Opposing Effects Of Hnp1 (Alpha-Defensin-1) On Plasma Cholesterol And Atherogenesis

Atherosclerosis, the predominant cause of death in well-resourced countries, may develop in the presence of plasma lipid levels within the normal range. Inflammation may contribute to lesion development in these individuals, but the underlying mechanisms are not well understood. Transgenic mice expressing alpha-def-1 released from activated neutrophils develop larger lipid and macrophage-rich lesions in the proximal aortae notwithstanding hypocholesterolemia caused by accelerated clearance of alpha-def-1/low-density lipoprotein (LDL) complexes from the plasma. The phenotype does not develop when the release of alpha-def-1 is prevented with colchicine. However, ApoE(-/-) mice crossed with alpha-def-1 mice or given exogenous alpha-def-1 develop smaller aortic lesions associated with reduced plasma cholesterol, suggesting a protective effect of accelerated LDL clearance. Experiments were performed to address this seeming paradox and to determine if alpha-def-1 might provide a means to lower cholesterol and thereby attenuate atherogenesis. We confirmed that exposing ApoE(-/-) mice to alpha-def-1 lowers total plasma cholesterol and decreases lesion size. However, lesion size was larger than in mice with total plasma cholesterol lowered to the same extent by inhibiting its adsorption or by ingesting a low-fat diet. Furthermore, alpha-def-1 levels correlated independently with lesion size in ApoE(-/-) mice. These studies show that alpha-def-1 has competing effects on atherogenesis. Although alpha-def-1 accelerates LDL clearance from plasma, it also stimulates deposition and retention of LDL in the vasculature, which may contribute to development of atherosclerosis in individuals with normal or even low plasma levels of cholesterol. Inhibiting alpha-def-1 may attenuate the impact of chronic inflammation on atherosclerotic vascular disease.