首页> 外文期刊>American Journal of Physiology >Elevated systemic TGF-beta impairs aortic vasomotor function through activation of NADPH oxidase-driven superoxide production and leads to hypertension, myocardial remodeling, and increased plaque formation in apoE(-/-) mice.
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Elevated systemic TGF-beta impairs aortic vasomotor function through activation of NADPH oxidase-driven superoxide production and leads to hypertension, myocardial remodeling, and increased plaque formation in apoE(-/-) mice.

机译:全身性TGF-β升高通过激活NADPH氧化酶驱动的超氧化物产生损害主动脉血管舒缩功能,并导致高血压,心肌重塑和apoE(-/-)小鼠斑块形成增加。

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The role of circulating, systemic TGF-beta levels in endothelial function is not clear. TGF-beta(1) may cause endothelial dysfunction in apolipoprotein E-deficient (apoE(-/-)) mice via stimulation of reactive oxygen species (ROS) production by the NADPH oxidase (NOX) system and aggravate aortic and heart remodeling and hypertension. Thoracic aorta (TA) were isolated from 4-mo-old control (C57Bl/6), apoE(-/-), TGF-beta(1)-overexpressing (TGFbeta(1)), and crossbred apoE(-/-) x TGFbeta(1) mice. Endothelium-dependent relaxation was measured before and after incubation with apocynin (NOX inhibitor) or superoxide dismutase (SOD; ROS scavenger). Superoxide production within the vessel wall was determined by dihydroethidine staining under confocal microscope. In 8-mo-old mice, aortic and myocardial morphometric changes, plaque formation by en face fat staining, and blood pressure were determined. Serum TGF-beta(1) levels (ELISA) were elevated in TGFbeta(1) mice without downregulation of TGF-beta-I receptor (immunohistochemistry). In the aortic wall, superoxide production was enhanced and NO-dependent relaxation diminished in apoE(-/-) x TGFbeta(1) mice but improved significantly after apocynin or SOD. Myocardial capillary density was reduced, fibrocyte density increased, aortic wall was thicker, combined lesion area was greater, and blood pressure was higher in the apoE(-/-) x TGFbeta vs. C57Bl/6 mice. Our results demonstrate that elevated circulating TGF-beta(1) causes endothelial dysfunction through NOX activation-induced oxidative stress, accelerating atherosclerosis and hypertension in apoE(-/-) mice. These findings may provide a mechanism explaining accelerated atherosclerosis in patients with elevated plasma TGFbeta(1).
机译:循环系统的TGF-β水平在内皮功能中的作用尚不清楚。 TGF-beta(1)可能通过刺激NADPH氧化酶(NOX)系统产生的活性氧(ROS)产生载脂蛋白E缺乏症(apoE(-/-))小鼠内皮功能障碍,并加剧主动脉和心脏重塑以及高血压。从4个月大的对照(C57Bl / 6),apoE(-/-),TGF-beta(1)过表达(TGFbeta(1))和杂交apoE(-/-)分离胸主动脉(TA) x TGFbeta(1)小鼠。在与载脂蛋白(NOX抑制剂)或超氧化物歧化酶(SOD; ROS清除剂)孵育之前和之后测量内皮依赖性松弛。在共聚焦显微镜下通过二氢乙啶染色确定血管壁内超氧化物的产生。在8个月大的小鼠中,确定了主动脉和心肌的形态变化,通过脸部脂肪染色形成的斑块和血压。血清TGF-β(1)水平(ELISA)在TGFbeta(1)小鼠中升高,而没有下调TGF-β-I受体(免疫组化)。在主动脉壁,超氧化物歧化酶的产生被增强,并且在apoE(-/-)x TGFbeta(1)小鼠中NO依赖的弛豫减少,但在Apocynin或SOD后明显改善。与C57Bl / 6小鼠相比,apoE(-/-)x TGFbeta小鼠的心肌毛细血管密度降低,纤维细胞密度增加,主动脉壁变厚,合并病变面积更大,血压更高。我们的结果表明,升高的循环中TGF-β(1)通过NOX激活引起​​的氧化应激导致内皮功能障碍,从而加速apoE(-/-)小鼠的动脉粥样硬化和高血压。这些发现可能提供解释血浆TGFbeta(1)升高的患者加速动脉粥样硬化的机制。

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