Downregulated calmodulin expression contributes to endothelial cell impairment in diabetes
Downregulated calmodulin expression contributes to endothelial cell impairment in diabetes
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DOI：
10.1038/s41401-023-01127-1
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发表时间：
2023-07-19
影响因子：
8.2
通讯作者：
Luo，Da-li
中科院分区：
文献类型：
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作者：
Liu，Tian-tian;Xu，Huan-huan;Luo，Da-li
内皮功能障碍是糖尿病心血管发病机制的中心标志，其特征在于内皮型一氧化氮合酶（eNOS）和NO生物利用度受损。然而，其潜在机制仍不清楚。在这项研究中，我们的目的是确定钙调素（CaM）在糖尿病eNOS功能障碍中的作用。高糖（HG）处理的人脐静脉内皮细胞和小鼠内皮祖细胞（EPCs）表现出下调的CaM mRNA/蛋白和血管内皮生长因子（VEGF）表达，并阻碍eNOS磷酸化和细胞迁移/管形成。这些扰动在CALM 1敲除细胞中重复，但在CALM 1过表达细胞中被阻止。2型糖尿病动物的EPCs表现出与HG处理的正常EPCs相似的行为，这可以通过CALM 1基因转导来拯救。一致地，糖尿病动物显示受损的eNOS磷酸化，内皮依赖性扩张，和钙调素在主动脉中的表达，以及在腓肠肌中的钙调素和eNOS的物理相互作用不足。将LocalCALM 1基因递送到糖尿病小鼠缺血后肢中改善了钝肢体血液灌注和腓肠肌血管生成以及足部损伤。糖尿病患者足部微血管自身调节不足，eNOS磷酸化和NO生成不足，动脉内皮中CaM表达下调，全基因组测序分析显示CALM 1转录异常。因此，我们的研究结果表明，下调钙调素的表达是负责内皮功能障碍和血管生成障碍的糖尿病，并提供了一个新的机制和目标，以防止糖尿病内皮损伤。
Endothelial dysfunction, a central hallmark of cardiovascular pathogenesis in diabetes mellitus, is characterized by impaired endothelial nitric oxide synthase (eNOS) and NO bioavailability. However, the underlying mechanisms remain unclear. Here in this study, we aimed to identify the role of calmodulin (CaM) in diabetic eNOS dysfunction. Human umbilical vein endothelial cells and murine endothelial progenitor cells (EPCs) treated with high glucose (HG) exhibited downregulated CaM mRNA/protein and vascular endothelial growth factor (VEGF) expression with impeded eNOS phosphorylation and cell migration/tube formation. These perturbations were reduplicated inCALM1-knockdown cells but prevented inCALM1-overexpressing cells. EPCs from type 2 diabetes animals behaved similarly to HG-treated normal EPCs, which could be rescued byCALM1-gene transduction. Consistently, diabetic animals displayed impaired eNOS phosphorylation, endothelium-dependent dilation, and CaM expression in the aorta, as well as deficient physical interaction of CaM and eNOS in the gastrocnemius. LocalCALM1gene delivery into a diabetic mouse ischemic hindlimb improved the blunted limb blood perfusion and gastrocnemius angiogenesis, and foot injuries. Diabetic patients showed insufficient foot microvascular autoregulation, eNOS phosphorylation, and NO production with downregulated CaM expression in the arterial endothelium, and abnormalCALM1transcription in genome-wide sequencing analysis. Therefore, our findings demonstrated that downregulated CaM expression is responsible for endothelium dysfunction and angiogenesis impairment in diabetes, and provided a novel mechanism and target to protect against diabetic endothelial injury.