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Oxidative Stress by Ca2+ Overload is Critical for Phosphate-Induced Vascular Calcification
American Journal of Physiology-Heart and Circulatory Physiology ( IF 4.8 ) Pub Date : 2020-10-23 , DOI: 10.1152/ajpheart.00305.2020
Nhung Thi Nguyen 1, 2 , Tuyet Thi Nguyen 1, 3 , Dat Da Ly 1, 2 , Jing-Bo Xia 4 , Xu-Feng Qi 4 , In-Kyu Lee 5 , Seung-Kuy Cha 1, 2 , Kyu-Sang Park 1, 2
Affiliation  

Hyperphosphatemia is the primary risk factor for vascular calcification, which is closely associated with cardiovascular morbidity and mortality. Recent evidence showed that oxidative stress by high inorganic phosphate (Pi) mediates calcific changes in vascular smooth muscle cells (VSMCs). However, intracellular signalings responsible for Pi-induced oxidative stress remain unclear. Here, we investigated molecular mechanisms of Pi-induced oxidative stress related with intracellular Ca2+ ([Ca2+]i) disturbance, which is critical for calcification of VSMCs. VSMCs isolated from rat thoracic aorta or A7r5 cells were incubated with high Pi-containing medium. Extracellular signal-regulated kinase (ERK) and mammalian target of rapamycin were activated by high Pi that was required for vascular calcification. High Pi upregulated expressions of type III sodium-phosphate cotransporters, PiT-1 and -2, and stimulated their trafficking to the plasma membrane. Interestingly, high Pi increased [Ca2+]i exclusively dependent on extracellular Na+ and Ca2+ as well as PiT-1/2 abundance. Furthermore, high Pi induced plasma membrane depolarization mediated by PiT-1/2. Pretreatment with verapamil, as a voltage-gated Ca2+ channel (VGCC) blocker, inhibited Pi-induced [Ca2+]i elevation, oxidative stress, ERK activation and osteogenic differentiation. These protective effects were reiterated by extracellular Ca2+ free condition, intracellular Ca2+ chelation or suppression of oxidative stress. Mitochondrial superoxide scavenger also effectively abrogated ERK activation and osteogenic differentiation of VSMCs by high Pi. Taken together, we suggest that high Pi activates depolarization-triggered Ca2+ influx via VGCC, and subsequent [Ca2+]i increase elicits oxidative stress and osteogenic differentiation. PiT-1/2 mediates Pi-induced [Ca2+]i overload and oxidative stress, but in turn, PiT-1/2 is upregulated by consequences of these alterations.

中文翻译:

Ca 2+超载引起的氧化应激对于磷酸盐诱导的血管钙化至关重要

高磷酸盐血症是血管钙化的主要危险因素,其与心血管疾病的发病率和死亡率密切相关。最近的证据表明,高无机磷酸盐(Pi)引起的氧化应激介导了血管平滑肌细胞(VSMC)的钙化变化。然而,负责Pi诱导的氧化应激的细胞内信号仍然不清楚。在这里,我们调查了Pi诱导的与细胞内Ca 2 +([Ca 2+ ] i)干扰,这对于VSMC钙化至关重要。从大鼠胸主动脉或A7r5细胞中分离出的VSMC与高含Pi的培养基孵育。细胞外信号调节激酶(ERK)和雷帕霉素的哺乳动物靶标被血管钙化所需的高Pi激活。高Pi上调了III型磷酸钠共转运蛋白PiT-1和-2的表达,并刺激了它们向质膜的转运。有趣的是,高Pi增加[Ca 2+ ] i仅取决于细胞外Na +和Ca 2+以及PiT-1 / 2的丰度。此外,高Pi诱导PiT-1 / 2介导的质膜去极化。用维拉帕米预处理,作为电压门控的Ca 2+通道(VGCC)阻滞剂,抑制Pi诱导的[Ca 2+ ] i升高,氧化应激,ERK活化和成骨分化。这些保护作用通过细胞外Ca 2+游离条件,细胞内Ca 2+螯合或抑制氧化应激而得以重申。线粒体超氧化物清除剂还通过高Pi有效消除了VSMCs的ERK活化和成骨分化。两者合计,我们建议高Pi通过VGCC激活去极化触发的Ca 2+内流,随后的[Ca 2+ ] i增加引起氧化应激和成骨分化。PiT-1 / 2介导Pi诱导的[Ca 2+ ] i 超载和氧化应激,但反过来,这些改变的结果会上调PiT-1 / 2。
更新日期:2020-10-27
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