Abstract

Inflammation and oxidative stress are the two processes crucial in atherogenesis. Platelet-activating factor acetylhydrolase (PAF-AH), a plasma lipoprotein-associated enzyme, degrades pro-inflammatory lipids generated within oxidatively modified lipoproteins. Extensive evidence shows that incretin-based drugs, a new class of anti-diabetic agents, can provide cardiovascular protection that cannot be attributed to their glucose-lowering effects. The present study was undertaken to determine whether the antiatherogenic effects of the GLP-1(glucagon-like peptide-1) receptor agonist (exenatide) and DPP-4(dipeptidyl peptidase-4) inhibitors (sitagliptin) may occur via the regulation of platelet-activating factor acetylhydrolase (PAF-AH) activity/mass and inhibition of low-density lipoprotein (LDL) oxidation in the fructose-fed rats.

Normal and fructose-fed rats (8 wk) were treated (4 wk) with sitagliptin (5 and 10 mg/kg p.o.) or with exenatide (5 and 10 μg/kg, s.c.). Plasma PAF-AH activity and phosphatidylcholine (PC) concentration were measured colorimetrically. Plasma PAF-AH concentration, oxidized LDL (oxLDL), hexanoyl-Lys adduct (HEL), lyso-PC, apolipoprotein A-I (apoA-I), apoB, platelet-activating factor (PAF), monocyte chemoattractant protein-1 (MCP-1) and endothelin-1 (ET-1) were measured by ELISA.

The four-week exenatide (5 μg/kg, sc.) treatment of fructose fed-rats significantly increased plasma PAF-AH activity (+33%, P<0.001) and decreased the level of circulating oxLDL (-42%, P<0.05) and MCP-1 (-23%, P<0.01). These changes were accompanied by the decrease in plasma PC/lyso-PC (-47%, P<0.001) and apoB/apoA-I ratio (-75%, P<0.001). The effect of exenatide on enzyme activity was associated with only a minor effect on metabolic parameters and was independent of weight reduction.

Exenatide but not sitagliptin inhibits oxidative modification of LDL probably due to favorable effect on plasma PAF-AH activity.