KDM3A Inhibition Ameliorates Hyperglycemia-Mediated Myocardial Injury by Epigenetic Modulation of Nuclear Factor Kappa-B/P65.
KDM3A Inhibition Ameliorates Hyperglycemia-Mediated Myocardial Injury by Epigenetic Modulation of Nuclear Factor Kappa-B/P65.
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KDM3A 抑制通过核因子 Kappa-B/P65 的表观遗传调节改善高血糖介导的心肌损伤
DOI：
10.3389/fcvm.2022.870999
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发表时间：
2022
影响因子：
3.6
通讯作者：
Chen, Jing
中科院分区：
文献类型：
--
作者：
Zhang, Bofang;Zhang, Jing;Liu, Gen;Guo, Xin;Liu, Xiaopei;Chen, Jing
即使在血糖水平恢复正常后，高血糖诱导的心功能不全以及活性氧（ROS）的产生、炎症反应和细胞凋亡继续恶化，显示出对心脏功能和结构的长期不良影响。我们的目的是揭示高血糖引起的持续性心肌损伤和心功能不全的分子和细胞机制。近年来，越来越多的证据表明表观遗传调控是高血糖导致持续性心血管功能障碍的决定性因素。赖氨酸特异性去甲基化酶3A（Lysine-specific demethylase 3A，KDM 3A）作为一种重要的组蛋白去甲基化酶，在糖尿病心肌组织中表达持续增加，即使接受降糖治疗，H3 K9 me 2水平也持续下降。此外，通过利用获得和丧失功能的方法，我们确定KDM 3A作为一种新的调节剂，加速高血糖介导的心肌损伤，通过促进ROS的产生，聚集炎症反应，并促进细胞凋亡在体外和体内。KDM 3A抑制剂可显著改善糖尿病模型和糖尿病强化血糖控制模型的高血糖不良反应。在机制上，我们的研究发现KDM 3A可以促进核因子κ B（NF-κB/P65）的表达和转录活性，随后的拯救实验进一步证实KDM 3A以NF-κB/P65依赖的方式调节高血糖诱导的心肌损伤。本研究揭示组蛋白修饰酶KDM 3A通过调节NF-κB/P65的转录驱动糖尿病心脏中持续的氧化应激、炎症、凋亡和随后的心肌损伤。
Even after the glucose level returns to normal, hyperglycemia-induced cardiac dysfunction as well as reactive oxygen species (ROS) generation, inflammatory responses, and apoptosis continued deterioration, showing a long-lasting adverse effect on cardiac function and structure. We aimed to unveil the molecular and cellular mechanisms underlying hyperglycemia-induced persistent myocardial injury and cardiac dysfunction. Recently, the accumulated evidence indicated epigenetic regulation act as a determining factor in hyperglycemia-induced continuous cardiovascular dysfunction. As an important histone demethylase, the expression of lysine-specific demethylase 3A (KDM3A) was continually increased, accompanied by a sustained decline of H3K9me2 levels in diabetic myocardium even if received hypoglycemic therapy. Besides, by utilizing gain- and loss-of-functional approaches, we identified KDM3A as a novel regulator that accelerates hyperglycemia-mediated myocardial injury by promoting ROS generation, aggregating inflammatory reaction, and facilitating cell apoptosis in vitro and in vivo. The KDM3A inhibition could significantly ameliorate the adverse effect of hyperglycemia in both diabetes model and diabetic intensive glycemic control model. Mechanically, our data uncovered that KDM3A could promote the expression and transcriptional activity of nuclear factor kappa-B (NF-κB/P65), and the succedent rescue experiments further verified that KDM3A regulates hyperglycemia-induced myocardial injury in an NF-κB/P65 dependent manner. This study revealed histone-modifying enzymes KDM3A drives persistent oxidative stress, inflammation, apoptosis, and subsequent myocardial injury in the diabetic heart by regulating the transcription of NF-κB/P65.
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影响因子：
11.1
作者：
Islam MR;Lbik D;Sakib MS;Maximilian Hofmann R;Berulava T;Jiménez Mausbach M;Cha J;Goldberg M;Vakhtang E;Schiffmann C;Zieseniss A;Katschinski DM;Sananbenesi F;Toischer K;Fischer A
通讯作者：
Fischer A
影响因子：
3.5
作者：
Costantino, Sarah;Paneni, Francesco;Cosentino, Francesco
通讯作者：
Cosentino, Francesco
影响因子：
39.3
作者：
Costantino, Sarah;Paneni, Francesco;Cosentino, Francesco
通讯作者：
Cosentino, Francesco
影响因子：
29.4
作者：
Dandawate, Prasad;Ghosh, Chandrayee;Dhar, Animesh
通讯作者：
Dhar, Animesh
影响因子：
4.8
作者：
Li, Yan;Reddy, Marpadga A.;Natarajan, Rama
通讯作者：
Natarajan, Rama