Dietary nitrate improves age-related hypertension and metabolic abnormalities in rats via modulation of angiotensin II receptor signaling and inhibition of superoxide generation
Dietary nitrate improves age-related hypertension and metabolic abnormalities in rats via modulation of angiotensin II receptor signaling and inhibition of superoxide generation
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DOI：
10.1016/j.freeradbiomed.2016.07.025
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发表时间：
2016-10-01
影响因子：
7.4
通讯作者：
Carlstrom, Mattias
中科院分区：
文献类型：
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作者：
Hezel, Michael;Peleli, Maria;Carlstrom, Mattias
高龄与心血管疾病和2型糖尿病的风险增加有关。提出的中心事件是由于内皮NO合酶（eNOS）产生减少和氧化应激增加而导致的一氧化氮（NO）量减少。此外，血管紧张素II（ANG II）信号传导增加也通过加速活性氧的形成而参与内皮功能障碍和高血压的发病机制。本研究旨在验证膳食补充硝酸盐可通过减弱NADPH氧化酶活性和ANG II受体信号传导来降低老年大鼠的血压并改善葡萄糖耐量的假设。膳食补充硝酸盐两周可降低老年大鼠的血压（10-15 mmHg）并改善葡萄糖清除率，但对年轻大鼠无影响。这些有利的作用与胰岛素反应增加、血浆肌酐降低以及对乙酰胆碱的内皮舒张改善和对ANG II的收缩减弱有关。从机制上讲，硝酸盐减少了心血管系统中NADPH氧化酶介导的氧化应激，并增加了cGMP信号。最后，硝酸盐治疗使老年大鼠的ANG II受体（AT（1A），AT（2），AT（1A）/AT（2）比值）而不改变血浆肾素或ANG II水平。我们的研究结果表明，增强硝酸盐-亚硝酸盐-NO途径可以部分补偿年龄-通过抑制NADPH氧化酶和调节ANG II受体表达，内源性NO产生的相关紊乱。这些新的发现可能对基于营养的预防和治疗心血管和代谢疾病的策略有影响。(C)2016 Elsevier Inc. All rights reserved.
Advanced age is associated with increased risk for cardiovascular disease and type 2 diabetes. A proposed central event is diminished amounts of nitric oxide (NO) due to reduced generation by endothelial NO synthase (eNOS) and increased oxidative stress. In addition, it is widely accepted that increased angiotensin II (ANG II) signaling is also implicated in the pathogenesis of endothelial dysfunction and hypertension by accelerating formation of reactive oxygen species. This study was designed to test the hypothesis that dietary nitrate supplementation could reduce blood pressure and improve glucose tolerance in aged rats, via attenuation of NADPH oxidase activity and ANG II receptor signaling.Dietary nitrate supplementation for two weeks reduced blood pressure (10-15 mmHg) and improved glucose clearance in old, but not in young rats. These favorable effects were associated with increased insulin responses, reduced plasma creatinine as well as improved endothelial relaxation to acetylcholine and attenuated contractility to ANG II in resistance arteries. Mechanistically, nitrate reduced NADPH oxidase-mediated oxidative stress in the cardiovascular system and increased cGMP signaling. Finally, nitrate treatment in aged rats normalized the gene expression profile of ANG II receptors (AT(1A), AT(2), AT(1A)/AT(2) ratio) in the renal and cardiovascular systems without altering plasma levels of renin or ANG II.Our results show that boosting the nitrate-nitrite-NO pathway can partly compensate for age-related disturbances in endogenous NO generation via inhibition of NADPH oxidase and modulation of ANG II receptor expression. These novel findings may have implications for nutrition-based preventive and therapeutic strategies against cardiovascular and metabolic diseases. (C) 2016 Elsevier Inc. All rights reserved.