Abstract
Endothelial activation and dysfunction are hallmarks of inflammation. Neutrophil-vascular endothelium interactions have significant effects on vascular wall physiology and pathology. Myeloperoxidase (MPO)-derived products released from activated neutrophils can mediate the inflammatory response and contribute to endothelial dysfunction. 2-Chlorofatty aldehyde (2-ClFALD) is the direct oxidation product of MPO-derived hypochlorous acid (HOCl) targeting plasmalogen phospholipids. The role of 2-ClFALD in endothelial dysfunction is poorly understood and may be dependent on the vascular bed. This study compared the role of 2-ClFALD in eliciting endothelial dysfunction in human coronary artery endothelial cells (HCAEC), human lung microvascular endothelial cells (HLMVEC), and human kidney endothelial cells (HKEC). Profound increases in selectin surface expression as well as ICAM-1 and VCAM-1 surface expression were observed in HCAEC and HLMVEC. The surface expression of these adherence molecules resulted in robust adherence of neutrophils and platelets to 2-ClFALD treated endothelial cells. In contrast to HCAEC and HLMVEC, 2-ClFALD-treated HKEC had substantially reduced adherence molecule surface expression with no resulting increase in platelet adherence. 2-ClFALD-treated HKEC did have an increase in neutrophil adherence. All three endothelial cell lines treated with 2-ClFALD displayed a time-dependent loss of barrier function. Further studies revealed 2-ClHDyA localizes to ER and Golgi when using a synthetic alkyne analog of 2-ClFALD in HCAEC and HLMVEC. These findings indicate 2-ClFALDs promote endothelial cell dysfunction with disparate degrees of responsiveness depending on the vascular bed of origin.
Highlights
Changes at the blood-endothelial interface can elicit profound changes in organ physiology
Endothelial dysfunction is an early event in the pathophysiological sequelae of diseases including atherosclerosis, Abbreviations: 2-ClFALD, 2-chlorofatty aldehyde; 2-ClHDA, 2-chlorohexadecanal; 2-ClHDyA, 2-chlorohexadec-15-ynal; human coronary artery endothelial cells (HCAEC), human coronary artery endothelial cell; HDA, hexadecanal; HDyA, hexadec-15-ynal; MPO, myeloperoxidase; PFBBr, pentafluorobenzyl bromide; VWF, von Willebrand factor
Plasmalogens, a major phospholipid in many human organs, are targeted by hypochlorous acid (HOCl) leading to the production of 2-ClFALDs (Dorman et al, 1976; Chilton and Connell, 1988; Ford and Gross, 1989; Murphy et al, 1992; Hazen et al, 1993; Portilla and Creer, 1995; McHowat et al, 1997; Albert et al, 2001; Hsu et al, 2003). 2-ClFALDs can enter the fatty acid-fatty alcohol cycle as an intermediate leading to their oxidation to 2-chlorofatty acids (2-ClFAs) (Rizzo et al, 1987; Wildsmith et al, 2006; Anbukumar et al, 2010; Brahmbhatt et al, 2010)
Summary
Changes at the blood-endothelial interface can elicit profound changes in organ physiology. Leukocytes can initiate an inflammatory response in the vascular wall resulting in the release of inflammatory mediators and oxidants (Szekanecz and Koch, 2004; Langer and Chavakis, 2009), which may lead to dysfunction at the blood-endothelium interface. Once activated the endothelium releases many mediators that can contribute to leukocyte adherence, coagulation, and changes in barrier function (Ait-Oufella et al, 2010). Through this escalating inflammation, leukocyteproduced reactive oxygen species and released proteolytic enzymes propagate tissue damage and are involved in organ failure (Rossaint and Zarbock, 2015; Santos et al, 2016). 2-ClFALDs and 2-ClFAs are produced at the site of neutrophil infiltration and likely alter nearby cell function (Ford, 2010)
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Free) 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
