Endothelial HO - 1 induction by model TG - rich lipoproteins is regulated through a NOX 4 - Nrf 2 pathway 1 Sally

This article is available online at http://www.jlr.org Atherosclerosis and CVD are driven by endothelial dysfunction, a condition associated with low-grade systemic inflammation and characterized by inappropriate inflammatory activation of vascular endothelial cells (ECs). This disruption of endothelial homeostasis is coupled with impaired anti-inflammatory and antioxidant defense capacity, resulting in reduced resistance to oxidative and inflammatory insult, excessive reactive oxygen species (ROS) production, and development of oxidative stress (1). Thus, improving or maintaining endogenous mechanisms of endothelial protection may offer a strategy to mitigate development of CVD. ECs are continuously challenged by the complex molecular milieu of circulating nutrients, cells, and blood constituents, including TG-rich lipoproteins (TRLs) [VLDLs, chylomicrons, and chylomicron remnants (CMRs)]. TRLs increase postprandially, but while endogenous lipoprotein involvement in CVD development is well-documented, how exogenous TRLs carrying dietary fats influence endothelial homeostasis is far less well understood, despite strong evidence implicating CMRs in the initiation of endothelial dysfunction (2–6). This is thought to involve a process now termed “postprandial inflammation” (7) in which CMRs migrate into the subendothelial space, activate circulating leukocytes, and increase immune cell Abstract Circulating levels of chylomicron remnants (CMRs) increase postprandially and their composition directly reflects dietary lipid intake. These TG-rich lipoproteins likely contribute to the development of endothelial dysfunction, albeit via unknown mechanisms. Here, we investigated how the FA composition of CMRs influences their actions on human aortic endothelial cells (HAECs) by comparing the effects of model CMRs—artificial TG-rich CMR-like particles (A-CRLPs)—containing TGs extracted from fish, DHA-rich algal, corn, or palm oils. HAECs responded with distinct transcriptional programs according to A-CRLP TG content and oxidation status, with genes involved in antioxidant defense and cytoprotection most prominently affected by n-3 PUFA-containing A-CRLPs. These particles were significantly more efficacious inducers of heme oxygenase-1 (HO-1) than n-6 PUFA corn or saturated FA-rich palm CRLPs. Mechanistically, HO-1 induction by all CRLPs requires NADPH oxidase 4, with PUFA-containing particles additionally dependent upon mitochondrial reactive oxygen species. Activation of both p38 MAPK and PPAR/ culminates in increased nuclear factor erythroid 2-related factor 2 (Nrf2) expression/nuclear translocation and HO-1 induction. These studies define new molecular pathways coupling endothelial cell activation by model CMRs with adaptive regulation of Nrf2-dependent HO-1 expression and may represent key mechanisms through which dietary FAs differentially impact progression of endothelial dysfunction.— Latham Birt, S. H., R. Purcell, K. M. Botham, and C. P. D. Wheeler-Jones. Endothelial HO-1 induction by model TG-rich lipoproteins is regulated through a NOX4-Nrf2 pathway. J. Lipid Res. 2016. 57: 1204–1218.