Targeted reduction of vascular Msx1 and Msx2 mitigates arteriosclerotic calcification and aortic stiffness in LDLR-deficient mice fed diabetogenic diets.
Targeted reduction of vascular Msx1 and Msx2 mitigates arteriosclerotic calcification and aortic stiffness in LDLR-deficient mice fed diabetogenic diets.
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作者：
Cheng SL;Behrmann A;Shao JS;Ramachandran B;Krchma K;Bello Arredondo Y;Kovacs A;Mead M;Maxson R;Towler DA
当喂食高脂饲料时，雄性LDLR−/−小鼠会出现肥胖、高脂血症、高血糖和动脉钙化。成骨Msx-Wnt调节程序在脉管系统中伴随上调。为了更好地了解糖尿病动脉硬化的机制，我们产生了SM 22-Cre; Msx 1（fl/fl）; Msx 2（fl/fl）;LDLR−/−小鼠，评估Msx 1 + Msx 2基因缺失对血管肌成纤维细胞和平滑肌细胞的影响。与Msx 1（fl/fl）; Msx 2（fl/fl）;LDLR−/−对照组相比，SM 22-Cre; Msx 1（fl/fl）; Msx 2（fl/fl）; LDLR −/−动物的主动脉Msx 2和Msx 1分别降低了95%和34%。与对照组相比，SM 22-Cre; Msx 1（fl/fl）; Msx 2（fl/fl）;LDLR−/−小鼠的主动脉钙降低了31%，脉搏波速度（僵硬指数）降低。空腹血糖和血脂没有差异，但SM 22-Cre; Msx 1（fl/fl）; Msx 2（fl/fl）;LDLR−/−兄弟姐妹变得更加肥胖。来自SM 22-Cre; Msx 1（fl/fl）; Msx 2（fl/fl）;LDLR−/−小鼠的主动脉外膜肌成纤维细胞表现出成骨基因表达和矿化潜力降低，同时多个Wnt基因降低。主动脉成骨祖细胞的标志物Sonic hedgehog（Shh）和Sca 1也减少，与碱性磷酸酶（TNAP）阳性外膜肌成纤维细胞减少78%平行。RNA干扰显示，虽然Msx 1 + Msx 2支持TNAP和Wnt 7 b的表达，Msx 1选择性地维持Shh和Msx 2维持Wnt 2，Wnt 5a和Sca 1在主动脉外膜肌成纤维细胞培养表达。因此，Msx 1和Msx 2通过指导糖尿病动脉硬化中主动脉祖细胞的成骨编程来支持血管矿化。
When fed high-fat diets, male LDLR−/− mice develop obesity, hyperlipidemia, hyperglycemia, and arteriosclerotic calcification. An osteogenic Msx-Wnt regulatory program is concomitantly upregulated in the vasculature. To better understand the mechanisms of diabetic arteriosclerosis, we generated SM22-Cre;Msx1(fl/fl);Msx2(fl/fl);LDLR−/− mice, assessing the impact of Msx1+Msx2 gene deletion in vascular myofibroblast and smooth muscle cells. Aortic Msx2 and Msx1 were decreased by 95% and 34% in SM22-Cre;Msx1(fl/fl);Msx2(fl/fl);LDLR−/− animals versus Msx1(fl/fl);Msx2(fl/fl);LDLR−/− controls, respectively. Aortic calcium was reduced by 31%, and pulse wave velocity, an index of stiffness, was decreased in SM22-Cre;Msx1(fl/fl);Msx2(fl/fl);LDLR−/− mice vs. controls. Fasting blood glucose and lipids did not differ, yet SM22-Cre;Msx1(fl/fl);Msx2(fl/fl);LDLR−/− siblings became more obese. Aortic adventitial myofibroblasts from SM22-Cre;Msx1(fl/fl);Msx2(fl/fl);LDLR−/− mice exhibited reduced osteogenic gene expression and mineralizing potential with concomitant reduction in multiple Wnt genes. Sonic hedgehog (Shh) and Sca1, markers of aortic osteogenic progenitors, were also reduced, paralleling a 78% reduction in alkaline phosphatase (TNAP)–positive adventitial myofibroblasts. RNA interference revealed that although Msx1+Msx2 supports TNAP and Wnt7b expression, Msx1 selectively maintains Shh and Msx2 sustains Wnt2, Wnt5a, and Sca1 expression in aortic adventitial myofibroblast cultures. Thus, Msx1 and Msx2 support vascular mineralization by directing the osteogenic programming of aortic progenitors in diabetic arteriosclerosis.
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影响因子：
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作者：
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通讯作者：
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影响因子：
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作者：
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DOI：
10.1073/pnas.0504750102
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影响因子：
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影响因子：
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作者：
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DOI：
10.1161/atvbaha.107.153668
发表时间：
2007-12-01
影响因子：
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通讯作者：
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