Alpha-ketoglutarate ameliorates pressure overload-induced chronic cardiac dysfunction in mice.
Alpha-ketoglutarate ameliorates pressure overload-induced chronic cardiac dysfunction in mice.
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DOI：
10.1016/j.redox.2021.102088
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发表时间：
2021-10
期刊：
影响因子：
11.4
通讯作者：
Xu D
中科院分区：
文献类型：
--
作者：
An D;Zeng Q;Zhang P;Ma Z;Zhang H;Liu Z;Li J;Ren H;Xu D
越来越多的证据表明，心肌氧化损伤和线粒体功能障碍参与了心力衰竭的病理生理过程。α-酮戊二酸(AKG)是三羧酸(TCA)循环的中间代谢产物，参与不同的细胞代谢和调节途径。AKG循环浓度随增龄而降低，急性运动和耐力运动后及心力衰竭时升高。最近在实验模型中的研究表明，饮食AKG减少了活性氧(ROS)的产生和全身炎症细胞因子的水平，调节了新陈代谢，延长了寿命，并延缓了年龄相关性衰退的发生。然而，AKG对心力衰竭的影响尚不清楚。在本研究中，我们探讨了AKG对横断性主动脉缩窄(TAC)小鼠左心收缩功能、心肌组织ROS含量和线粒体吞噬功能的影响。AKG可抑制压力超负荷所致的心肌肥大和纤维化，改善心脏收缩功能障碍；在体外，AKG可降低Ang II诱导的β-MHC和ANP的上调，减少ROS的产生和心肌细胞的凋亡，修复Ang II介导的线粒体膜电位的损伤。AKG在TAC小鼠身上的这些好处可能是通过增强线粒体吞噬作用而获得的，它清除了受损的线粒体。综上所述，我们的研究表明，AKG通过促进线粒体吞噬功能，清除受损的线粒体，减少ROS的产生，从而改善压力超负荷心脏的心肌肥厚重构、纤维化和左心室收缩功能障碍；因此，AKG可能具有治疗心衰的潜力。AKG可减轻压力超负荷所致的心肌纤维化和肥厚重构。AKG可改善TAC小鼠的心功能和左心室张力。AKG增加心肌有丝分裂吞噬功能以清除受损的线粒体，并挽救Ang II诱导的TAC小鼠心肌线粒体膜损伤。AKG可降低压力超负荷心脏细胞内ROS和心肌细胞凋亡。
Increasing evidence indicates the involvement of myocardial oxidative injury and mitochondrial dysfunction in the pathophysiology of heart failure (HF). Alpha-ketoglutarate (AKG) is an intermediate metabolite of the tricarboxylic acid (TCA) cycle that participates in different cellular metabolic and regulatory pathways. The circulating concentration of AKG was found to decrease with ageing and is elevated after acute exercise and resistance exercise and in HF. Recent studies in experimental models have shown that dietary AKG reduces reactive oxygen species (ROS) production and systemic inflammatory cytokine levels, regulates metabolism, extends lifespan and delays the occurrence of age-related decline. However, the effects of AKG on HF remain unclear. In the present study, we explored the effects of AKG on left ventricular (LV) systolic function, the myocardial ROS content and mitophagy in mice with transverse aortic constriction (TAC). AKG supplementation inhibited pressure overload-induced myocardial hypertrophy and fibrosis and improved cardiac systolic dysfunction; in vitro, AKG decreased the Ang II-induced upregulation of β-MHC and ANP, reduced ROS production and cardiomyocyte apoptosis, and repaired Ang II-mediated injury to the mitochondrial membrane potential (MMP). These benefits of AKG in the TAC mice may have been obtained by enhanced mitophagy, which cleared damaged mitochondria. In summary, our study suggests that AKG improves myocardial hypertrophy remodelling, fibrosis and LV systolic dysfunction in the pressure-overloaded heart by promoting mitophagy to clear damaged mitochondria and reduce ROS production; thus, AKG may have therapeutic potential for HF. AKG attenuated pressure overload-induced myocardial fibrosis and hypertrophy remodelling. AKG improved cardiac function and left ventricular strain in TAC mice. AKG increased myocardial mitophagy to clear damaged mitochondria and rescued Ang II-induced MMP impairment in TAC mice. AKG reduced intracellular ROS and myocardial apoptosis in the pressure overloaded heart.
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DOI：
10.1093/gerona/gly139
发表时间：
2019-03-14
期刊：
The journals of gerontology. Series A, Biological sciences and medical sciences
影响因子：
--
作者：
de Lucia C;Wallner M;Eaton DM;Zhao H;Houser SR;Koch WJ
通讯作者：
Koch WJ
影响因子：
24
作者：
Cheng, Mei-Ling;Wang, Chao-Hung;Yang, Ning-I
通讯作者：
Yang, Ning-I
阿魏酸可增加 TAC 小鼠肠道乳酸菌并改善心脏功能。
影响因子：
7.5
作者：
Liu, Zuheng;Ma, Zhuang;Xu, Dingli
通讯作者：
Xu, Dingli
影响因子：
2
作者：
Guo, Shuangshuang;Duan, Rui;Ding, Binying
通讯作者：
Ding, Binying
影响因子：
37.8
作者：
Nayor M;Shah RV;Miller PE;Blodgett JB;Tanguay M;Pico AR;Murthy VL;Malhotra R;Houstis NE;Deik A;Pierce KA;Bullock K;Dailey L;Velagaleti RS;Moore SA;Ho JE;Baggish AL;Clish CB;Larson MG;Vasan RS;Lewis GD
通讯作者：
Lewis GD