FBXW7 alleviates hyperglycemia-induced endothelial oxidative stress injury via ROS and PARP inhibition.
FBXW7 alleviates hyperglycemia-induced endothelial oxidative stress injury via ROS and PARP inhibition.
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DOI：
10.1016/j.redox.2022.102530
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发表时间：
2022-12
期刊：
影响因子：
11.4
通讯作者：
Wei, Fang
中科院分区：
文献类型：
--
作者：
Li, Shenping;Deng, Junjie;Sun, Dandan;Chen, Shimei;Yao, Xieyi;Wang, Ning;Zhang, Jian;Gu, Qing;Zhang, Shuchang;Wang, Jing;Zhu, Shaopin;Zhu, Hong;Li, Huiming;Xu, Xun;Wei, Fang
糖尿病视网膜病变（DR）和其他糖尿病血管并发症是血糖控制欠佳患者死亡和残疾的主要原因。在糖尿病血管疾病的发病机制中，高血糖诱导的氧化应激、DNA损伤和多聚ADP核糖聚合酶（PARP）过度活化在内皮细胞损伤中起重要作用。脂肪分化相关蛋白FBXW 7被报道调节PGC-1α的稳定性和线粒体的稳态。在此，我们研究了FBXW 7在高血糖条件下修复内皮氧化应激损伤中的作用和机制。FBXW 7促进同源重组和非同源物末端连接途径的受阻活性，以修复DNA双链断裂损伤，是PARP过度活化和糖尿病血管并发症的起始因子。FBXW 7介导的DNA损伤修复的大量动员抑制PARP活化，导致人内皮细胞和糖尿病大鼠视网膜中PARP表达和活性下调。这为抑制PARP提供了一种新的方法，在治疗糖尿病血管并发症方面优于PARP抑制剂上级。此外，FBXW 7挽救了下调的NAD+水平并改善了线粒体功能障碍，从而减少了高血糖条件下的超氧化物产生。这些作用逆转了糖尿病大鼠视网膜的氧化损伤和血管渗漏，为未来的治疗策略提供了潜在的可能。
Diabetic retinopathy (DR) and other diabetic vascular complications are the leading cause of death and disability in patients with suboptimum glycemic control. In the pathogenesis of diabetic vascular diseases, hyperglycemia-induced oxidative stress, DNA damage, and poly-ADP-ribose-polymerase (PARP) hyperactivation play important roles in endothelial cell impairment. Adipose differentiation-related protein FBXW7 was reported to regulate PGC-1α stability and mitochondrial homeostasis. Here, we investigated the role and mechanism of FBXW7 in repairing endothelial oxidative stress injuries under hyperglycemic conditions. FBXW7 promoted the hampered activity of homologous recombination and non-homologues end joining pathway for repairing DNA double-strand breaks damage, an initiating factor for PARP hyperactivation and diabetic vascular complications. The abundant mobilization of DNA damage repair mediated by FBXW7 suppressed PARP activation, leading to downregulation of PARP expression and activity in both human endothelial cells and diabetic rat retinas. This provided a new method for PARP inhibition, superior to PARP inhibitors for treating diabetic vascular complication. Furthermore, FBXW7 rescued downregulated NAD+ levels and ameliorated mitochondrial dysfunction, thereby reducing superoxide production under hyperglycemic conditions. These effects reversed oxidative injury and vascular leakage in diabetic rat retina, providing a potential future treatment strategy.
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影响因子：
19
作者：
Ceccaldi R;Rondinelli B;D'Andrea AD
通讯作者：
D'Andrea AD
DOI：
10.1056/nejmoa1001288
发表时间：
2010-07-15
期刊：
The New England journal of medicine
影响因子：
--
作者：
ACCORD Study Group;ACCORD Eye Study Group;Chew EY;Ambrosius WT;Davis MD;Danis RP;Gangaputra S;Greven CM;Hubbard L;Esser BA;Lovato JF;Perdue LH;Goff DC Jr;Cushman WC;Ginsberg HN;Elam MB;Genuth S;Gerstein HC;Schubart U;Fine LJ
通讯作者：
Fine LJ
Nox2 NADPH氧化酶参与视网膜新生血管形成
影响因子：
4.4
作者：
Chan, Elsa C.;van Wijngaarden, Peter;Dusting, Gregory J.
通讯作者：
Dusting, Gregory J.
影响因子：
5.3
作者：
Hu L;Lv X;Li D;Zhang W;Ran G;Li Q;Hu J
通讯作者：
Hu J
FBXW7通过调节MITF调节线粒体转录程序。
影响因子：
4.3
作者：
Abbate F;Badal B;Mendelson K;Aydin IT;Serasinghe MN;Iqbal R;Mohammed JN;Solovyov A;Greenbaum BD;Chipuk JE;Celebi JT
通讯作者：
Celebi JT