Elevated circulating amyloid concentrations in obesity and diabetes promote vascular dysfunction
Elevated circulating amyloid concentrations in obesity and diabetes promote vascular dysfunction
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DOI：
10.1172/jci122237
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发表时间：
2020-08-03
影响因子：
15.9
通讯作者：
Ashford, Michael L. J.
中科院分区：
文献类型：
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作者：
Meakin, Paul J.;Coull, Bethany M.;Ashford, Michael L. J.
糖尿病、肥胖症和阿尔茨海默病 (AD) 与血管并发症和一氧化氮 (NO) 生成受损有关。此外，β位点淀粉样蛋白前体蛋白裂解（APP裂解）酶1（BACE1）、APP和β-淀粉样蛋白（Aβ）的增加与血管疾病的发展有关，并且BACE1和Aβ的增加伴随着高血糖和高脂血症。然而，肥胖与糖尿病、Ap升高和血管功能障碍之间的因果关系尚不清楚。我们报告说，饮食诱导的肥胖 (DIO) 小鼠血浆和血管 Aβ 42 增加，这与 NO 生物利用度降低、内皮功能障碍和血压升高相关。 BACE1 活性和 A beta 42 的遗传或药理学降低分别阻止和逆转了这些结果。相比之下，在小鼠中表达人类突变体 APP 或将 A beta 42 输注到对照饮食喂养的小鼠中以模仿肥胖水平，会损害 NO 产生、血管松弛和血压升高。在人类中，血浆 A beta 42 升高与糖尿病和内皮功能障碍相关。从机制上讲，较高的 A beta 42 会降低内皮 NO 合酶 (eNOS)、环鸟苷酸 (cGMP) (cGMP) 和蛋白激酶 G (PKG) 活性，而与饮食无关，而饮食和 A beta 42 会增加内皮素-1。降低 A beta 42 可逆转 eNOS/cGMP/PKG 途径中的 DIO 缺陷，并减少内皮素-1。我们的研究结果表明，BACE1 抑制剂可能对治疗与糖尿病相关的血管疾病具有治疗价值。
Diabetes, obesity, and Alzheimer's disease (AD) are associated with vascular complications and impaired nitric oxide (NO) production. Furthermore, increased beta-site amyloid precursor protein-cleaving (APP-cleaving) enzyme 1 (BACE1), APP, and beta-amyloid (A beta) are linked with vascular disease development and increased BACE1 and A beta accompany hyperglycemia and hyperlipidemia. However, the causal relationship between obesity and diabetes, increased Ap, and vascular dysfunction is unclear. We report that diet-induced obesity (DIO) in mice increased plasma and vascular A beta 42 that correlated with decreased NO bioavailability, endothelial dysfunction, and increased blood pressure. Genetic or pharmacological reduction of BACE1 activity and A beta 42 prevented and reversed, respectively, these outcomes. In contrast, expression of human mutant APP in mice or A beta 42 infusion into control diet-fed mice to mimic obese levels impaired NO production, vascular relaxation, and raised blood pressure. In humans, increased plasma A beta 42 correlated with diabetes and endothelial dysfunction. Mechanistically, higher A beta 42 reduced endothelial NO synthase (eNOS), cyclic GMP (cGMP), and protein kinase G (PKG) activity independently of diet, whereas endothelin-1 was increased by diet and A beta 42. Lowering A beta 42 reversed the DIO deficit in the eNOS/cGMP/PKG pathway and decreased endothelin-1. Our findings suggest that BACE1 inhibitors may have therapeutic value in the treatment of vascular disease associated with diabetes.