High Density Lipoproteins Inhibit Vascular Endothelial Inflammation by Increasing 3β-Hydroxysteroid-Δ24 Reductase Expression and Inducing Heme Oxygenase-1
Rationale:: Lipid-free apolipoprotein (apo) A-I and discoidal reconstituted high density lipoproteins containing apoA-I, (A-I)rHDL, inhibit vascular inflammation by increasing 3β-hydroxysteroid-∆24 reductase (DHCR24) expression.
Objective:: To determine if the lipid-free apoA-I- and (A-I)rHDL-mediated increase in DHCR24 expression induces the cytoprotective and potentially cardioprotective enzyme, heme oxygenase-1 (HO-1).
Methods and Results: In vivo: A single intravenous infusion of lipid-free apoA-I (8 mg/kg) administered 24 h before inserting a non-occlusive peri-arterial carotid collar into New Zealand White rabbits decreased collar-induced endothelial vascular cell adhesion molecule-1 (VCAM-1) and intercellular adhesion molecule-1 (ICAM-1) expression, reduced intima/media neutrophil infiltration, and increased DHCR24 and HO-1 mRNA levels. Knockdown of vascular DHCR24 and HO-1 and systemic administration of tin-protoporphyrin-IX (SnPP), a heme oxygenase (HO) inhibitor, abolished these anti-inflammatory effects. In vitro: Pre-incubation of human coronary artery endothelial cells (HCAECs) with (A-I)rHDL prior to activation with tumor necrosis factor-α increased DHCR24 and HO-1 mRNA levels and inhibited cytokine-induced VCAM-1 and ICAM-1 expression. Transfection of the cells with DHCR24 and HO-1 siRNA, and SnPP treatment abolished these effects. The (A-I)rHDL-mediated induction of HO-1 was reduced in HCAECs transfected with DHCR24 siRNA. Transfection of HCAECs with HO-1 siRNA and SnPP treatment did not inhibit the (A-I)rHDL-mediated increase in DHCR24 expression. Inhibition of phosphatidylinositol 3-kinase/Akt (PI3K/Akt) reduced the (A-I)rHDL-mediated increase in HO-1, but not DHCR24 expression. The activation of PI3K/Akt by (A-I)rHDL was decreased in HCAECs that were transfected with DHCR24 siRNA.
Conclusions: Lipid-free apoA-I and (A-I)rHDL inhibit inflammation by increasing DHCR24 expression, which, in turn, activates PI3K/Akt and induces HO-1.
- heme oxygenase-1
- 3β-hydroxysteroid-∆24 reductase
- high-density lipoprotein
- Received May 3, 2012.
- Revision received October 23, 2012.
- Accepted November 1, 2012.
- Copyright © 2012, Circulation Research