Effect of HDL/APOA-I deficiency on coronory atherosclerosis, extravascular lipid deposition and immune-inflammatory profile

Aim. HDL and its main protein component, apolipoprotein A-I, exert a pivotal role in regulating cell cholesterol homeostasis and in modulating inflammatory response and immune cell activation. This study was aimed at investigating the impact of genetic manipulation of HDL/apoA-I levels on lipid deposition in heart vessels and extravascular tissues in relation to local and systemic immune-inflammatory activation. Methods. ApoE deficient (EKO) mice, apoE/apoA-I double deficient (DKO) mice, DKO mice overexpressing human apoA-I (DKO/hA-I) and C57Bl/6 control mice were fed chow diet until 30 weeks of age. Plasma lipids were quantified, atherosclerosis development at the aor tic sinus and in coronary arteries was measured, skin ultrastructure was evaluated by electron microscopy. Blood and lymphoid organs were characterized through histological, immunocytofluorimetric and whole transcriptome analyses. Results. DKO mice were characterized by an almost complete lack of plasma HDL-cholesterol and by total cholesterol levels comparable to those of control mice. Only DKO mice showed severe alterations of skin morphology and skin-draining lymph nodes, whose transcriptome analysis revealed increased activation of the immune system and an unbalanced expression of genes involved in energy metabolism. An increased presence of CD4+ T ef fector memor y cells was detected in blood, spleen and in the skin-draining lymph nodes of DKO mice. A worsening of atherosclerosis at the aor tic sinus and coronar y ar teries was also observed in DKO mice vs EKO mice. Human apoA-I overexpression in the DKO background was able to rescue the skin phenotype and to halt atherosclerosis development. Conclusions. HDL deficiency, in the absence of hyperlipidemia, is associated with severe alterations of skin morphology, coronary atherosclerosis, local and systemic inflammation.