RESUMO
The long-term effect of elevated levels of human apolipoprotein AI (apoAI) on atherosclerosis was assessed using human apoAI transgenic mice on a double mutant LDL receptor-deficient (LDLr-/-) and mouse apoAI-deficient (apoAI-/-) background. When they were fed a high fat diet, atherosclerosis in transgenic human apoAI, LDLr-/-, apoAI-/- mice (huapoAITg) was compared with LDLr-/- mice that expressed normal amounts of apoAI (msapoAI) or LDLr-/- mice that lacked mouse apoAI (noapoAI). The atheroprotective effect of human apoAI was demonstrated by a greater than six-fold inhibition in lesion areas in the aortic wall and heart valves compared to the two control strains after 27 or 36 weeks. Plasma apoAI concentrations in huapoAITg mice were considerably higher than in msapoAI mice (600 and 37 mg/dL, respectively). The human apoAI transgene led to several plasma HDL subpopulations, with high levels of prebeta-HDL and a significant decrease in total plasma cholesterol. This was observed without a change in total HDL cholesterol levels. Thus, elevated levels of human apoAI in LDL receptor-deficient mice lacking mouse apoAI conferred profound protection against diet-induced over extended periods of time.
Assuntos
Apolipoproteína A-I/genética , Expressão Gênica , Receptores de LDL/deficiência , Animais , Apolipoproteína A-I/sangue , Aterosclerose/sangue , Aterosclerose/genética , Aterosclerose/prevenção & controle , Biomarcadores/sangue , HDL-Colesterol/sangue , Cromatografia Líquida , Modelos Animais de Doenças , Eletroforese em Gel de Ágar , Seguimentos , Humanos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Proteínas de Transferência de Fosfolipídeos/sangue , Fatores de TempoRESUMO
Systemic phospholipid transfer protein (PLTP) is a recognized risk factor for coronary heart disease. In apolipoprotein E-deficient mice, systemic PLTP deficiency is atheroprotective, whereas PLTP overexpression is proatherogenic. As expected, we also observed significantly smaller lesions (P < 0.0001) in hypercholesterolemic double mutant low density lipoprotein receptor-deficient (LDLr(-/-)) PLTP-deficient (PLTP(-/-)) mice compared with LDLr(-/-) mice expressing systemic PLTP. To assess the specific contribution of only macrophage-derived PLTP to atherosclerosis progression, bone marrow transplantation was performed in LDLr(-/-) mice that also lacked systemic PLTP. Groups of double mutant PLTP(-/-)LDLr(-/-) mice were irradiated with 1,000 rad and injected with bone marrow (BM) cells collected from either PLTP(-/-) or wild-type mice. When fed a high-fat diet, BM cell expression of PLTP decreased plasma cholesterol of PLTP(-/-)LDLr(-/-) mice from 878 +/- 220 to 617 +/- 183 mg/dl and increased HDL cholesterol levels from 54 +/- 11 to 117 +/- 19 mg/dl. This decreased total plasma cholesterol and increased HDL cholesterol contributed to the significantly smaller atherosclerotic lesions in both aortas and heart sinus valves observed in these mice. Thus, unlike total systemic PLTP, locally produced macrophage-derived PLTP beneficially alters lipoprotein metabolism and reduces lesion progression in hyperlipidemic mice.