CRIF1 Deficiency Increased Homocysteine Production by Disrupting Dihydrofolate Reductase Expression in Vascular Endothelial Cells.
CRIF1 Deficiency Increased Homocysteine Production by Disrupting Dihydrofolate Reductase Expression in Vascular Endothelial Cells.
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DOI：
10.3390/antiox10111645
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发表时间：
2021-10-20
期刊：
影响因子：
--
通讯作者：
Kim CS
中科院分区：
文献类型：
--
作者：
Lee I;Piao S;Kim S;Nagar H;Choi SJ;Jeon BH;Oh SH;Irani K;Kim CS
血浆同型半胱氨酸水平升高可诱导血管内皮功能障碍;然而，调节受损内皮细胞中同型半胱氨酸代谢的机制目前尚不清楚。在这项研究中，我们删除了人脐静脉内皮细胞（HUVECs）和小鼠中的关键线粒体基因CR 6相互作用因子1（CRIF 1），以诱导内皮细胞功能障碍，然后，我们监测同型半胱氨酸的积累。我们发现CRIF 1下调导致细胞内和血浆中同型半胱氨酸浓度显著增加，这与叶酸循环中间体如5-甲基四氢叶酸（MTHF）和四氢叶酸（THF）水平降低有关。此外，二氢叶酸还原酶（DHFR），叶酸介导的代谢中的关键酶，在CRIF 1敲低内皮细胞中表现出受损的活性和降低的蛋白表达。补充叶酸不能恢复CRIF 1缺失或DHFR敲低的内皮细胞中DHFR表达水平或MTHF和同型半胱氨酸浓度。然而，CRIF 1敲低内皮细胞中DHFR的过表达导致同型半胱氨酸的积累减少。总之，我们的研究结果表明，CRIF 1缺失的内皮细胞积累更多的同型半胱氨酸，与对照细胞相比，这主要是由DHFR表达的破坏介导的。
Elevated plasma homocysteine levels can induce vascular endothelial dysfunction; however, the mechanisms regulating homocysteine metabolism in impaired endothelial cells are currently unclear. In this study, we deleted the essential mitoribosomal gene CR6 interacting factor 1 (CRIF1) in human umbilical vein endothelial cells (HUVECs) and mice to induce endothelial cell dysfunction; then, we monitored homocysteine accumulation. We found that CRIF1 downregulation caused significant increases in intracellular and plasma concentrations of homocysteine, which were associated with decreased levels of folate cycle intermediates such as 5-methyltetrahydrofolate (MTHF) and tetrahydrofolate (THF). Moreover, dihydrofolate reductase (DHFR), a key enzyme in folate-mediated metabolism, exhibited impaired activity and decreased protein expression in CRIF1 knockdown endothelial cells. Supplementation with folic acid did not restore DHFR expression levels or MTHF and homocysteine concentrations in endothelial cells with a CRIF1 deletion or DHFR knockdown. However, the overexpression of DHFR in CRIF1 knockdown endothelial cells resulted in decreased accumulation of homocysteine. Taken together, our findings suggest that CRIF1-deleted endothelial cells accumulated more homocysteine, compared with control cells; this was primarily mediated by the disruption of DHFR expression.
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影响因子：
120.7
作者：
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通讯作者：
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影响因子：
5.4
作者：
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DOI：
10.1016/s0378-4347(01)00521-7
发表时间：
2002-01-25
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3
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