Activation of Transient Receptor Potential Channel Vanilloid 4 by DPP-4 (Dipeptidyl Peptidase-4) Inhibitor Vildagliptin Protects Against Diabetic Endothelial Dysfunction
Activation of Transient Receptor Potential Channel Vanilloid 4 by DPP-4 (Dipeptidyl Peptidase-4) Inhibitor Vildagliptin Protects Against Diabetic Endothelial Dysfunction
复制标题
DPP-4（二肽基肽酶 4）抑制剂维格列汀激活瞬时受体电位通道 Vanilloid 4，可预防糖尿病内皮功能障碍。
DOI：
10.1161/hypertensionaha.119.13778
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发表时间：
2020-01-01
期刊：
影响因子：
8.3
通讯作者：
Zhu, Zhiming
中科院分区：
文献类型：
--
作者：
Gao, Peng;Li, Li;Zhu, Zhiming
内皮功能障碍是糖尿病心血管疾病进展的早期步骤。除了抗糖尿病作用外，DPP-4(二肽基肽酶-4)抑制剂还可以减少糖尿病患者的心血管事件。然而，DPP-4抑制剂对血管内皮细胞功能的有益作用的潜在机制仍不清楚。在这项研究中，我们用维达格列汀干预1型或2型糖尿病模型小鼠4周，并测量血管反应性。我们发现，Vildagliptin改善了糖尿病小鼠的内皮依赖性血管扩张，这不依赖于GLP-1(葡萄糖样肽-1)，但这种作用可被SIRT1(Sirtuin 1)抑制剂Ex527阻断。机制上，维达格列汀激活瞬时受体电位通道香草素4(TRPV4)促进内皮细胞细胞外钙摄取，激活AMPK/SIRT1通路，对抗高血糖诱导的内皮细胞活性氧的产生和衰老。维达格列汀通过形成氢键直接与TRPV4结合，这是维达格列汀诱导内皮细胞钙摄取的关键。敲除或抑制TRPV4可消除维达格列汀的有益作用。此外，SRT1720激活SIRT1可改善不依赖TRPV4的内皮功能，并减少TRPV4的转录以维持适当的钙水平。综上所述，我们的研究结果证明维达格列汀通过激活TRPV4介导的钙摄取来对抗高血糖所致的内皮功能障碍，这有助于重新理解DPP-4抑制剂的作用机制，扩大治疗范围。
Endothelial dysfunction is an early step to the progression of cardiovascular diseases in diabetes. Apart from their anti-diabetic action, DPP-4 (dipeptidyl peptidase-4) inhibitors also reduce cardiovascular events in diabetic patients. However, the underlying mechanism of the beneficial effect of DPP-4 inhibitor on endothelial function is still obscure. In this study, we intervened type 1 or 2 diabetic model mice with vildagliptin for 4 weeks and measured the vascular reactivity. We found that vildagliptin improved endothelium-dependent vasodilation in diabetic mice independent of GLP-1 (glucagonlike peptide-1), but this effect was blocked by a SIRT1 (Sirtuin 1) inhibitor, Ex527. Mechanistically, vildagliptin-activated Transient Receptor Potential Channel Vanilloid 4 (TRPV4) to promote extracellular calcium uptake in endothelial cells, which activated AMPK (AMP-activated protein kinase)/SIRT1 pathway to counteract hyperglycemia-induced endothelial reactive oxygen species generation and senescence. Vildagliptin directly binds to TRPV4 by forming a hydrogen bond, which is critical to vildagliptin-evoked endothelial calcium intake. Knockout or inhibition of TRPV4 erased the beneficial role of vildagliptin. In addition, activation of SIRT1 by SRT1720 improved endothelial function independent of TRPV4 and reduced TRPV4 transcription to maintain an appropriate calcium level. In summary, our findings prove that vildagliptin protects against hyperglycemia-induced endothelial dysfunction by activating TRPV4-meditaed Ca2+ uptake, which helps to re-understand the mechanism of DPP-4 inhibitors and expand the therapeutic scope.