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 α-def-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.
Highlights
We found that using cholestyramine or diet modification to lower plasma cholesterol and low-density lipoprotein (LDL) in ApoE-/- mice to the levels seen in ApoE−/−human neutrophil peptides (HNPs)-1tg/tg leads to smaller lipid streaks than those developed in ApoE-/- mice exposed to exogenous α-def-1
We examined the effect of exogenous α-def-1 on total plasma cholesterol (TCH) and the extent of fatty streaks formed in the aortic roots of ApoE-/- mice fed a high fat diet (HFD)
We previously reported data suggesting that α-defensins promote atherogenesis, based on studies in transgenic mice expressing α-def-1 in their neutrophils[12] (Def++ mice) that have been fed a high fat diet[12] and by the correlation in humans between tissue deposition of αdefensins and the severity of coronary artery disease[5]
Summary
Atherosclerosis and its thrombotic sequelae are the predominant causes of death in highly resourced countries and its incidence is increasing in “developing” parts of the world[1].PLOS ONE | https://doi.org/10.1371/journal.pone.0231582 April 17, 2020Opposing effects of α-defensin-1 on plasma cholesterol and atherogenesis included in the method section. The methodology section regarding the quantification of lipid deposition was expanded. Photographic evidence supporting the intimal damage score results shown in Fig 1B were added in the new Fig 1C.
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
