Department of Physiology, College of Medicine, University of Saskatchewan, 107 Wiggins Road, Saskatoon, Saskatchewan, Canada.
Endocrinology. 2010 Feb;151(2):549-60. doi: 10.1210/en.2009-0471. Epub 2009 Dec 16.
Accumulating clinical evidence indicates that impaired glucose tolerance is a common phenomenon in essential hypertension. Although recent evidence underscores the role of heme-oxygenase (HO) in diabetes, its effects on insulin sensitivity and glucose metabolism in spontaneously hypertensive rat (SHR), a model of essential hypertension with characteristics of metabolic syndrome including insulin resistance/impaired glucose metabolism remains largely unclear. Here we report the effects of the HO inducer, hemin, and the HO blocker, chromium-mesoporphyrin on insulin sensitivity and glucose metabolism in SHRs. Adult SHRs were severely hypertensive but normoglycemic. Hemin therapy lowered blood pressure, increased plasma insulin, decreased glycemia, and enhanced insulin sensitivity by improving glucose tolerance (ip glucose tolerance test) and insulin tolerance (ip insulin tolerance test) but reduced insulin resistance (homeostasis model assessment index). These effects were accompanied by increased gastrocnemius muscle HO-1, HO activity, cGMP, cAMP alongside antioxidants including bilirubin, ferritin, superoxide dismutase, catalase, and the total antioxidant capacity, whereas oxidative/inflammatory mediators like 8-isoprostane, nuclear-factor-kappaB, activating-protein-1, activating-protein-2, c-Jun-NH2-terminal-kinase, and heme were abated. Furthermore, hemin reduced proteinuria/albuminuria and enhanced the depressed levels of adiponectin, AMP-activated protein-kinase, and glucose transporter-4 in SHRs, suggesting that although SHRs are normoglycemic, insulin signaling and renal function may be impaired. Contrarily, the HO inhibitor chromium-mesoporphyrin exacerbated oxidative stress, aggravated insulin resistance, glucose tolerance, insulin tolerance and nephropathy. Hemin also enhanced HO signaling in Wistar Kyoto and Sprague Dawley rats and increased insulin sensitivity albeit less intensely than in SHRs, suggesting greater selectivity of HO in SHRs with dysfunctional insulin signaling. These results suggest that perturbations of insulin signaling may be a forerunner to hyperglycemia in essential hypertension. By concomitantly potentiating insulin-sensitizing agents, suppressing insulin/glucose intolerance, and abating oxidative stress, HO inducers may prevent metabolic and cardiovascular complications in essential hypertension.
越来越多的临床证据表明，葡萄糖耐量受损是原发性高血压的常见现象。虽然最近的证据强调了血红素加氧酶 (HO) 在糖尿病中的作用，但它对自发性高血压大鼠 (SHR) 胰岛素敏感性和葡萄糖代谢的影响，SHR 是一种具有代谢综合征特征的原发性高血压模型，包括胰岛素抵抗/葡萄糖代谢受损，在很大程度上仍不清楚。在这里，我们报告 HO 诱导剂血红素和 HO 阻断剂铬中卟啉对 SHRs 胰岛素敏感性和葡萄糖代谢的影响。成年 SHR 血压严重升高但血糖正常。血红素治疗降低血压，增加血浆胰岛素，降低血糖，并通过改善葡萄糖耐量（口服葡萄糖耐量试验）和胰岛素耐量（口服胰岛素耐量试验）增强胰岛素敏感性，但降低胰岛素抵抗（稳态模型评估指数）。这些作用伴随着腓肠肌 HO-1、HO 活性、cGMP、cAMP 的增加以及胆红素、铁蛋白、超氧化物歧化酶、过氧化氢酶和总抗氧化能力等抗氧化剂的增加，而氧化/炎症介质如 8-异前列腺素、核因子-κB、激活蛋白-1、激活蛋白-2、c-Jun-NH2 末端激酶和血红素则减少。此外，血红素降低 SHRs 的蛋白尿/白蛋白尿，并增强了降低的脂联素、AMP 激活蛋白激酶和葡萄糖转运蛋白-4 水平，表明尽管 SHRs 血糖正常，但胰岛素信号和肾功能可能受损。相反，HO 抑制剂铬中卟啉加剧了氧化应激，加重了胰岛素抵抗、葡萄糖耐量、胰岛素耐量和肾病。血红素还增强了 Wistar Kyoto 和 Sprague Dawley 大鼠的 HO 信号转导，尽管不如 SHRs 那样增强胰岛素敏感性，这表明 HO 在胰岛素信号转导功能障碍的 SHRs 中具有更大的选择性。这些结果表明，胰岛素信号转导的紊乱可能是原发性高血压高血糖的先兆。通过同时增强胰岛素增敏剂、抑制胰岛素/葡萄糖耐量以及减轻氧化应激，HO 诱导剂可能预防原发性高血压中的代谢和心血管并发症。
