Increased atherosclerotic lesion calcification in a novel mouse model combining insulin resistance, hyperglycemia, and Hypercholesterolemia
Increased atherosclerotic lesion calcification in a novel mouse model combining insulin resistance, hyperglycemia, and Hypercholesterolemia
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DOI：
10.1161/circresaha.107.154401
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发表时间：
2007-11-09
影响因子：
20.1
通讯作者：
Ylae-Herttuala, Seppo
中科院分区：
文献类型：
--
作者：
Heinonen, Suvi E.;Leppaenen, Pia;Ylae-Herttuala, Seppo
目前还没有可用的小鼠模型，可以在动脉粥样硬化背景下诱导2型糖尿病，而不伴随显著的血脂水平变化。我们杂交了2个转基因小鼠品系，以获得一种既表达动脉粥样硬化又表达2型糖尿病特征的模型。对于动脉粥样硬化的背景，我们使用了只合成载脂蛋白B100(LDLR-/-ApoB(100/100))的低密度脂蛋白受体缺陷小鼠。糖尿病背景来源于在胰岛β细胞中高表达胰岛素样生长因子-II(IGF-II)的转基因小鼠。在6个月和15个月大的小鼠中，对正常和高脂肪西方饮食的小鼠进行了彻底的表型表征。结果表明，与高胆固醇血症小鼠LDLR-/-ApoB(100/100)相比，转IGF-II基因的LDLR-/-ApoB(100/100)小鼠表现出胰岛素抵抗、高血糖和轻度高胰岛素血症。此外，老年IGF-II/LDLR-/-ApoB(100/100)小鼠的病变钙化显著增加，这更多地与胰岛素抵抗有关，而不是与血糖水平有关，而且与钙化和炎症相关的几个基因在主动脉中的基线表达显著增加。在任何时间，IGF-II/LDLR-/-ApoB(100/100)组小鼠的血脂水平与LDLR-/-ApoB100/100对照组没有差异。总之，在一种新的糖尿病大血管病变小鼠模型中，2型糖尿病因素导致钙化和病变进展增加，而没有任何脂质变化。
No mouse model is currently available where the induction of type 2 diabetes on an atherosclerotic background could be achieved without significant concomitant changes in plasma lipid levels. We crossbred 2 genetically modified mouse strains to achieve a model expressing both atherosclerosis and characteristics of type 2 diabetes. For atherosclerotic background we used low-density lipoprotein receptor-deficient mice synthetizing only apolipoprotein B100 (LDLR-/- ApoB(100/100)). Diabetic background was obtained from transgenic mice overexpressing insulin-like growth factor-II (IGF-II) in pancreatic beta cells. Thorough phenotypic characterization was performed in 6- and 15-month-old mice on both normal and high-fat Western diet. Results indicated that IGF-II transgenic LDLR-/- ApoB(100/100) mice demonstrated insulin resistance, hyperglycemia, and mild hyperinsulinemia compared with hypercholesterolemic LDLR-/- ApoB(100/100) controls. In addition, old IGF-II/LDLR-/- ApoB(100/100) mice displayed significantly increased lesion calcification, which was more related to insulin resistance than glucose levels, and significantly higher baseline expression in aorta of several genes related to calcification and inflammation. Lipid levels of IGF-II/LDLR-/- ApoB(100/100) mice did not differ from LDLR-/- ApoB100/100 controls at any time. In conclusion, type 2 diabetic factors induce increased calcification and lesion progression without any lipid changes in a new mouse model of diabetic macroangiopathy.