JAHA:Sirtuin 3通过调节TIGAR和心肌细胞代谢缓解糖尿病心肌病

2021-02-17 MedSci原创 MedSci原创

SIRT3可能是糖尿病异常能量代谢的新靶点

糖尿病心肌病的患病率正以惊人的速度上升,虽然包括氧化应激、凋亡、心脏纤维化、血管生成受损和糖解代谢在内的多种因素被认为是重要的病理生理因素,但糖尿病心肌病的基本机制仍未被完全理解

糖尿病心肌病是心力衰竭的主要原因,因此,确定潜在的治疗靶标对降低糖尿病患者的发病率和死亡率有十分重要的意义

近日,密西西比大学的一个研究小组在Journal of the American heart association上发表题为Sirtuin 3 Alleviates Diabetic Cardiomyopathy by Regulating TIGAR and Cardiomyocyte Metabolism的研究论文探讨了SIRT3(Sirtuin3)在心肌细胞葡萄糖代谢和心脏功能中的作用

SIRT3(sirtuin 3)通过其底物的脱乙酰基作用来调节细胞代谢。证据显示SIRT3在心血管和代谢性疾病(如心力衰竭,糖尿病和肥胖症)中发挥了重要的调节作用。

研究还显示,糖尿病患者心脏中SIRT3的表达和活性降低,SIRT3的降低与肥胖诱导的微血管稀疏和心脏功能障碍有关。糖尿病患者SIRT3的上调,能增加心肌血管密度从而减轻缺血引起的心脏功能障碍。

SIRT3 改善 HG 诱导的 ROS 形成和细胞凋亡

此外,内皮细胞中SIRT3的特异性敲除导致氧化磷酸化的增加和糖酵解的减少,继而引发血管生成和舒张功能障碍。

TP53诱导的糖酵解和细胞凋亡调节剂TIGAR是肿瘤抑制因子p53的新型下游靶基因。TIGAR参与了各种生物过程,包括糖酵解代谢,细胞凋亡,细胞周期和细胞死亡。

p53在衰竭心脏中的积累有两个作用,诱导细胞周期停滞,导致增殖细胞停滞在细胞周期的G1期,从而诱导衰老和抑制血管生成。

在缺氧条件下,心肌细胞中激活了p53及其转录靶基因TIGARp53的表达在心肌细胞中也升高。p53的升高通过抑制肥厚性心脏中的缺氧诱导因子—而减少了毛细血管的形成。

内皮细胞ECp53的敲除可减少EC凋亡并增加毛细血管密度。TIGAR的敲除也显示可减轻缺血性心力衰竭。

在HG条件下,TIGAR的敲除改善了心肌细胞的代谢

研究结果表明,SIRT3通过调节p53乙酰化和TIGAR表达来减轻糖尿病心肌病。因此,SIRT3可能是糖尿病异常能量代谢的新靶点

原始出处:

Lanfang Li, Heng Zeng, Xiaochen He, and Jian‐Xiong Chen. Sirtuin 3 Alleviates Diabetic Cardiomyopathy by Regulating TIGAR and Cardiomyocyte.  Metabolismhttps://www.ahajournals.org/doi/full/10.1161/JAHA.120.018913

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    2021-02-17 misszhang

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