Cal Lorenzo A, Maso Lucia Dal, Caielli Paola, Pagnin Elisa, Fusaro Maria, Davis Paul A, Pessina Achille C
Department of Clinical and Experimental Medicine, University of Padova, Italy.
Blood Press. 2011 Dec;20(6):376-82. doi: 10.3109/08037051.2011.575570. Epub 2011 Apr 20.
The role of oxidative stress in the pathophysiology of hypertension and target organ damage is widely recognized. Using a molecular biology approach, we report, in essential hypertensive patients, the effect of the angiotensin II type 1 receptor blocker olmesartan on the mononuclear cell (PBMC) protein expression of major elements in the oxidative stress and vascular remodeling-related pathways, p22(phox) and HO-1, along with the phosphorylation state of ERK1/2 and plasma oxidized low-density lipoproteins (oxLDL). Twenty untreated essential hypertensive patients (range blood pressure: 142?156/94?98 mmHg) were treated with olmesartan medoxomil (20 mg/day for 6 months) and blood samples collected at baseline, 3 and 6 months for PBMC p22(phox) and HO-1 protein expression, phosphorylation state of ERK1/2 (western blot) and oxLDL level (ELISA) evaluations. Olmesartan normalized blood pressure since the third month (149 ? 4.7/94.88 ? 1.9 mmHg vs 137.89 ? 2.08/88.44 ? 2.0 at 3 months and vs 135.44 ? 2.18/85.78 ? 1.2 at 6 months, analysis of variance: p < 0.001). p22(phox) protein level declined at 3 months (7.10 ? 2.61 vs 9.32 ? 2.43 densitometric units (d.u.; p < 0.001), further declining at 6 months (4.55 ? 1.26 d.u., p < 0.001). HO-1 levels increased at 3 months (10.87 ? 1.92 vs 7.70 ? 0.71 d.u., p = 0.001) and remained elevated (11.11 ? 1.89 d.u., p = 0.001), without further increase at 6 months. Phosphorylated ERK1/2 declined at 3 months (3.94 ? 1.44 vs 5.62 ? 1.11 d.u., p = 0.001), further declining at 6 months (1.94 ? 0.87, p < 0.001). oxLDL significantly declined at 3 and 6 months. These results demonstrate that olmesartan inhibits oxidative stress. Given the involvement of oxidative stress and its signaling in atherogenesis, and the available evidence of olmesartan's vasoprotective, anti-inflammatory and antiatherosclerotic effects derived from clinical trials in humans, the results of our study provide a mechanistic rationale for the omelsartan's antioxidant and anti-inflammatory potential translation, in the long term, toward the antiatherosclerotic and antiremodeling effects reported on the clinical ground.
氧化应激在高血压病理生理学和靶器官损害中的作用已得到广泛认可。我们采用分子生物学方法，报告了在原发性高血压患者中，血管紧张素II 1型受体阻滞剂奥美沙坦对氧化应激和血管重塑相关途径中主要元素（p22(phox)和HO-1）的单核细胞（PBMC）蛋白表达、ERK1/2的磷酸化状态以及血浆氧化型低密度脂蛋白（oxLDL）的影响。20例未经治疗的原发性高血压患者（血压范围：142?156/94?98 mmHg）接受奥美沙坦酯治疗（20 mg/天，共6个月），并在基线、3个月和6个月采集血样，用于评估PBMC的p22(phox)和HO-1蛋白表达、ERK1/2的磷酸化状态（蛋白质印迹法）以及oxLDL水平（酶联免疫吸附测定法）。自第三个月起，奥美沙坦使血压恢复正常（3个月时为149 ± 4.7/94.88 ± 1.9 mmHg，6个月时为137.89 ± 2.08/88.44 ± 2.0 mmHg，方差分析：p < 0.001）。p22(phox)蛋白水平在3个月时下降（光密度单位分别为7.10 ± 2.61和9.32 ± 2.43；p < 0.001），在6个月时进一步下降（4.55 ± 1.26光密度单位，p < 0.001）。HO-1水平在3个月时升高（光密度单位分别为10.87 ± 1.92和7.70 ± 0.71，p = 0.001），并持续升高（11.11 ± 1.89光密度单位，p = 0.001），在6个月时无进一步升高。磷酸化的ERK1/2在3个月时下降（光密度单位分别为3.94 ± 1.44和5.62 ± 1.11，p = 0.001），在6个月时进一步下降（1.94 ± 0.87，p < 0.001）。oxLDL在3个月和6个月时显著下降。这些结果表明奥美沙坦可抑制氧化应激。鉴于氧化应激及其信号传导参与动脉粥样硬化的发生，以及临床试验中得出的奥美沙坦具有血管保护、抗炎和抗动脉粥样硬化作用的现有证据，我们的研究结果为奥美沙坦的抗氧化和抗炎潜力从长期来看转化为临床报道的抗动脉粥样硬化和抗重塑作用提供了机制依据。
