Background and Aims: ApoA-I/HDL play a unique role in regulating cell cholesterol homeostasis and in modulating inflammatory response and immune cell activation. In the present study, we investigated the impact of genetic manipulation of apoA-I/HDL levels on lipid deposition in skin and heart vessels 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 wild-type mice were fed chow diet until 30 weeks of age. Plasma lipids were quantified, atherosclerosis development at the aortic sinus and in coronary arteries was measured, skin ultrastructure was evaluated by electron mi- croscopy. Blood and lymphoid organs were characterized through histological, immunocytofluorimetric and whole transcriptome analyses. Results: DKO mice were characterized by almost complete HDL deficiency and by plasma total cholesterol levels comparable to those of control mice. Only DKO mice showed xanthoma formation and severe inflammation in the skin-draining lymph nodes, whose transcriptome analysis revealed a dramatic impairment in energy metabolism and fatty acid oxidation pathways. An increased presence of CD4+ T effector memory cells was detected in blood, spleen and in the skin-draining lymph nodes of DKO mice. A worsening of atherosclerosis at the aortic sinus and coronary arteries 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, aortic and coronary atherosclerosis, local and systemic inflammation.
APOA-I deficiency in APOE-Knockout mice induces coronary atherosclerosis and perturbs systemic inflammation / G. Chiesa, S. Manzini, A. Colombo, E. Donetti, E. Scanziani, D. Norata, M. Busnelli. - In: ATHEROSCLEROSIS. - ISSN 1879-1484. - 331:(2021), pp. e2-e2. (Intervento presentato al convegno European Atherosclerosis Society (EAS) tenutosi a Helsinki nel 2021).
APOA-I deficiency in APOE-Knockout mice induces coronary atherosclerosis and perturbs systemic inflammation
G. Chiesa
;S. Manzini;A. Colombo;E. Donetti;E. Scanziani;D. Norata;M. Busnelli
2021
Abstract
Background and Aims: ApoA-I/HDL play a unique role in regulating cell cholesterol homeostasis and in modulating inflammatory response and immune cell activation. In the present study, we investigated the impact of genetic manipulation of apoA-I/HDL levels on lipid deposition in skin and heart vessels 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 wild-type mice were fed chow diet until 30 weeks of age. Plasma lipids were quantified, atherosclerosis development at the aortic sinus and in coronary arteries was measured, skin ultrastructure was evaluated by electron mi- croscopy. Blood and lymphoid organs were characterized through histological, immunocytofluorimetric and whole transcriptome analyses. Results: DKO mice were characterized by almost complete HDL deficiency and by plasma total cholesterol levels comparable to those of control mice. Only DKO mice showed xanthoma formation and severe inflammation in the skin-draining lymph nodes, whose transcriptome analysis revealed a dramatic impairment in energy metabolism and fatty acid oxidation pathways. An increased presence of CD4+ T effector memory cells was detected in blood, spleen and in the skin-draining lymph nodes of DKO mice. A worsening of atherosclerosis at the aortic sinus and coronary arteries 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, aortic and coronary atherosclerosis, local and systemic inflammation.File | Dimensione | Formato | |
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