Myocyte specific overexpression of myoglobin impairs angiogenesis after hind-limb ischemia.
Myocyte specific overexpression of myoglobin impairs angiogenesis after hind-limb ischemia.
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DOI：
10.1161/atvbaha.108.170951
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发表时间：
2008-12
期刊：
影响因子：
--
通讯作者：
Annex BH
中科院分区：
文献类型：
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作者：
Hazarika S;Angelo M;Li Y;Aldrich AJ;Odronic SI;Yan Z;Stamler JS;Annex BH
在外周动脉疾病的临床前模型中，血管生成反应通常是强大的，尽管在高胆固醇血症和糖尿病等内皮功能障碍的情况下，血管生成反应可能会受到损害。肌红蛋白(Mb)仅在横纹肌细胞中表达。我们假设，即使在正常内皮存在的情况下，肌细胞特异性的肌红蛋白过表达也能减弱缺血诱导的血管生成。MB高表达转基因(MbTg，n=59)和野生型(WT，n=56)C57BL/6小鼠进行单侧股动脉结扎/切除。用激光多普勒监测血流灌注恢复情况。用蛋白质和免疫组织化学方法检测缺血诱导的肌肉变化。测定亚硝酸盐/硝酸盐、蛋白结合态NO和血管反应性。MbTg和WT的血管反应性相似。在缺血肌肉中，在结扎后第14天，MbTg与WT小鼠一样，增加了VEGF-A，激活了eNOS，但硝酸盐/亚硝酸盐降低，蛋白结合NO升高。MbTg在d21(0.37±0.03vs0.47±0.02，P<；0.05)、d28(0.40±0.03vs0.50±0.04，P<；0.05)、更大的肢体坏死率(65.2%比15%，P<；0.001)、更低的毛细血管密度和更多的细胞凋亡。心肌细胞Mb表达增加通过结合NO和降低其生物利用度来减少后肢缺血后的血管生成。肌红蛋白即使在正常血管内皮细胞的情况下也能调节对缺血的血管生成反应。
In preclinical models of peripheral arterial disease the angiogenic response is typically robust, though it can be impaired in conditions such as hypercholesterolemia and diabetes where the endothelium is dysfunctional. Myoglobin (Mb) is expressed exclusively in striated muscle cells. We hypothesized that myocyte specific overexpression of myoglobin attenuates ischemia-induced angiogenesis even in the presence of normal endothelium. Mb overexpressing transgenic (MbTg, n=59) and wild-type (WT, n=56) C57Bl/6 mice underwent unilateral femoral artery ligation/excision. Perfusion recovery was monitored using Laser Doppler. Ischemia-induced changes in muscle were assessed by protein and immunohistochemistry assays. Nitrite/nitrate and protein-bound NO, and vasoreactivity was measured. Vasoreactivity was similar between MbTg and WT. In ischemic muscle, at d14 postligation, MbTg increased VEGF-A, and activated eNOS the same as WT mice but nitrate/nitrite were reduced whereas protein-bound NO was higher. MbTg had attenuated perfusion recovery at d21 (0.37±0.03 versus 0.47±0.02, P<0.05), d28 (0.40±0.03 versus 0.50±0.04, P<0.05), greater limb necrosis (65.2% versus 15%, P<0.001), a lower capillary density, and greater apoptosis versus WT. Increased Mb expression in myocytes attenuates angiogenesis after hind-limb ischemia by binding NO and reducing its bioavailability. Myoglobin can modulate the angiogenic response to ischemia even in the setting of normal endothelium.