Warburg Effect as a Novel Mechanism for Homocysteine-Induced Features of Age-Related Macular Degeneration.
Warburg Effect as a Novel Mechanism for Homocysteine-Induced Features of Age-Related Macular Degeneration.
复制标题
瓦尔堡效应作为同型半胱氨酸诱导的黄斑变性特征的新机制。
DOI：
10.3390/ijms24021071
复制
发表时间：
2023-01-05
影响因子：
5.6
通讯作者：
Tawfik, Amany
中科院分区：
文献类型：
--
作者：
Samra, Yara A.;Zaidi, Yusra;Rajpurohit, Pragya;Raghavan, Raju;Cai, Lun;Kaddour-Djebbar, Ismail;Tawfik, Amany
关键词：
视网膜相关性黄斑变性（AMD）是导致失明的主要原因。最近的研究报告了具有高乳酸/丙酮酸比率的AMD患者的糖酵解受损。在几项临床研究中观察到同型半胱氨酸（Hcy）升高（高同型半胱氨酸血症，HHcy），报告了HHcy与AMD之间的相关性。我们建立了高同型半胱氨酸对屏障功能，视网膜色素上皮（RPE）结构，并诱导脉络膜新生血管（CNV）的影响。我们假设HHcy通过诱导线粒体中的代谢转换而导致AMD，其中细胞主要通过高速率的糖酵解或“瓦尔堡”效应产生能量。糖酵解增加导致乳酸产生增加、细胞酸度增加、血管生成激活、RPE屏障功能障碍和CNV。通过海马分析、免疫荧光和蛋白质印迹实验评估HHcy下细胞能量产生的评估。海马分析评价了细胞外酸化率（ECAR）作为糖酵解的指标。与野生型小鼠和RPE细胞相比，HHcy在体内使用（胱硫醚β-合酶）cbs+/−和cbs−/−小鼠视网膜和体外（Hcy处理的ARPE-19）均显示ECAR显著增加。此外，在Hcy处理的ARPE-19和从cbs+/+、cbs+/−和cbs−/−小鼠视网膜分离的原代RPE细胞中，HHcy上调糖酵解酶（葡萄糖转运蛋白-1（GlUT-1）、乳酸脱氢酶（LDH）和己糖激酶1（HK 1））。抑制GLUT-1或阻断N-甲基-D-天冬氨酸受体（NMDAR）可减少Hcy处理的RPE中的糖酵解，并改善Hcy注射小鼠眼中的白蛋白渗漏和CNV诱导。目前的研究表明，在AMD期间，HHcy导致RPE细胞中从线粒体呼吸到糖酵解的代谢转换，并证实NMDAR参与了这一过程。因此，靶向糖酵解或NMDAR可能是AMD的新治疗靶点。
Age-related macular degeneration (AMD) is a major cause of blindness. Recent studies have reported impaired glycolysis in AMD patients with a high lactate/pyruvate ratio. Elevated homocysteine (Hcy) (Hyperhomocysteinemia, HHcy) was observed in several clinical studies, reporting an association between HHcy and AMD. We established the effect of HHcy on barrier function, retinal pigment epithelium (RPE) structure, and induced choroidal neovascularization (CNV) in mice. We hypothesize that HHcy contributes to AMD by inducing a metabolic switch in the mitochondria, in which cells predominantly produce energy by the high rate of glycolysis, or “Warburg”, effect. Increased glycolysis results in an increased production of lactate, cellular acidity, activation of angiogenesis, RPE barrier dysfunction, and CNV. Evaluation of cellular energy production under HHcy was assessed by seahorse analysis, immunofluorescence, and western blot experiments. The seahorse analysis evaluated the extracellular acidification rate (ECAR) as indicative of glycolysis. HHcy showed a significant increase in ECAR both in vivo using (Cystathionine β-synthase) cbs+/− and cbs−/− mice retinas and in vitro (Hcy-treated ARPE-19) compared to wild-type mice and RPE cells. Moreover, HHcy up-regulated glycolytic enzyme (Glucose transporter-1 (GlUT-1), lactate dehydrogenase (LDH), and hexokinase 1 (HK1)) in Hcy-treated ARPE-19 and primary RPE cells isolated from cbs+/+, cbs+/−, and cbs−/− mice retinas. Inhibition of GLUT-1 or blocking of N-methyl-D-aspartate receptors (NMDAR) reduced glycolysis in Hcy-treated RPE and improved albumin leakage and CNV induction in Hcy-injected mice eyes. The current study suggests that HHcy causes a metabolic switch in the RPE cells from mitochondrial respiration to glycolysis during AMD and confirms the involvement of NMDAR in this process. Therefore, targeting Glycolysis or NMDAR could be a novel therapeutic target for AMD.
登录
查看更多内容
影响因子：
4.4
作者：
Ganapathy, Preethi S.;Perry, Richard L.;Smith, Sylvia B.
通讯作者：
Smith, Sylvia B.
DOI：
10.1042/bj20111148
发表时间：
2012-01-15
期刊：
The Biochemical journal
影响因子：
--
作者：
Gnana-Prakasam JP;Tawfik A;Romej M;Ananth S;Martin PM;Smith SB;Ganapathy V
通讯作者：
Ganapathy V
DOI：
10.1007/s00417-005-0108-2
发表时间：
2006-05-01
影响因子：
2.7
作者：
Kamburoglu, Gunhal;Gumus, Koray;Eldem, Bora
通讯作者：
Eldem, Bora
影响因子：
4.4
作者：
Chan, Eric Chun Yong;Koh, Poh Koon;Keun, Hector C.
通讯作者：
Keun, Hector C.
影响因子：
4.7
作者：
Iacobini C;Vitale M;Pugliese G;Menini S
通讯作者：
Menini S