HDL-associated lysosphingolipids inhibit NAD(P)H oxidase-dependent monocyte chemoattractant protein-1 production

Area of Science:

• Cardiovascular Biology
• Lipid Metabolism
• Inflammation Research

Background:

• High-density lipoprotein (HDL) is known to protect against atherosclerosis, but the underlying mechanisms are not fully understood.
• Monocyte chemoattractant protein-1 (MCP-1) is an early inflammatory marker in atherosclerosis development.
• Vascular smooth muscle cells (VSMCs) play a crucial role in the inflammatory processes of atherosclerosis.

Purpose of the Study:

• To investigate the effect of HDL on MCP-1 production in VSMCs and rat aortic explants.
• To elucidate the role of reactive oxygen species (ROS) and NAD(P)H oxidase in HDL-mediated inhibition of MCP-1.
• To identify specific HDL components and signaling pathways involved in atheroprotection.

Main Methods:

• Assessed HDL's effect on thrombin-induced MCP-1 production in VSMCs.
• Measured ROS generation and NAD(P)H oxidase activity in response to HDL.
• Utilized lysosphingolipids (S1P, SPC), apolipoprotein A-I, and receptor antagonists (VPC23019, JTE013) to probe mechanisms.
• Examined HDL's effects in aortic explants from S1P(3)- and SR-B1-deficient mice.

Main Results:

• HDL significantly inhibited MCP-1 production in a concentration-dependent manner.
• This inhibition was associated with reduced ROS generation and suppressed NAD(P)H oxidase and Rac1 activation.
• HDL-associated lysosphingolipids (S1P, SPC) mimicked HDL's inhibitory effects, unlike apolipoprotein A-I.
• Inhibition required signaling through S1P(3) and SR-B1 receptors, as evidenced by experiments with receptor antagonists and deficient mice.

Conclusions:

• HDL-associated lysosphingolipids are key mediators of HDL's anti-inflammatory effects.
• HDL inhibits MCP-1 production by suppressing NAD(P)H oxidase-dependent ROS generation.
• This atheroprotective mechanism necessitates coordinated signaling via S1P(3) and scavenger receptor class B type 1 (SR-B1).