Gomes Diego Juvenal, Velosa Ana Paula, Okuda Ligia Shimabukuro, Fusco Fernanda Bueno, da Silva Karolinne Santana, Pinto Paula Ramos, Nakandakare Edna Regina, Correa-Giannella Maria Lucia, Woods Tom, Brimble Margaret Anne, Pickford Russell, Rye Kerry-Anne, Teodoro Walcy Rosolia, Catanozi Sergio, Passarelli Marisa
Lipids Laboratory (LIM 10), Medical School, University of São Paulo, São Paulo, Brazil.
Rheumatology Division (LIM 17), Medical School, University of São Paulo, São Paulo, Brazil.
J Diabetes Complications. 2016 Nov-Dec;30(8):1614-1621. doi: 10.1016/j.jdiacomp.2016.07.001. Epub 2016 Jul 5.
Advanced glycated albumin (AGE-albumin) adversely impairs macrophage lipid homeostasis in vitro, which may be prevented by angiotensin receptor blockers. In vivo studies are inconclusive whether AGE-albumin itself plays important role in early-stage atherogenesis. We aimed at investigating how AGE-albumin by itself drives atherosclerosis development in dyslipidemic non-diabetic mice and if its effects are due to the activation of renin-angiotensin system in the arterial wall and the expression of genes and proteins involved in lipid flux.
Murine albumin glycation was induced by incubation with 10mM glycolaldehyde and C-albumin with PBS alone. Twelve-week-old-male apoE knockout mice were submitted to a daily IP injection of control (C) or AGE-albumin (2mg/mL) during 30days with or without losartan (LOS: 100mg/L; C+LOS and AGE+LOS). Aortic arch was removed, and gene expression was determined by RT-PCR and protein content by immunofluorescence. Plasma lipid and glucose levels were similar among groups. Systolic blood pressure was similarly reduced in both groups treated with LOS. In comparison to C-albumin, aortic lipid infiltration was 5.3 times increased by AGE-albumin, which was avoided by LOS. LOS prevented the enhancement induced by AGE-albumin in Ager, Tnf and Cybb mRNA levels but did not reduce Olr1. Nfkb and Agt mRNA levels were unchanged by AGE-albumin. LOS similarly reduced Agtr1a mRNA level in both C and AGE-albumin groups. In AGE-albumin-treated mice, immunofluorescence for carboxymethyl-lysine, 4-hydroxynonenal and RAGE was respectively, 4.8, 2.6 and 1.7 times enhanced in comparison to C-albumin. These increases were all avoided by LOS.
AGE-albumin evokes a pre-stage of atherogenesis in dyslipidemic mice independently of the presence of diabetes mellitus or modulation in the RAS in part by the induction of lipid peroxidation and inflammation.
晚期糖基化白蛋白（AGE-白蛋白）在体外会对巨噬细胞脂质稳态产生不利影响，血管紧张素受体阻滞剂可能会预防这种影响。关于AGE-白蛋白本身在早期动脉粥样硬化形成中是否起重要作用，体内研究尚无定论。我们旨在研究AGE-白蛋白自身如何在血脂异常的非糖尿病小鼠中驱动动脉粥样硬化发展，以及其作用是否归因于动脉壁肾素-血管紧张素系统的激活以及参与脂质通量的基因和蛋白质的表达。
通过与10mM乙醇醛孵育诱导小鼠白蛋白糖基化，而对照白蛋白仅与PBS孵育。12周龄雄性载脂蛋白E基因敲除小鼠在30天内每天腹腔注射对照（C）或AGE-白蛋白（2mg/mL），同时有或没有氯沙坦（LOS：100mg/L；C+LOS和AGE+LOS）。取出主动脉弓，通过RT-PCR测定基因表达，通过免疫荧光测定蛋白质含量。各组间血浆脂质和葡萄糖水平相似。用LOS治疗的两组收缩压均有类似降低。与对照白蛋白相比，AGE-白蛋白使主动脉脂质浸润增加了5.3倍，而LOS可避免这种情况。LOS可防止AGE-白蛋白诱导的Ager、Tnf和Cybb mRNA水平升高，但未降低Olr1。AGE-白蛋白对Nfkb和Agt mRNA水平无影响。LOS在C组和AGE-白蛋白组中均同样降低了Agtr1a mRNA水平。在AGE-白蛋白处理的小鼠中，与对照白蛋白相比，羧甲基赖氨酸、4-羟基壬烯醛和RAGE的免疫荧光分别增强了4.8倍、2.6倍和1.7倍。这些增加均被LOS避免。
AGE-白蛋白在血脂异常小鼠中引发动脉粥样硬化前期，这与糖尿病的存在无关，部分是通过诱导脂质过氧化和炎症，独立于肾素-血管紧张素系统的调节。
