Oxidized High-Density Lipoprotein Induces Endothelial Fibrosis Promoting Hyperpermeability, Hypotension, and Increased Mortality

Abstract

During systemic inflammation, reactive oxygen species (ROS) are generated in the bloodstream, producing large amounts of oxidized HDL (oxHDL). OxHDL loses the vascular protective features of native HDL, acquiring detrimental actions. Systemic inflammation promotes endothelial fibrosis, characterized by adhesion protein downregulation and fibrotic-specific gene upregulation, disrupting endothelial monolayer integrity. Severe systemic inflammatory conditions, as found in critically ill patients in the intensive care unit (ICU), exhibit endothelial hyperpermeability, hypotension, and organ hypoperfusion, promoting organ dysfunction and increased mortality. Because endothelial fibrosis disturbs the endothelium, it is proposed that it is the cellular and molecular origin of endothelial hyperpermeability and the subsequent deleterious consequences. However, whether oxHDL is involved in this process is unknown. The aim of this study was to investigate the fibrotic effect of oxHDL on the endothelium, to elucidate the underlying molecular and cellular mechanism, and to determine its effects on vascular permeability, blood pressure, and mortality. The results showed that oxHDL induces endothelial fibrosis through the LOX-1/NOX-2/ROS/NF-κB pathway, TGF-β secretion, and ALK-5/Smad activation. OxHDL-treated rats showed endothelial hyperpermeability, hypotension, and an enhanced risk of death and mortality, which was prevented using an ALK-5 inhibitor and antioxidant diet consumption. Additionally, the ICU patients showed fibrotic endothelial cells, and the resuscitation fluid volume administered correlated with the plasma oxHDL levels associated with an elevated risk of death and mortality. We conclude that oxHDL generates endothelial fibrosis, impacting blood pressure regulation and survival.

Sepsis-Induced Coagulopathy Phenotype Induced by Oxidized High-Density Lipoprotein Associated with Increased Mortality in Septic-Shock Patients

“…However, it is well known that during sepsis, a large amount of ROS is generated and interacts with HDL to generate oxHDL, which exhibits dysfunctional functions directly involved in pathophysiological processes [ 32 , 33 ]. Increased oxHDL and decreased HDL plasma levels in SSP are involved in other inflammatory diseases, including obesity and type 2 diabetes mellitus [ 35 , 36 , 59 , 60 ]. Additionally, increased levels of HDL have been associated with endothelial dysfunction [ 61 , 62 , 63 ].…”

Effect of Dietary Supplements with ω-3 Fatty Acids, Ascorbic Acid, and Polyphenolic Antioxidant Flavonoid on Gene Expression, Organ Failure, and Mortality in Endotoxemia-Induced Septic Rats

“…Endothelial fibrosis has been detected in septic ICU patients, and the expression changes of VE۔cadherin have emerged as an accurate diagnostic tool. In endotoxemic rats, the pharmacological inhibition of endotoxemia-induced endothelial fibrosis improves MODS and survival [ 13 , 20 , 21 ].…”

“…Endotoxin-induced endothelial fibrosis is mediated through a process known as endothelial-to-mesenchymal transition (EndMT) in a similar way to that observed using the best-studied EndMT inducer, tumor growth factor β (TGF-β) [ 15 , 16 , 17 , 18 , 19 ]. Endothelial fibrosis has been detected in septic ICU patients and in several animal septic models, and the pharmacological inhibition of endotoxemia-induced endothelial fibrosis improves organ failure and survival [ 13 , 20 , 21 ]. Endotoxemia-induced endothelial fibrosis is characterized by a massive change in the endothelial gene-expression profile, which downregulates endothelial markers, including vascular endothelial cadherin (VE-cadherin) and platelet endothelial cell adhesion molecule 1 (PECAM-1).…”