当前位置: X-MOL 学术Circ. Res. › 论文详情
Our official English website, www.x-mol.net, welcomes your feedback! (Note: you will need to create a separate account there.)
Lactate Promotes Synthetic Phenotype in Vascular Smooth Muscle CellsNovelty and Significance
Circulation Research ( IF 16.5 ) Pub Date : 2017-11-10 , DOI: 10.1161/circresaha.117.311819
Libang Yang 1 , Ling Gao 1 , Thomas Nickel 1 , Jing Yang 1 , Jingyi Zhou 1 , Adam Gilbertsen 1 , Zhaohui Geng 1 , Caitlin Johnson 1 , Bernice Young 1 , Craig Henke 1 , Glenn R. Gourley 1 , Jianyi Zhang 1
Affiliation  

Rationale: The phenotypes of vascular smooth muscle cells (vSMCs) comprise a continuum bounded by predominantly contractile and synthetic cells. Some evidence suggests that contractile vSMCs can assume a more synthetic phenotype in response to ischemic injury, but the mechanisms that activate this phenotypic switch are poorly understood.
Objective: To determine whether lactate, which increases in response to regional ischemia, may promote the synthetic phenotype in vSMCs.
Methods and Results: Experiments were performed with vSMCs that had been differentiated from human induced pluripotent stem cells and then cultured in glucose-free, lactate-enriched (L+) medium or in standard (L) medium. Compared with the L medium, the L+ medium was associated with significant increases in synthetic vSMC marker expression, proliferation, and migration and with significant declines in contractile and apoptotic activity. Furthermore, these changes were accompanied by increases in the expression of monocarboxylic acid transporters and were generally attenuated both by the blockade of monocarboxylic acid transporter activity and by transfection with iRNA for NDRG (N-myc downstream regulated gene). Proteomics, biomarker, and pathway analyses suggested that the L+ medium tended to upregulate the expression of synthetic vSMC markers, the production of extracellular proteins that participate in tissue construction or repair, and the activity of pathways that regulate cell proliferation and migration. Observations in hypoxia-cultured vSMCs were similar to those in L+-cultured vSMCs, and assessments in a swine myocardial infarction model suggested that measurements of lactate levels, lactate-dehydrogenase levels, vSMC proliferation, and monocarboxylic acid transporter and NDRG expression were greater in the ischemic zone than in nonischemic tissues.
Conclusions: These results demonstrate for the first time that vSMCs assume a more synthetic phenotype in a microenvironment that is rich in lactate. Thus, mechanisms that link glucose metabolism to vSMC phenotypic switching could play a role in the pathogenesis and treatment of cardiovascular disease.


中文翻译:

乳酸促进血管平滑肌细胞合成表型的新颖性和意义

原理:血管平滑肌细胞(vSMC)的表型包括一个以收缩和合成细胞为主的连续体。一些证据表明,收缩性vSMC可以对缺血性损伤做出更综合的表型,但是激活这种表型转换的机制知之甚少。
目的:确定响应局部缺血而增加的乳酸是否可以促进vSMCs的合成表型。
方法和结果:实验用的是已经从人诱导多能干细胞分化,然后在不含葡萄糖的,乳酸盐富集(L培养血管平滑肌进行+)培养基中或在标准(L -培养基)。用L相比-介质中,L +培养基用在合成的VSMC标志物表达,增殖和迁移,并用在收缩和细胞凋亡活性显著下降显著增加相关。此外,这些变化伴随着单羧酸转运蛋白表达的增加,并且通常由于单羧酸转运蛋白活性的阻断和iRNA对NDRG的转染而减弱N-myc下游调控基因)。蛋白质组学,生物标记和途径分析表明,L +培养基倾向于上调合成vSMC标记的表达,参与组织构建或修复的细胞外蛋白的产生以及调节细胞增殖和迁移的途径的活性。低氧培养的vSMC中的观察与L +培养的vSMC中的观察相似,并且在猪心肌梗塞模型中的评估表明,乳酸水平,乳酸脱氢酶水平,vSMC增殖,单羧酸转运蛋白和NDRG表达的测量值更高。缺血区比非缺血组织中要好。
结论:这些结果首次证明vSMC在富含乳酸的微环境中呈现出更综合的表型。因此,将葡萄糖代谢与vSMC表型转换联系起来的机制可能在心血管疾病的发病机理和治疗中发挥作用。
更新日期:2017-11-09
down
wechat
bug