Chronic iron overload induces vascular dysfunction in resistance pulmonary arteries associated with right ventricular remodeling in rats
Chronic iron overload induces vascular dysfunction in resistance pulmonary arteries associated with right ventricular remodeling in rats
复制标题
DOI：
10.1016/j.toxlet.2018.07.010
复制
发表时间：
2018-10-01
影响因子：
3.5
通讯作者：
dos Santos, Leonardo
中科院分区：
文献类型：
--
作者：
Bertoli, Sabrina Rodrigues;Marques, Vinicius Bermond;dos Santos, Leonardo
尽管铁过量对脉管系统有毒，甚至在这种情况下也有肺动脉高压的报道，但铁超负荷本身的作用仍有待澄清。本研究旨在测试大鼠慢性铁超负荷对阻力肺动脉（RPA）和右心室（RV）重塑的形态生理学的影响。给大鼠注射盐水或右旋糖酐铁（10、100 和 200 毫克/公斤/天），持续 28 天。我们的结果表明循环铁增加并伴有显着的肺部沉积。此外，接受最高剂量治疗的大鼠表现出右心室功能障碍和肥大； RPA 的向内重塑和血管收缩增加。血管高反应性伴随着一氧化氮 (NO) 的减少，通过与二甲亚砜、过氧化氢酶和 Tempol 一起孵育可逆转。由于铁超载，NADPH 氧化酶亚基 gp91 phox 增加，与血管紧张素 II 1 型受体 (AT1) 拮抗剂氯沙坦一起孵育不仅可以减少氧化应激，还可以恢复血管功能。因此，我们得出结论，AT1途径通过增加氧化应激和降低NO生物利用度在肺血管功能障碍中发挥作用，从而促进血管重塑和铁超负荷的肺动脉高压。这一发现应该会激发未来关于铁超负荷情况下体内 AT1 受体阻断的有益影响的研究。
Although iron excess is toxic to the vasculature and even that pulmonary hypertension has been reported in this scenario, the role of iron overload per se remains to be clarified. This study aimed to test the effects of chronic iron-overload in rats on the morphophysiology of resistance pulmonary arteries (RPA) and right ventricle (RV) remodeling. Rats were injected with saline or iron-dextran (10, 100 and 200 mg/kg/day i.p.) for 28 days. Our results indicated increased circulating iron with significant lung deposits. Moreover, rats treated with the highest dose exhibited RV dysfunction and hypertrophy; inward remodeling and increased vasoconstriction of the RPA. Vascular hyperreactivity was accompanied by reduced nitric oxide (NO), and was reversed by incubation with Dimethylsulfoxide, Catalase and Tempol. The NADPH oxidase subunit gp91 phox was increased due to iron overload, and incubation with angiotensin II type-1 receptor (AT1) antagonist losartan not only reduced oxidative stress but also restored vascular function. Thus, we concluded that AT1 pathway plays a role in pulmonary vascular dysfunction by increasing oxidative stress and reducing NO bioavailability, thereby contributing to vascular remodeling and pulmonary hypertension of iron-overload. This finding should instigate future studies on the beneficial impacts of in vivo blockade of AT1 receptor under iron overload.