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Moderate dose alcohol protects against serum amyloid protein A1‐induced endothelial dysfunction via both notch‐dependent and notch‐independent pathways
Author(s) -
Rajendran Naresh K.,
Liu Weimin,
Chu Charles C.,
Cahill Paul A.,
Redmond Eileen M.
Publication year - 2021
Publication title -
alcoholism: clinical and experimental research
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.267
H-Index - 153
eISSN - 1530-0277
pISSN - 0145-6008
DOI - 10.1111/acer.14706
Subject(s) - notch signaling pathway , notch 1 , endothelial dysfunction , amyloid (mycology) , medicine , chemistry , microbiology and biotechnology , biology , signal transduction , pathology
Background Arterial endothelium plays a critical role in maintaining vessel homeostasis and preventing atherosclerotic cardiovascular disease (CVD). Low‐to‐moderate alcohol (EtOH) consumption is associated with reduced atherosclerosis and stimulates Notch signaling in endothelial cells. The aim of this study was to determine whether EtOH protects the endothelium against serum amyloid A1 (SAA1)‐induced activation/injury, and to determine whether this protection is exclusively Notch‐dependent. Methods and Results Human coronary artery endothelial cells (HCAEC) were stimulated or not with “pro‐atherogenic” SAA1 (1 μM) in the absence or presence of EtOH (25 mM), the Notch ligand DLL4 (3 μg/ml), or the Notch inhibitor DAPT (20 μM). EtOH stimulated Notch signaling in HCAEC, as evidenced by increased expression of the Notch receptor and hrt target genes. Treatment with EtOH alone or stimulation of Notch signaling by DLL4 increased eNOS activity and enhanced HCAEC barrier function as assessed by trans‐endothelial electrical resistance. Moreover, EtOH and DLL4 both inhibited SAA1‐induced monolayer leakiness, cell adhesion molecule (ICAM, VCAM) expression, and monocyte adhesion. The effects of EtOH were Notch‐dependent, as they were blocked with DAPT and by Notch receptor (N1, N4) knockdown. In contrast, EtOH’s inhibition of SAA1‐induced inflammatory cytokines (IL‐6, IFN‐γ) and reactive oxygen species (ROS) was Notch‐independent, as these effects were unaffected by DAPT or by N1 and/or N4 knockdown. Conclusions EtOH at moderate levels protects against SAA1‐induced endothelial activation via both Notch‐dependent and Notch‐independent mechanisms. EtOH's maintenance of endothelium in a nonactivated state would be expected to preserve vessel homeostasis and protect against atherosclerosis development.