Department of Pharmacology, Ruijin Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, China.
J Physiol. 2011 Nov 1;589(Pt 21):5153-65. doi: 10.1113/jphysiol.2011.213686. Epub 2011 Sep 19.
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.
虽然糖尿病和高血压都是心血管疾病的危险因素，但高血糖本身在血管内皮功能障碍中的作用仍存在争议。本研究旨在探讨高血糖（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）的血管内皮功能障碍。在 2 个月大的 SHRSP 和年龄匹配的正常血压 Wistar-Kyoto（WKY）大鼠中用链脲佐菌素诱导高血糖。诱导高血糖 8 周后分离主动脉，记录其功能，并通过透射电镜检查其形态。用 Western blot 法测定内皮/诱导型一氧化氮合酶（eNOS/iNOS）和诱导/组成型血红素加氧酶（HO-1/HO-2）水平。在体外孵育于高血糖、高渗溶液后，测定主动脉内皮功能和活性氧和一氧化氮的产生。8 周的链脲佐菌素诱导糖尿病并未导致正常血压 WKY 大鼠的内皮功能障碍。相反，高血糖 WKY 大鼠显示出明显增强的内皮依赖性血管舒张，同时阻断 NOS 和 HO 可消除这种舒张。增强的血管舒张与血管 eNOS 和 HO-1 的升高有关。在 SHRSP 主动脉中发现明显的内皮功能障碍和大量巨噬细胞-单核细胞浸润（内膜中巨噬细胞与内皮细胞的数量比，以百分比表示，在 SHRSP 中为 20.9±2.8%，在 WKY 大鼠中为 1.9±0.5%，P<0.01），这种浸润在高血糖 SHRSP 中显著减轻（11.3±1.6%，P<0.01 与 SHRSP 相比）。急性高血糖（10 min）加重 SHRSP 的内皮功能障碍，细胞内活性氧和 NO 生成明显增加。持续体外孵育于高血糖/高渗条件下（在常规缓冲液中额外加入 50 mmol/L 的葡萄糖或甘露醇，使终渗透压达到 350 mosmol/L）5 小时，增强了内皮依赖性血管舒张，增加了血管 NO 生成，并上调了 eNOS/HO-1 蛋白。持续高血糖不会加重 SHRSP 的内皮功能障碍和巨噬细胞浸润。高血糖/高渗诱导的 eNOS 和 HO-1 上调可能在这种内皮功能的矛盾适应中发挥作用。
