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 H₂O₂ 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 H₂O₂ 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.

氧化还原生物学和氧化应激的改变与心力衰竭的发展有关。Glutaredoxin-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性脱谷胱甘肽化。Sirtuin-3（SIRT3）是III类组蛋白脱乙酰基酶，调节线粒体中的赖氨酸乙酰化。GRX2和SIRT3都被认为是保护心肌免受氧化损伤的关键。两者之一的剔除都会导致不利的心脏病，包括肥大，高血压和心脏功能障碍。在这里，我们创建并表征了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作用，并加剧线粒体功能和心肌结构重塑。野生型单基因敲除（比较了Sirt3 ^-/-，Grx2 ^-/-和双敲除小鼠（Grx2 ^-/- / Sirt3 ^-/-）的心脏重量，组织学，线粒体呼吸和H ₂ O ₂产生。总体而言，与野生型相比，来自Grx2 ^-/- / Sirt3 ^-//小鼠的心脏显示出纤维化和肥大。在Grx2 ^-/-和Sirt3 ^-/-中，我们观察到了线粒体氧化能力的变化，但这仅与Sirt3 ^-/-中的H ₂ O ₂排放升高有关^。。在Grx2 ^-/- / Sirt3 ^-/-小鼠的心脏中观察到了类似的变化，但没有恶化，表明这些变化不是累加的。在人类心肌中，使用人类基因型组织表达协会的遗传和组织病理学数据，我们证实SIRT3表达与心脏病理学呈负相关。总而言之，GRX2和SIRT3在控制心脏线粒体的氧化还原和氧化过程中很重要，但是它们的联合缺失并不会加剧这种作用，这与它们在心脏的复杂氧化还原和抗氧化系统中共同发挥作用的总体结论一致。