Boardman Neoma T, Migally Baher, Pileggi Chantal, Parmar Gaganvir S, Xuan Jian Ying, Menzies Keir, Harper Mary-Ellen
Department of Biochemistry, Microbiology and Immunology, Ottawa Institute of Systems Biology, Faculty of Medicine, University of Ottawa, Ottawa, ON, Canada; Department of Medical Biology, Faculty of Health Sciences, UiT-Arctic University of Norway, Tromsø, Norway.
Department of Biochemistry, Microbiology and Immunology, Ottawa Institute of Systems Biology, Faculty of Medicine, University of Ottawa, Ottawa, ON, Canada.
Biochim Biophys Acta Mol Basis Dis. 2021 Jan 1;1867(1):165982. doi: 10.1016/j.bbadis.2020.165982. Epub 2020 Sep 28.
Altered redox biology and oxidative stress have been implicated in the progression of heart failure. Glutaredoxin-2 (GRX2) is a glutathione-dependent oxidoreductase and catalyzes the reversible deglutathionylation of mitochondrial proteins. Sirtuin-3 (SIRT3) is a class III histone deacetylase and regulates lysine acetylation in mitochondria. Both GRX2 and SIRT3 are considered as key in the protection against oxidative damage in the myocardium. Knockout of either contributes to adverse heart pathologies including hypertrophy, hypertension, and cardiac dysfunction. Here, we created and characterized a GRX2 and SIRT3 double-knockout mouse model, hypothesizing that their deletions would have an additive effect on oxidative stress, and exacerbate mitochondrial function and myocardial structural remodeling. Wildtype, single-gene knockout (Sirt3, Grx2), and double-knockout mice (Grx2/Sirt3) were compared in heart weight, histology, mitochondrial respiration and HO production. Overall, the hearts from Grx2/Sirt3 mice displayed increased fibrosis and hypertrophy versus wildtype. In the Grx2 and the Sirt3 we observed changes in mitochondrial oxidative capacity, however this was associated with elevated HO emission only in the Sirt3. Similar changes were observed but not worsened in hearts from Grx2/Sirt3 mice, suggesting that these changes were not additive. In human myocardium, using genetic and histopathological data from the human Genotype-Tissue Expression consortium, we confirmed that SIRT3 expression correlates inversely with heart pathology. Altogether, GRX2 and SIRT3 are important in the control of cardiac mitochondrial redox and oxidative processes, but their combined absence does not exacerbate effects, consistent with the overall conclusion that they function together in the complex redox and antioxidant systems in the heart.
氧化还原生物学改变和氧化应激与心力衰竭的进展有关。谷氧还蛋白-2（GRX2）是一种依赖谷胱甘肽的氧化还原酶，催化线粒体蛋白的可逆去谷胱甘肽化反应。沉默调节蛋白3（SIRT3）是一种Ⅲ类组蛋白脱乙酰酶，调节线粒体中的赖氨酸乙酰化。GRX2和SIRT3均被认为是保护心肌免受氧化损伤的关键因素。敲除其中任何一个都会导致不良心脏病变，包括肥大、高血压和心脏功能障碍。在此，我们构建并鉴定了GRX2和SIRT3双敲除小鼠模型，假设它们的缺失会对氧化应激产生累加效应，并加剧线粒体功能和心肌结构重塑。对野生型、单基因敲除（Sirt3、Grx2）和双敲除小鼠（Grx2/Sirt3）的心脏重量、组织学、线粒体呼吸和HO生成进行了比较。总体而言，与野生型相比，Grx2/Sirt3小鼠的心脏显示出纤维化和肥大增加。在Grx2和Sirt3中，我们观察到线粒体氧化能力的变化，然而，这仅在Sirt3中与HO释放增加有关。在Grx2/Sirt3小鼠的心脏中观察到类似变化，但未恶化，表明这些变化不是累加性的。在人类心肌中，利用来自人类基因型-组织表达联合体的遗传和组织病理学数据，我们证实SIRT3表达与心脏病变呈负相关。总之，GRX2和SIRT3在控制心脏线粒体氧化还原和氧化过程中很重要，但它们共同缺失不会加剧影响，这与它们在心脏复杂的氧化还原和抗氧化系统中共同发挥作用的总体结论一致。
