Human Neutrophil Peptide 1 Limits Hypercholesterolemia-induced Atherosclerosis by Increasing Hepatic LDL Clearance

Abstract

Increases in plasma LDL-cholesterol have unequivocally been established as a causal risk factor for atherosclerosis. Hence, strategies for lowering of LDL-cholesterol may have immediate therapeutic relevance. Here we study the role of human neutrophil peptide 1 (HNP1) in a mouse model of atherosclerosis and identify its potent atheroprotective effect both upon transgenic overexpression and therapeutic delivery. The effect was found to be due to a reduction of plasma LDL-cholesterol. Mechanistically, HNP1 binds to apolipoproteins enriched in LDL. This interaction facilitates clearance of LDL particles in the liver via LDL receptor. Thus, we here identify a non-redundant mechanism by which HNP1 allows for reduction of LDL-cholesterol, a process that may be therapeutically instructed to lower cardiovascular risk.

Opposing effects of HNP1 (α-defensin-1) on plasma cholesterol and atherogenesis

“…Our results confirm previous finding that α-def-1, here given exogenously to ApoE -/mice, lowers total serum cholesterol and decreases lesion size in the aortic root [13]. Similar effects were seen when plasma cholesterol was lowered by inhibiting adsorption using cholestyramine or using a MFD.…”

“…untreated mice) ( Fig 1A), accompanied by proportional decrease in LDL, confirming previous reports from our group [12] and others [13]. The percentage of the circumferences of aortic roots occupied by fatty streaks decreased from 39.9 ± 6.6 to 34.4 ± 3.7% (p < 0.05) and 23.4 ± 2.5% (P< 0.001), respectively following injection of α-def-1 (Fig 1B & 1C), both consistent with previous findings [13].…”

“…More recently, formation of LDL/ α-def-1 complexes, enhanced blood clearance of LDL and low plasma LDL were also found in mice double transgenic for α-def-1 and apoE (ApoE −/ − HNP-1tg/tg) and in ApoE -/mice given exogenous α-def-1 [13]. However, in this context, the lower plasma levels of LDL were associated with attenuated development of lipid streaks, showing an apparent protective effect of α-defs in this model and suggesting these peptides might serve as a pharmacological vehicle to prevent atherosclerosis [13].…”

“…The increase in the size of lipid rich lesions in the proximal aortas of Def ++ mice [12] fed a HFD was observed even though α-def-1 stimulated hepatic clearance of LDL leading to hypocholesterolemia [12]. However, a decrease in lesion size was seen when ApoE -/mice were crossed with the same Def ++ mice or were exposed to exogenous α-def-1 showing an apparent protective effect, presumably as a result of accelerated LDL clearance from the plasma [13].…”

“…One set of mice was fed a HFD for 6 weeks without or with 1.5% or 3% cholestyramine [18]. A second set of mice on a HFD, received an intravenous (IV) injection, via tail vein, of αdef-1 (10 or 30 μg) or vehicle (PBS) control every other day [13,19]. A sixth group, studied in parallel, was fed a MFD for 6 weeks.…”