Dysregulation of ghrelin in diabetes impairs the vascular reparative response to hindlimb ischemia in a mouse model; clinical relevance to peripheral artery disease
Dysregulation of ghrelin in diabetes impairs the vascular reparative response to hindlimb ischemia in a mouse model; clinical relevance to peripheral artery disease
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DOI：
10.1038/s41598-020-70391-6
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发表时间：
2020-08-12
影响因子：
4.6
通讯作者：
Schwenke, Daryl O.
中科院分区：
文献类型：
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作者：
Neale, Joshua P. H.;Pearson, James T.;Schwenke, Daryl O.
2 型糖尿病是外周动脉疾病 (PAD) 的一个重要危险因素。然而，糖尿病和 PAD 之间的机制联系仍不清楚。这项研究提出，内源性激素生长素释放肽（一种有效的血管功能调节剂）的失调是糖尿病与外周动脉疾病之间因果关系的基础。此外，本研究旨在证明外源性生长素释放肽在糖尿病小鼠 PAD 模型中的治疗潜力。使用标准 ELISA 分析来量化和比较 (i) 患有或不患有 PAD 的人类糖尿病患者（诊所）和 (ii) db/db 糖尿病小鼠和非糖尿病小鼠（实验室）之间的生长素释放肽循环水平。 Db/db 小鼠经历单侧后肢缺血 (HLI) 14 天，并使用或不使用外源性生长素释放肽（150 μg/kg/天）治疗。随后使用激光多普勒成像、显微 CT、显微血管造影以及蛋白质和微小 RNA (miRNA) 分析评估血管修复、血管生成、后肢灌注、结构和功能。我们进一步检查了 ghrelin KO 小鼠的后肢灌注恢复情况，以确定对 HLI 的血管反应受损是否与糖尿病中的 ghrelin 失调有关。与健康个体相比，患有 PAD 的患者，无论是否患有糖尿病，内源性生长素释放肽的循环水平均显着降低。糖尿病 db/db 小鼠的生长素释放肽水平仅为非糖尿病小鼠的 7%。与非糖尿病小鼠相比，糖尿病 db/db 小鼠响应 HLI 的血管修复能力受损，重要的是，与 ghrelin KO 小鼠相当。 HLI 后 14 天每天用 ghrelin 治疗 db/db 小鼠，刺激血管生成，改善骨骼肌结构和细胞存活，这与促血管生成 miRNA-126 和 -132 的增加有关。这些发现揭示了内源性生长素释放肽在肢体缺血后血管修复中的重要作用，而糖尿病患者的生长素释放肽似乎下调。此外，这些结果表明外源性生长素释放肽是一种潜在的新疗法，可以增强下肢 PAD 患者（尤其是糖尿病患者）的灌注。
Type 2 diabetes is a prominent risk factor for peripheral artery disease (PAD). Yet, the mechanistic link between diabetes and PAD remains unclear. This study proposes that dysregulation of the endogenous hormone ghrelin, a potent modulator of vascular function, underpins the causal link between diabetes and PAD. Moreover, this study aimed to demonstrate the therapeutic potential of exogenous ghrelin in a diabetic mouse model of PAD. Standard ELISA analysis was used to quantify and compare circulating levels of ghrelin between (i) human diabetic patients with or without PAD (clinic) and (ii) db/db diabetic and non-diabetic mice (lab). Db/db mice underwent unilateral hindlimb ischaemia (HLI) for 14 days and treated with or without exogenous ghrelin (150 mu g/kg/day.) Subsequently vascular reparation, angiogenesis, hindlimb perfusion, structure and function were assessed using laser Doppler imaging, micro-CT, microangiography, and protein and micro-RNA (miRNA) analysis. We further examined hindlimb perfusion recovery of ghrelin KO mice to determine whether an impaired vascular response to HLI is linked to ghrelin dysregulation in diabetes. Patients with PAD, with or without diabetes, had significantly lower circulating levels of endogenous ghrelin, compared to healthy individuals. Diabetic db/db mice had ghrelin levels that were only 7% of non-diabetic mice. The vascular reparative capacity of diabetic db/db mice in response to HLI was impaired compared to non-diabetic mice and, importantly, comparable to ghrelin KO mice. Daily therapeutic treatment of db/db mice with ghrelin for 14 days post HLI, stimulated angiogenesis, and improved skeletal muscle architecture and cell survival, which was associated with an increase in pro-angiogenic miRNAs-126 and -132. These findings unmask an important role for endogenous ghrelin in vascular repair following limb ischemia, which appears to be downregulated in diabetic patients. Moreover, these results implicate exogenous ghrelin as a potential novel therapy to enhance perfusion in patients with lower limb PAD, especially in diabetics.