Moderate dose alcohol protects against serum amyloid protein A1‐induced endothelial dysfunction via both notch‐dependent and notch‐independent pathways

• Published in: Alcoholism, clinical and experimental research clinical and experimental research, 2021-11, Vol.45 (11), p.2217-2230
• Main Authors: Rajendran, Naresh K., Liu, Weimin, Chu, Charles C., Cahill, Paul A., Redmond, Eileen M.
• Format: Article
• Language: English
• Subjects: alcohol; Alcohol use; Alcoholism; Amyloid; Amyloidogenic Proteins - metabolism; Arteriosclerosis; Atherosclerosis; cardiovascular; Cardiovascular diseases; Cell adhesion molecules; Cell Movement - drug effects; Coronary artery; Coronary Vessels - drug effects; Coronary Vessels - metabolism; Dose-Response Relationship, Drug; Electrical resistivity; endothelial; Endothelial cells; Endothelial Cells - drug effects; Endothelium; Endothelium, Vascular - drug effects; Endothelium, Vascular - metabolism; Ethanol; Ethanol - pharmacology; Homeostasis; Humans; Inflammation; Interferon; Monocytes; notch; Notch protein; Protective Agents; Reactive oxygen species; Receptor, Notch1 - metabolism; Receptors, Notch - metabolism; SAA1
• ISSN: 0145-6008; 1530-0277
• DOI: 10.1111/acer.14706

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. Arteriosclerosis is a hardening and narrowing of the arteries that underlies cardiovascular disease. We report that alcohol, at moderate levels, maintains arterial endothelium stimulated by a proinflammatory serum protein (SAA‐1) in a non‐activated state by both Notch‐dependent and Notchindependent mechanisms. The consequence of such alcohol effects would be expected to preserve vessel homeostasis, despite a pro‐atherogenic milieu, and thus protect against arteriosclerosis. These findings might explain, in part, the reduced cardiovascular disease and sequalae reported in alcohol consumers.