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Modulation of p66Shc impairs cerebrovascular myogenic tone in low renin but not low nitric oxide models of systemic hypertension
American Journal of Physiology-Heart and Circulatory Physiology ( IF 4.8 ) Pub Date : 2021-10-29 , DOI: 10.1152/ajpheart.00542.2021
William E Hughes 1 , Joe Hockenberry 1 , Bradley Miller 1 , Andrey Sorokin 1 , Andreas M Beyer 1
Affiliation  

Cerebral blood flow and perfusion are tightly maintained through autoregulation despite changes in transmural pressure. Oxidative stress impairs cerebral blood flow, precipitating cerebrovascular events. Phosphorylation of the adaptor protein p66Shc increases mitochondrial-derived oxidative stress. The effect of p66Shc gain or loss of function in non-hypertensive rats is unclear. We hypothesized that p66Shc gain of function would impair autoregulation of cerebral microcirculation under physiological and pathological conditions. Three previously established transgenic (salt-sensitive background; SS) p66Shc rats were utilized, p66-Del/SS (express p66Shc with a 9-amino acid deletion), p66Shc-KO/SS (frameshift premature termination codon), and p66Shc-S36A/SS (substitution of Ser36Ala). The p66Shc-Del were also bred on Sprague-Dawley backgrounds (p66-Del/SD), and a subset was exposed to a hypertensive stimulus (L-NAME) for 4 weeks. Active and passive diameters to increasing transmural pressure were measured and myogenic tone was calculated. Myogenic responses to increasing pressure were impaired in p66Shc-Del/SS rats relative to WT/SS and knock-in substitution of S36A (P<0.05). p66-Del/SD rats did not demonstrate changes in active/passive diameters or myogenic tone relative to WT/SD, but did demonstrate attenuated passive diameter responses to higher transmural pressure relative to p66-Del/SS. 4 weeks of a hypertensive stimulus (L-NAME) did not alter active or passive diameter responses to increasing transmural pressure (P=0.86-0.99), but increased myogenic responses relative to p66-Del/SD (P<0.05). Collectively, we demonstrate the functional impact of modulation of p66Shc within the cerebral circulation and demonstrate that the genetic background of p66Shc rats largely drives changes in cerebrovascular function.

中文翻译:

p66Shc 的调节会损害低肾素而非低一氧化氮系统性高血压模型中的脑血管肌原性张力

尽管跨壁压发生变化,但脑血流量和灌注通过自动调节得到严格维持。氧化应激损害脑血流,诱发脑血管事件。衔接蛋白 p66Shc 的磷酸化会增加线粒体衍生的氧化应激。p66Shc 功能获得或丧失对非高血压大鼠的影响尚不清楚。我们假设 p66Shc 功能获得会损害生理和病理条件下脑微循环的自动调节。使用了三个先前建立的转基因(盐敏感背景;SS)p66Shc 大鼠,p66-Del/SS(表达具有 9 个氨基酸缺失的 p66Shc)、p66Shc-KO/SS(移码过早终止密码子)和 p66Shc-S36A /SS(Ser36Ala 的替代)。p66Shc-Del 也在 Sprague-Dawley 背景下繁殖 (p66-Del/SD),并且一个子集暴露于高血压刺激 (L-NAME) 4 周。测量了增加跨壁压的主动和被动直径,并计算了肌原性张力。相对于 WT/SS 和 S36A 的敲入替代,p66Shc-Del/SS 大鼠对增加压力的生肌反应受损 (P<0.05)。p66-Del/SD 大鼠没有表现出相对于 WT/SD 的主动/被动直径或生肌张力的变化,但确实表现出相对于 p66-Del/SS 对更高跨壁压力的被动直径反应减弱。4 周的高血压刺激 (L-NAME) 并未改变主动或被动直径对增加跨壁压的反应 (P=0.86-0.99),但增加了相对于 p66-Del/SD 的生肌反应 (P<0.05)。总的来说,
更新日期:2021-10-30
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