Center for Experimental Therapeutics and Reperfusion Injury, Department of Anesthesiology, Perioperative and Pain Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts 02115, USA.
Am J Pathol. 2012 Jan;180(1):104-12. doi: 10.1016/j.ajpath.2011.09.026. Epub 2011 Nov 8.
Diabetes, stress, pharmaceuticals, surgery, and physical trauma can lead to hyperglycemic conditions. A consistent relationship has been found between chronic inflammation and the cardiovascular complications of hyperglycemia. We hypothesized that cardiomyopathy and vasculopathy resulting from acute hyperglycemia are dependent on mannose-binding lectin (MBL) and lectin complement pathway activation. Hyperglycemia was induced in wild-type (WT) C57BL/6 and MBL-null mice after streptozotocin administration. Echocardiographic data and tissue samples were collected after 4, 7, or 14 days of acute hyperglycemia. Hyperglycemic WT mice demonstrated dilated cardiomyopathy with significantly increased short and long axis area measurements during systole and diastole compared to hyperglycemic MBL-null mice. The EC(50) for acetylcholine-induced relaxation of mesenteric arterioles in WT mice after 4 days of hyperglycemia demonstrated a significant loss of nitric oxide-mediated relaxation compared to normoglycemic WT or hyperglycemic MBL-null mice. Myocardial histochemistry and Western blot analysis revealed a significant influx of macrophages, altered morphology, and increased elastin and collagen deposition in hyperglycemic WT hearts compared to MBL-null hearts. Serum transforming growth factor-β1 levels were significantly lower in hyperglycemic MBL-null compared to WT mice, suggesting decreased profibrotic signaling. Together, these data suggest that MBL and the lectin complement pathway play a significant role in vascular dysfunction and cardiomyopathy after acute hyperglycemia.
糖尿病、压力、药物、手术和身体创伤会导致高血糖症。慢性炎症与高血糖引起的心血管并发症之间存在一致的关系。我们假设急性高血糖引起的心肌病和血管病变依赖于甘露糖结合凝集素 (MBL) 和凝集素补体途径的激活。链脲佐菌素给药后，在野生型 (WT) C57BL/6 和 MBL 缺失小鼠中诱导高血糖症。在急性高血糖症 4、7 或 14 天后收集超声心动图数据和组织样本。与高血糖 MBL 缺失小鼠相比，高血糖 WT 小鼠在收缩期和舒张期显示扩张型心肌病，短轴和长轴面积测量明显增加。与正常血糖 WT 或高血糖 MBL 缺失小鼠相比，高血糖 4 天后 WT 小鼠肠系膜小动脉乙酰胆碱诱导舒张的 EC(50) 显示一氧化氮介导的舒张明显丧失。心肌组织化学和 Western blot 分析显示，与 MBL 缺失小鼠相比，高血糖 WT 心脏中的巨噬细胞大量涌入，形态发生改变，弹性蛋白和胶原蛋白沉积增加。与 WT 小鼠相比，高血糖 MBL 缺失小鼠的血清转化生长因子-β1 水平明显降低，提示促纤维化信号减少。综上所述，这些数据表明 MBL 和凝集素补体途径在急性高血糖后血管功能障碍和心肌病中起重要作用。
