Institute of Laboratory Medicine, Clinical Chemistry and Molecular Diagnostic, University Hospital Leipzig, 04103 Leipzig, Germany.
Institute of Experimental Internal Medicine, Medical Faculty, Otto von Guericke University, Leipziger Str. 44, 39120 Magdeburg, Germany.
Nutrients. 2022 May 10;14(10):1991. doi: 10.3390/nu14101991.
Diabetes mellitus, which is largely driven by nutritional and behavioral factors, is characterized by accelerated atherosclerosis with impaired plaque stability. Atherosclerosis and associated complications are the major cause of mortality in diabetic patients. Efficient therapeutic concepts for diabetes-associated atherosclerosis are lacking. Atherosclerosis among diabetic patients is associated with reduced endothelial thrombomodulin (TM) expression and impaired activated protein C (aPC) generation. Here, we demonstrate that atherosclerotic plaque stability is reduced in hyperglycemic mice expressing dysfunctional TM (TM mice), which have a pro-coagulant phenotype due to impaired thrombin inhibition and markedly reduced aPC generation. The vessel lumen and plaque size of atherosclerotic lesions in the truncus brachiocephalic were decreased in diabetic TM ApoE mice compared to diabetic ApoE mice. While lipid accumulation in lesions of diabetic TM ApoE mice was lower than that in diabetic ApoE mice, morphometric analyses revealed more prominent signs of instable plaques, such as a larger necrotic core area and decreased fibrous cap thickness in diabetic TM ApoE mice. Congruently, more macrophages and fewer smooth muscle cells were observed within lesions of diabetic TM ApoE mice. Thus, impaired TM function reduces plaque stability, a characteristic of hyperglycemia-associated plaques, thus suggesting the crucial role of impaired TM function in mediating diabetes-associated atherosclerosis.
糖尿病主要由营养和行为因素驱动，其特征是动脉粥样硬化加速，斑块稳定性受损。动脉粥样硬化和相关并发症是糖尿病患者死亡的主要原因。缺乏针对糖尿病相关动脉粥样硬化的有效治疗概念。糖尿病患者的动脉粥样硬化与内皮血栓调节蛋白 (TM) 表达减少和激活蛋白 C (aPC) 生成受损有关。在这里，我们证明了表达功能失调 TM 的高血糖小鼠（TM 小鼠）中动脉粥样硬化斑块的稳定性降低，由于凝血酶抑制受损和 aPC 生成明显减少，这些小鼠具有促凝表型。与糖尿病 ApoE 小鼠相比，糖尿病 TM ApoE 小鼠的肱动脉干粥样硬化病变的血管腔和斑块大小减小。尽管糖尿病 TM ApoE 小鼠病变中的脂质积累低于糖尿病 ApoE 小鼠，但形态学分析显示更明显的不稳定斑块迹象，例如糖尿病 TM ApoE 小鼠中的坏死核心区域更大，纤维帽厚度减小。一致地，糖尿病 TM ApoE 小鼠的病变中观察到更多的巨噬细胞和更少的平滑肌细胞。因此，TM 功能受损会降低斑块稳定性，这是与高血糖相关斑块的特征，这表明 TM 功能受损在介导糖尿病相关动脉粥样硬化中起着至关重要的作用。
