Endothelial dysfunction plays a crucial role in the progress of diabetic vasculopathy. C1q/tumor necrosis factor–related protein 13 (CTRP13) is a secreted adipokine that can ameliorate atherosclerosis and vascular calcification. However, the role of CTRP13 in regulating endothelial function in diabetes has yet to be explored. In this study, CTRP13 treatment improved endothelium-dependent relaxation in the aortae and mesenteric arteries of both db/db mice and streptozotocin-injected mice. CTRP13 supplement also rescued the impaired endothelium-dependent relaxation ex vivo in the db/db mouse aortae and in high glucose (HG)–treated mouse aortae. Additionally, CTRP13 treatment reduced reactive oxygen species overproduction and improved nitric oxide (NO) production and endothelial NO synthase (eNOS) coupling in the aortae of diabetic mice and in HG-treated human umbilical vein endothelial cells. Mechanistically, CTRP13 could increase GTP cyclohydrolase 1 (GCH1) expression and tetrahydrobiopterin (BH4) levels to ameliorate eNOS coupling. More importantly, CTRP13 rescued HG-induced inhibition of protein kinase A (PKA) activity. Increased PKA activity enhanced phosphorylation of the peroxisome proliferator–activated receptor α and its recruitment to the GCH1 promoter, thus activating GCH1 transcription and, ultimately, endothelial relaxation. Together, these results suggest that CTRP13 preserves endothelial function in diabetic mice by regulating GCH1/BH4 axis-dependent eNOS coupling, suggesting the therapeutic potential of CTRP13 against diabetic vasculopathy.

中文翻译：

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CTRP13 通过靶向糖尿病中的 GTP 环化水解酶 1 来保持内皮功能

内皮功能障碍在糖尿病血管病变的进展中起着至关重要的作用。C1q/肿瘤坏死因子相关蛋白 13 (CTRP13) 是一种分泌性脂肪因子，可以改善动脉粥样硬化和血管钙化。然而，CTRP13在调节糖尿病内皮功能中的作用还有待探索。在这项研究中，CTRP13 治疗改善了 db/db 小鼠和注射链脲佐菌素的小鼠的主动脉和肠系膜动脉的内皮依赖性松弛。CTRP13 补充剂还在 db/db 小鼠主动脉和高糖 (HG) 处理的小鼠主动脉中挽救了体外受损的内皮依赖性松弛。此外，CTRP13 处理减少了糖尿病小鼠主动脉和 HG 处理的人脐静脉内皮细胞中的活性氧过量产生并改善了一氧化氮 (NO) 产生和内皮 NO 合酶 (eNOS) 偶联。从机制上讲，CTRP13 可以增加 GTP 环化水解酶 1 (GCH1) 表达和四氢生物蝶呤 (BH4) 水平，以改善 eNOS 偶联。更重要的是，CTRP13 挽救了 HG 诱导的蛋白激酶 A (PKA) 活性抑制。增加的 PKA 活性增强了过氧化物酶体增殖物激活受体 α 的磷酸化及其向 GCH1 启动子的募集，从而激活 GCH1 转录，并最终激活内皮松弛。总之，这些结果表明 CTRP13 通过调节 GCH1/BH4 轴依赖性 eNOS 耦合来保护糖尿病小鼠的内皮功能，