ASK1 Mediates Apoptosis and Autophagy during oxLDL-CD36 Signaling in Senescent Endothelial Cells

Area of Science:

• Vascular Biology
• Cellular Signaling
• Oxidative Stress

Background:

• Oxidized low-density lipoprotein (oxLDL) contributes to vascular pathology by increasing reactive oxygen species (ROS) and cluster of differentiation 36 (CD36) expression.
• Senescent human aortic endothelial cells (HAECs) are particularly vulnerable to oxLDL-induced damage.
• The signaling pathways linking oxLDL, CD36, and cellular dysfunction require further elucidation.

Purpose of the Study:

• To investigate the role of apoptosis signal-regulating kinase 1 (ASK1) as a downstream effector of the oxLDL-CD36 signaling axis.
• To explore the mechanisms by which oxLDL-CD36 signaling influences apoptosis and autophagy in senescent HAECs and monocytes.
• To evaluate the therapeutic potential of targeting CD36 or ASK1 against oxLDL-induced vascular damage.

Main Methods:

• Senescent HAECs and monocytes were treated with oxLDL, a CD36-neutralizing antibody, or the ASK1 inhibitor NQDI-1.
• Levels of ROS, CD36 expression, and active ASK1 were measured.
• Apoptosis and autophagy were assessed in treated cells.
• Mechanisms of ASK1 involvement in monocytic autophagy were investigated.

Main Results:

• Oxidized low-density lipoprotein (oxLDL) increased ROS, CD36, and active ASK1 in senescent HAECs.
• ROS-induced apoptosis was prevented by CD36 neutralization or ASK1 inhibition.
• Blocking CD36 enhanced autophagy in senescent HAECs.
• In monocytes, oxLDL induced CD36 and autophagy, with autophagy persisting after ASK1 inhibition but not CD36 neutralization.

Conclusions:

• Oxidized low-density lipoprotein (oxLDL) activates ASK1 as a CD36 downstream responder, promoting apoptosis in senescent endothelial cells.
• ASK1 contributes to monocytic autophagy via endoplasmic reticulum stress induced by oxLDL.
• Active ASK1 mediates atherosclerotic endothelial dysfunction in aged vessels exposed to oxLDL.