Rajala Rahul, Griffin Courtney T
Cardiovascular Biology Research Program, Oklahoma Medical Research Foundation (R.R., C.T.G.).
Department of Cell Biology (R.R., C.T.G.), University of Oklahoma Health Sciences Center.
Arterioscler Thromb Vasc Biol. 2025 Jul 31. doi: 10.1161/ATVBAHA.125.323140.
Thrombin, a serine protease with increased activity in people with diabetes, signals through PAR (protease-activated receptor) 1 and 4 on endothelial cells (ECs). On these cells, PAR1 is a high-expressing, high-affinity, low-potency thrombin receptor, whereas PAR4 is a low-expressing, low-affinity, high-potency receptor. This study aims to determine how endothelial PARs influence diabetic pathology, thereby providing deeper insights into the roles and relationships between these receptors.
We generated mice with inducible deletion of in ECs () and induced diabetes with streptozotocin treatment. Blood glucose and insulin levels were assessed after streptozotocin administration. In addition, we measured insulin and glucose tolerance in mice. Lastly, we measured how the loss of endothelial PARs in cultured primary ECs affected IR (insulin receptor) activity/phosphorylation, and insulin transcytosis.
Although studying the roles of endothelial PAR1/4 in diabetic pathology, we found that mice displayed increased insulin sensitivity and were protected against streptozotocin-induced diabetes. Concordantly, we found that cultured primary ECs with PAR1/4 deficiency exhibited increased basal activity and phosphorylation of IR, as well as enhanced insulin transcytosis. This elevated IR activity correlated with reduced activity of PTP1B (protein tyrosine phosphatase 1B), a negative regulator of IR. Lastly, mice with additional deletion of 1 allele of the endothelial IR gene demonstrated restoration of diabetic phenotypes after streptozotocin treatment, indicating that insulin sensitivity in mice was driven by heightened IR activity in ECs.
These findings establish a novel link between endothelial PAR signaling and IR regulation, underscoring the critical role of ECs in metabolic homeostasis and identifying a potential therapeutic target for diabetes.
凝血酶是一种丝氨酸蛋白酶，在糖尿病患者中活性增加，通过内皮细胞（ECs）上的蛋白酶激活受体（PAR）1和4发出信号。在这些细胞上，PAR1是一种高表达、高亲和力、低效的凝血酶受体，而PAR4是一种低表达、低亲和力、高效的受体。本研究旨在确定内皮PARs如何影响糖尿病病理，从而更深入地了解这些受体之间的作用和关系。
我们构建了在内皮细胞中可诱导缺失（）的小鼠，并用链脲佐菌素诱导糖尿病。给予链脲佐菌素后评估血糖和胰岛素水平。此外，我们测量了小鼠的胰岛素和葡萄糖耐量。最后，我们测量了培养的原代内皮细胞中内皮PARs的缺失如何影响胰岛素受体（IR）活性/磷酸化以及胰岛素转胞吞作用。
在研究内皮PAR1/4在糖尿病病理中的作用时，我们发现小鼠表现出胰岛素敏感性增加，并对链脲佐菌素诱导的糖尿病具有保护作用。一致地，我们发现缺乏PAR1/4的培养原代内皮细胞表现出基础IR活性和磷酸化增加，以及胰岛素转胞吞作用增强。这种升高的IR活性与IR的负调节因子蛋白酪氨酸磷酸酶1B（PTP1B）的活性降低相关。最后，内皮IR基因的1个等位基因额外缺失的小鼠在链脲佐菌素治疗后表现出糖尿病表型的恢复，表明小鼠的胰岛素敏感性是由内皮细胞中IR活性的升高驱动的。
这些发现在内皮PAR信号传导与IR调节之间建立了新的联系，强调了内皮细胞在代谢稳态中的关键作用，并确定了糖尿病的潜在治疗靶点。
