细胞酸中毒和 NAD+/NADH 比率降低的协同作用是脓毒症中乳酸酸中毒诱发血管平滑肌细胞损伤的原因。

IF 9 2区 医学 Q1 CELL BIOLOGY
Philipp Terpe, Stefanie Ruhs, Virginie Dubourg, Michael Bucher, Michael Gekle
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引用次数: 0

摘要

背景:脓毒症期间,由于血管平滑肌细胞(VSMC)受损,导致血管痉挛、低血压和灌注不足,从而引发血管功能障碍,导致多器官衰竭,危及生命。此外,脓毒症患者的细胞代谢发生改变,导致乳酸中毒。患有乳酸酸中毒的脓毒症患者死亡率很高。此外,脓毒症幸存者还有继发血管疾病的风险。乳酸酸中毒是否以及如何导致血管内皮细胞发生变化的潜在机制尚不十分清楚。本研究旨在全面研究乳酸酸中毒对血管平滑肌细胞的影响,并将其与纯酸中毒和乳酸钠诱导的影响进行比较:方法:将原代人主动脉平滑肌细胞(HAoSMCs)分别用乳酸酸中毒(LA_pH 6.8)、盐酸(HCl_pH 6.8)、乳酸钠(Na+-lactate_pH 7.4)和各自的对照组(ctrl._pH 7.4;高渗对照组:甘露醇_pH 7.4),并比较分析了(i)转录组、(ii)能量代谢和(iii)表型的变化:结果:两种类型的酸中毒都导致了相当和持续的细胞内酸化,但不影响细胞活力。RNA测序和详细的转录组分析表明,乳酸酸中毒比盐酸酸中毒的变化更显著,而乳酸几乎不起作用,这表明酸中毒和乳酸在质量和数量上具有协同作用。实验证实了生物信息学对能量代谢和表型的预测。乳酸中毒导致糖酵解、谷氨酰胺酵解受到强烈抑制,线粒体呼吸发生改变,从而降低了细胞的 ATP 含量,这可能是由于 TXNIP 表达增加和 NAD+/NADH 比率改变所致。盐酸中毒引起的影响明显较小,NAD+/NADH 比率没有变化,ATP 含量保持不变。这些代谢变化导致了血管内皮细胞的骨性/软骨性/衰老性转分化,乳酸性酸中毒比单纯性酸中毒的影响更明显:总的来说,乳酸酸中毒对能量代谢的影响比单纯酸中毒大得多,而乳酸几乎没有影响,这反映了酸中毒和乳酸在质和量上的协同作用。因此,乳酸中毒可能会导致血管内皮细胞急性功能损伤、转录组的持续紊乱和细胞的去分化。此外,这些影响可能会导致脓毒症患者血管病理机制的急性化和长期化。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
The synergism of cytosolic acidosis and reduced NAD+/NADH ratio is responsible for lactic acidosis-induced vascular smooth muscle cell impairment in sepsis.

Background: During sepsis, serve vascular dysfunctions lead to life-threatening multiple organ failure, due to vascular smooth muscle cells (VSMC) impairments, resulting in vasoplegia, hypotension and hypoperfusion. In addition, septic patients have an altered cell metabolism that leads to lactic acidosis. Septic patients suffering from lactic acidosis have a high risk of mortality. In addition, septic survivors are at risk of secondary vascular disease. The underlying mechanisms of whether and how lactic acidosis leads to the changes in VSMCs is not well understood. The aim of this study was to comprehensively investigate the effect of lactic acidosis on VSMCs and additionally compare the effects with those induced by pure acidosis and sodium lactate.

Methods: Primary human aortic smooth muscle cells (HAoSMCs) were treated for 48 h with lactic acidosis (LA_pH 6.8), hydrochloric acid (HCl_pH 6.8), sodium lactate (Na+-lactate_pH 7.4) and the respective controls (ctrl._pH 7.4; hyperosmolarity control: mannitol_pH 7.4) and comparatively analyzed for changes in (i) transcriptome, (ii) energy metabolism, and (iii) phenotype.

Results: Both types of acidosis led to comparable and sustained intracellular acidification without affecting cell viability. RNA sequencing and detailed transcriptome analysis revealed more significant changes for lactic acidosis than for hydrochloric acidosis, with lactate being almost ineffective, suggesting qualitative and quantitative synergism of acidosis and lactate. Bioinformatic predictions in energy metabolism and phenotype were confirmed experimentally. Lactic acidosis resulted in strong inhibition of glycolysis, glutaminolysis, and altered mitochondrial respiration which reduced cellular ATP content, likely due to increased TXNIP expression and altered NAD+/NADH ratio. Hydrochloric acidosis induced significantly smaller effects without changing the NAD+/NADH ratio, with the ATP content remaining constant. These metabolic changes led to osteo-/chondrogenic/senescent transdifferentiation of VSMCs, with the effect being more pronounced in lactic acidosis than in pure acidosis.

Conclusions: Overall, lactic acidosis exerted a much stronger effect on energy metabolism than pure acidosis, whereas lactate had almost no effect, reflecting the qualitative and quantitative synergism of acidosis and lactate. As a consequence, lactic acidosis may lead to acute functional impairments of VSMC, sustained perturbations of the transcriptome and cellular dedifferentiation. Moreover, these effects may contribute to the acute and prolonged vascular pathomechanisms in septic patients.

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来源期刊
Journal of Biomedical Science
Journal of Biomedical Science 医学-医学:研究与实验
CiteScore
18.50
自引率
0.90%
发文量
95
审稿时长
1 months
期刊介绍: The Journal of Biomedical Science is an open access, peer-reviewed journal that focuses on fundamental and molecular aspects of basic medical sciences. It emphasizes molecular studies of biomedical problems and mechanisms. The National Science and Technology Council (NSTC), Taiwan supports the journal and covers the publication costs for accepted articles. The journal aims to provide an international platform for interdisciplinary discussions and contribute to the advancement of medicine. It benefits both readers and authors by accelerating the dissemination of research information and providing maximum access to scholarly communication. All articles published in the Journal of Biomedical Science are included in various databases such as Biological Abstracts, BIOSIS, CABI, CAS, Citebase, Current contents, DOAJ, Embase, EmBiology, and Global Health, among others.
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