (PP-sTG) can potentiate inflammatory responses in vascular endothelial cells (ECs) and thus serves as an independent risk factor for predicting increased cardiovascular morbidity. We examined postprandial triglyceride-rich lipoproteins (PP-TGRLs) in subjects ranging from normal to hypertriglyceridemic for their capacity to alter EC acute inflammatory responses. Cultured human aortic ECs (HAECs) were conditioned with PP-TGRLs isolated from human serum at the peak after a moderately high-fat meal. VLDL particle size increased postprandially and varied directly with the subject's PP-sTG level and waist circumference. PP-TGRL particles bound to HAECs and were internalized via LDL receptor-mediated endocytosis. PP-TGRL alone did not induce an inflammatory response over the range of individuals studied. However, combined with low-dose TNF-α stimulation (0.3 ng/ml), it elicited a net 10-15% increase above cytokine alone in the membrane expression of VCAM-1, ICAM-1, and E-selectin, which was not observed with fasting TGRLs. In contrast to upregulation of ICAM-1 and E-selectin, VCAM-1 transcription and expression varied in direct proportion with individual PP-sTG and waist circumference. The extent of monocyte arrest on inflamed HAECs under shear stress also correlated closely with VCAM-1 expression induced by conditioning with PP-TGRL and TNF-α stimulation. This ex vivo approach provides a quantitative means to assess an individual's inflammatory potential, revealing a greater propensity for endothelial inflammation in hypertriglyceridemic individuals with abdominal obesity.
Atherosclerosis, a chronic inflammatory arterial disease featured by focal accumulation of fat‐laden deposits, is exacerbated by prolonged circulation of elevated levels of triglyceride‐rich lipoproteins (TGRL). This study aims to examine the effects of TGRL on the inflammatory potential of endothelial cells and the mechanisms for enhanced recruitment of mononuclear cells using vascular mimetics. We have developed an ex vivo atherogenesis model, in which human aortic endothelial cells (HAEC) in culture are perfused with postprandial TGRL freshly isolated from high‐fat diet fed individuals under varied shear rates. The expressions of cell adhesion molecules (CAM) are examined by flow cytometry, while the binding and internalization of TGRL are visualized by immunofluorescence. The results show an enhanced CAM upregulation upon TNF‐stimulation in TGRL perfused HAECs. Moreover, a member of low density lipoprotein receptors, LR11 is found involved in TGRL binding and upregulated in TNF‐α stimulated HAECs. We conclude that excessive exposure of endothelium to TGRL primes them for enhanced inflammatory response to cytokines or pro‐athero shear flow profiles. This elevated inflammatory state further enhances the recruitment of TGRL, thus revealing a positive feedback loop for metabolically driven development of atherosclerosis.This study is supported by NIH RO1 HL 082689 to S.I.S.
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