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. A study by researchers at the University of Rochester Medical Center explored whether EtOH protects the endothelium against serum amyloid A1 (SAA1)-induced activation/injury and investigated whether this protection is exclusively Notch-dependent.
Human coronary artery endothelial cells (HCAEC) were stimulated or not with “pro-atherogenic” SAA1 (1 μM) in the absence or presence of EtOH, 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.
The authors conclude that EtOH at moderate levels protects against SAA1-induced endothelial activation via both Notch-dependent and Notch-independent mechanisms. Alcohol’s maintenance of endothelium in a nonactivated state would be expected to preserve vessel homeostasis and protect against atherosclerosis development.
Source: Rajendran, N. K., Liu, W., Chu, C. C., Cahill, P. A., & Redmond, E. M. (2021). Moderate dose alcohol protects against serum amyloid protein A1-induced endothelial dysfunction via both notch-dependent and notch-independent pathways. Alcoholism: Clinical and Experimental Research, 00, 1– 14.