Nascimento N R F, Lessa L M A, Kerntopf M R, Sousa C M, Alves R S, Queiroz M G R, Price J, Heimark D B, Larner J, Du X, Brownlee M, Gow A, Davis C, Fonteles M C
College of Veterinary Medicine, State University of Ceará, Fortaleza, 60455-970 Ceará, Brazil.
Proc Natl Acad Sci U S A. 2006 Jan 3;103(1):218-23. doi: 10.1073/pnas.0509779103. Epub 2005 Dec 22.
Endothelial dysfunction (ED) is an early feature of cardiovascular risk and diabetes. Hyperglycemia and hyperlipidemia are causative factors. Excessive endothelial mitochondrial superoxide (ROS) production with hyperglycemia and hyperlipidemia is a key mechanism. Inositol components of an insulin inositol glycan mediator, d-chiro-inositol (DCI) and 3-O-methyl DCI (pinitol), decrease hyperglycemia and hyperlipidemia. We tested whether these, myoinositol and dibutyryl DCI (db-DCI), would prevent or reverse ED in diabetic rats and rabbits. Oral inositols reduced hyperglycemia and hypertriglyceridemia with different potencies and prevented ED in rat aortic rings and mesenteric beds. Inositols added in vitro to five diabetic tissues reversed ED. Relaxation by Ach, NO, and electrical field stimulation was potentiated by inositols in vitro in rabbit penile corpus cavernosa. Inositols in vitro restored impaired contraction by the eNOS inhibitor l-NAME and increased NO effectiveness. DCI and db-DCI decreased elevated ROS in endothelial cells in high glucose and db-DCI reduced PKC activation, hexosamine pathway activity, and advanced glycation end products to basal levels. Xanthine/xanthine oxidase generated superoxide was reduced by superoxide dismutase or inositols, with db-DCI efficacious in a mechanism requiring chelated Fe(3+). Histochemical examination of rat aortic rings for protein SNO demonstrated a decrease in diabetic rings with restoration by inositols. In summary, inositols prevented and reversed ED in rat and rabbit vessels, reduced elevated ROS in endothelial cells, potentiated nitrergic or vasculo-myogenic relaxations, and preserved NO signaling. These effects are related to their metabolic actions, direct superoxide scavenging, and enhancing and protecting NO signaling. Of the inositols tested, db-DCI was most effective.
内皮功能障碍（ED）是心血管疾病风险和糖尿病的早期特征。高血糖和高血脂是致病因素。高血糖和高血脂导致内皮线粒体超氧化物（ROS）过度产生是关键机制。胰岛素肌醇聚糖介质的肌醇成分，D-手性肌醇（DCI）和3-O-甲基-DCI（松醇），可降低高血糖和高血脂。我们测试了这些物质，即肌醇和二丁酰-DCI（db-DCI），是否能预防或逆转糖尿病大鼠和兔子的ED。口服肌醇以不同效力降低了高血糖和高甘油三酯血症，并预防了大鼠主动脉环和肠系膜床的ED。体外添加到五种糖尿病组织中的肌醇逆转了ED。在兔阴茎海绵体中，体外添加肌醇可增强乙酰胆碱、一氧化氮（NO）和电场刺激引起的舒张。体外添加肌醇可恢复内皮型一氧化氮合酶（eNOS）抑制剂L-硝基精氨酸甲酯（L-NAME）所致的收缩功能受损，并提高NO的效能。DCI和db-DCI可降低高糖环境下内皮细胞中升高的ROS，db-DCI可将蛋白激酶C（PKC）激活、己糖胺途径活性和晚期糖基化终产物降低至基础水平。超氧化物歧化酶或肌醇可降低黄嘌呤/黄嘌呤氧化酶产生的超氧化物，db-DCI通过一种需要螯合铁（3+）的机制发挥有效作用。对大鼠主动脉环进行蛋白质亚硝基化修饰的组织化学检查显示，糖尿病环中的亚硝基化修饰减少，而肌醇可使其恢复。总之，肌醇可预防和逆转大鼠和兔子血管中的ED，降低内皮细胞中升高的ROS，增强一氧化氮能或血管肌源性舒张，并保留NO信号传导。这些作用与其代谢作用、直接清除超氧化物以及增强和保护NO信号传导有关。在所测试的肌醇中，db-DCI最为有效。
