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

Abstract

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 α-def-1 released from activated neutrophils develop larger lipid and macrophage-rich lesions in the proximal aortae notwithstanding hypocholesterolemia caused by accelerated clearance of α-def-1/low-density lipoprotein (LDL) complexes from the plasma. The phenotype does not develop when the release of αdef-1 is prevented with colchicine. However, ApoE-/mice crossed with α-def-1 mice or given exogenous α-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 α-def-1 might provide a means to lower cholesterol and thereby attenuate atherogenesis. We confirmed that exposing ApoE-/mice to α-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, α-def-1 levels correlated independently with lesion size in ApoE-/mice. These studies show that α-def-1 has competing effects on atherogenesis. Although α-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 α-def-1 may attenuate the impact of chronic inflammation on atherosclerotic vascular disease.

Association between tissue human neutrophil peptide 1–3 levels and cardiovascular phenotype: a prospective, longitudinal cohort study

“… 23 They claimed a potent atheroprotective effect of HNP ascribed to a reduction in plasma LDL-cholesterol levels by facilitating the clearance of LDL particles in the liver via the LDL receptor. In a follow-up study using ApoE −/− mice from our laboratory, 24 we showed a similar cholesterol-lowering effect of HNP and cholestyramine in mice, which led to a lower aortic lesion size than in ApoE −/− mice. However, the lesion size was larger in mice administered HNP than those administered cholestyramine.…”

Colchicine for COVID-19: targeting NLRP3 inflammasome to blunt hyperinflammation

“…Colchicine was also demonstrated to play a role in the crosstalk between inflammation and thrombosis, although most evidence on this derives from pre-clinical studies. Colchicine can inhibit the release of α-defensin from neutrophils in mice, thus reducing the size of thrombi [ 79 , 80 ]. Colchicine was also found to deform platelets through its effect on microtubules and block calcium entry into platelets [ 81 ], thus reducing platelet activity.…”

Contemporary Lifestyle and Neutrophil Extracellular Traps: An Emerging Link in Atherosclerosis Disease

“…Human neutrophil peptide 1 (HNP1) forms a heteromer with platelet-derived CCL5 that binds to the healthy endothelium and promotes recruitment of monocytes by CCR5 binding [118]. On a different note, neutrophil-derived alpha-defensin-1, also known as HNP1, captures LDL particles in the vessel wall and contributes to lipoprotein retention [119,120]. Alarmins such as the neutrophil-derived azurocidin, also known as HBP, can also stimulate ROS formation in circulating monocytes and activated macrophages, promoting their development into foam cells, thus leading to enhanced pro-inflammatory cytokine release and phagocytic activity [121,122].…”