Paradoxical effects of streptozotocin-induced diabetes on endothelial dysfunction in stroke-prone spontaneously hypertensive rats.
Paradoxical effects of streptozotocin-induced diabetes on endothelial dysfunction in stroke-prone spontaneously hypertensive rats.
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链脲佐菌素诱导的糖尿病对易发生中风的自发性高血压大鼠内皮功能障碍的矛盾作用
DOI：
10.1113/jphysiol.2011.213686
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发表时间：
2011-11-01
期刊：
影响因子：
--
通讯作者：
Chen H
中科院分区：
文献类型：
--
作者：
Zhong MF;Shen WL;Wang J;Yang J;Yuan WJ;He J;Wu PP;Wang Y;Zhang L;Higashino H;Chen H
血糖升高通常被认为是导致2型糖尿病患者发生冠心病的危险因素之一。然而，我们的研究表明，在诱导短期损伤后，高血糖随后对高血压动物的血管功能提供了矛盾的保护。血管可以适应持续的高血糖，产生不同的应激蛋白，在一定程度上抵消高血压带来的损害。这些结果有助于我们理解糖尿病血管适应的部分基础。糖尿病治疗的含义是，如果患者患有长期糖尿病和确定的心血管疾病，则血糖降低的目标应该不那么严格，并且逐渐达到，以避免突然取消预先存在的适应。虽然糖尿病和高血压都是心血管疾病的危险因素，但高血压本身在内皮功能障碍中的作用仍有争议。本研究旨在探讨高血压或链脲佐菌素诱导的糖尿病是否会加重易卒中型自发性高血压大鼠（SHRSP）的内皮功能障碍。在2月龄SHRSP和年龄匹配的血压正常的Wistar-Kyoto（WKY）大鼠中，用链脲佐菌素诱导高血压。诱导高血压8周后分离主动脉，记录其功能，并用透射电镜检查其形态。Western blotting检测内皮型/诱导型一氧化氮合酶（eNOS/iNOS）和诱导型/组成型血红素加氧酶（HO-1/HO-2）水平。在体外高渗高血溶液中孵育后，测定主动脉内皮功能和活性氧和一氧化氮的产生。在血压正常的WKY大鼠中，链脲佐菌素诱导的糖尿病持续8周未导致内皮功能障碍。相比之下，高血糖WKY大鼠的内皮依赖性血管舒张作用显着增强，但同时阻断NOS和HO可消除这种作用。血管舒张增强与血管eNOS和HO-1升高有关。SHRSP主动脉内皮功能明显受损，巨噬细胞-单核细胞浸润明显（巨噬细胞/内皮细胞比值，SHRSP组为20.9 ± 2.8%，WKY组为1.9 ± 0.5%，P < 0.01），高血压组明显降低（11.3 ± 1.6%，P < 0.01）。急性高脂血症（10分钟）加重了SHRSP的内皮功能障碍，细胞内活性氧和NO的产生显着增加。在高血容量/高渗条件下（在通常的缓冲液中加入额外的50 mmol L−1葡萄糖或甘露醇，使最终渗透压为350 mosmol L−1）持续体外孵育5 h，增强了内皮依赖性血管舒张，血管NO产生增加，eNOS/HO-1蛋白上调。持续性高脂血症不加重SHRSP的内皮功能障碍和巨噬细胞浸润。高血压/高渗诱导的eNOS和HO-1的上调可能在这种矛盾的适应内皮功能中发挥作用。
Elevated blood glucose is generally regarded as one of the risk factors that lead to coronary heart disease in patients with type 2 diabetes. However, our studies show that after inducing short-term damage, high blood glucose subsequently provides paradoxical protection for vessel function of animals with high blood pressure. Vessels can adapt to sustained high blood glucose and produce different stress proteins to counteract, to some extent, the damage brought about by hypertension. The results help us understand part of the basis for vessel adaptation in diabetes. The implication for treatment of diabetes is that if the patients have long-standing diabetes and established cardiovascular disease, the target of blood glucose lowering should be less stringent and reached gradually to avoid abrupt cancellation of the pre-existing adaptations. Although both diabetes and hypertension are risk factors for cardiovascular disease, the role of hyperglycaemia per se in endothelial dysfunction is controversial. This study was designed to examine whether hyperglycaemia, or streptozotocin-induced diabetes, could aggravate endothelial dysfunction in stroke-prone spontaneously hypertensive rats (SHRSP). Hyperglycaemia was induced by streptozotocin in 2-month-old SHRSP and age-matched normotensive Wistar–Kyoto (WKY) rats. The aorta was isolated 8 weeks after induction of hyperglycaemia to record its function and to examine its morphology with transmission electron microscopy. Endothelial/inducible nitric oxide synthase (eNOS/iNOS) and inducible/constitutive haem oxygenase (HO-1/HO-2) levels were determined with Western blotting. Aortic endothelial function and production of reactive oxygen species and nitric oxide were assayed after incubation in vitro in hyperglycaemic, hyperosmolar solution. Streptozotocin-induced diabetes of 8 weeks duration did not result in endothelial dysfunction in normotensive WKY rats. In contrast, hyperglycaemic WKY rats showed significantly enhanced endothelium-dependent vasodilatation, which was abrogated by simultaneous blocking of NOS and HO. The enhanced vasodilatation was associated with elevation of vascular eNOS and HO-1. Significant endothelial dysfunction and massive macrophage–monocyte infiltration were found in SHRSP aorta (the ratio of the number of macrophages to endothelial cells in the intima, expressed as a percentage, was 20.9 ± 2.8% in SHRSP versus 1.9 ± 0.5% in WKY rats, P < 0.01), which was attenuated significantly in hyperglycaemic SHRSP (11.3 ± 1.6%, P < 0.01 versus SHRSP). Acute hyperglycaemia (10 min) aggravated endothelial dysfunction in SHRSP, with a marked increase in intracellular reactive oxygen species and NO production. Sustained in vitro incubation in hyperglycaemic/hyperosmolar conditions (addition of an extra 50 mmol L−1 of glucose or mannitol to the usual buffer, to produce a final osmolarity of 350 mosmol L−1) for 5 h enhanced endothelium-dependent vasodilatation, with elevated vessel NO production and upregulation of eNOS/HO-1 proteins. Sustained hyperglycaemia does not aggravate endothelial dysfunction and macrophage infiltration in SHRSP. Hyperglycaemia/hyperosmolarity-induced upregulation of eNOS and HO-1 may play a role in this paradoxical adaptation of endothelial function.
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影响因子：
16.2
作者：
Molitch ME;Steffes M;Sun W;Rutledge B;Cleary P;de Boer IH;Zinman B;Lachin J;Epidemiology of Diabetes Interventions and Complications Study Group
通讯作者：
Epidemiology of Diabetes Interventions and Complications Study Group
影响因子：
168.9
作者：
Jackson, R;Lawes, CMM;Rodgers, A
通讯作者：
Rodgers, A
影响因子：
37.8
作者：
LIU, YG;THORNTON, JD;SCHAFFER, SW
通讯作者：
SCHAFFER, SW
影响因子：
13.2
作者：
Bakris, GL;Williams, M;Sowers, J
通讯作者：
Sowers, J
影响因子：
158.5
作者：
Duckworth, William;Abraira, Carlos;Huang, Grant D.
通讯作者：
Huang, Grant D.