Abstract 553: Scavenging Reactive Aldehydes With 5'-o-pentyl-pyridoxamine (PPM) Improves HDL Function and Reduces Atherosclerosis in Ldlr Deficient Mice

Background: Lipid peroxidation products impair the cholesterol efflux capacity of high-density lipoprotein (HDL) and contribute to the development of atherosclerosis. The effect of inhibition of HDL dysfunction by scavengers on HDL function and whether scavenging reactive aldehydes with PPM protects against the development of atherosclerosis was examined. Methods and Results: HDL of familial hypercholesterolemia (FH) subjects have impaired ability to promote cholesterol efflux and FH-HDL contain 5-fold more malondialdehyde adducts (MDA) than control HDL. In vitro studies revealed that reactive aldehyde MDA crosslinks apolipoprotein AI (apoAI) and impairs the ability of HDL to promote cholesterol efflux from Apoe -/- macrophages. 5'-O-pentyl-pyridoxamine (PPM), a potent scavenger of reactive aldehydes, abolished MDA-mediated crosslinking of apoA-I in HDL by 80 % (P<0.05). PPM prevents the reduction in cholesterol efflux capacity of MDA treated HDL in Apoe-/- macrophages. Furthermore, PPM significantly improved the cholesterol efflux capacity of HDL from Ldlr -/- mice fed a Western diet (WD) for 16 weeks (P<0.05), indicating that PPM protects HDL from modifications by reactive aldehydes and maintains HDL function in vivo. Importantly, administration of 1 mg/mL of the reactive aldehyde scavenger PPM, versus 1 mg/mL of the nonreactive analogue PPO, to Ldlr -/- mice consuming a WD for 16 weeks reduced the extent of proximal aortic atherosclerosis by 45% (P<0.05). Immunohistochemistry studies revealed that PPM reduced the macrophage content and the number of TUNEL positive cells by 55% (P<0.05) and by 60% (P<0.01) in advanced atherosclerotic lesions of Ldlr -/- mice, respectively. In addition, the necrotic core area was reduced by 52% (P<0.05) in advanced atherosclerotic lesions in Ldlr -/- mice treated with PPM compared to the control group. Conclusions: Treatment with PPM, a reactive aldehyde scavenger: 1) inhibits MDA-ApoA1 adduct formation thereby preserving HDL cholesterol efflux capacity in Ldlr -/- mice; 2) reduces the number of apoptotic cells in atherosclerotic lesions and the necrotic core area in lesions of Ldlr -/- mice. These results support the therapeutic potential of PPM in the treatment of atherosclerotic cardiovascular disease.