Hypertension is the key factor for the development of cardiac fibrosis and diastolic dysfunction. Our previous study showed that knockout of sirtuin 3 (SIRT3) resulted in diastolic dysfunction in mice. In the present study, we explored the role of SIRT3 in angiotensin II (Ang‐II)–induced cardiac fibrosis and pericyte‐myofibroblast transition. NG2 tracing reporter NG2‐DsRed mouse was crossed with wild‐type (WT) mice and SIRT3KO mice. Cardiac function, cardiac fibrosis and reactive oxygen species (ROS) were measured. Mice infused with Ang‐II for 28 days showed a significant reduction of SIRT3 expression in the mouse hearts. Knockout of SIRT3 sensitized Ang‐II‐induced elevation of isovolumic relaxation time (IVRT) and reduction of ejection fraction (EF) and fractional shortening (FS). Ang‐II‐induced cardiac fibrosis, capillary rarefaction and hypertrophy were further enhanced by knockout of SIRT3. NG2 pericyte tracing reporter mice infused with Ang‐II had a significantly increased number of NG2‐DsRed pericyte in the heart. Knockout of SIRT3 further enhanced Ang‐II‐induced increase of pericytes. To examine pericyte‐myofibroblast/fibroblast transition, DsRed pericytes were co‐stained with FSP‐1 and α‐SMA. Ang‐II infusion led to a significant increase in numbers of DsRed⁺/FSP‐1⁺ and DsRed⁺/α‐SMA⁺ cells, while SIRT3KO further developed pericyte‐myofibroblast/fibroblast transition. In addition, knockout of SIRT3 promoted Ang‐II‐induced NADPH oxidase‐derived ROS formation together with increased expression of transforming growth factor beta 1 (TGF‐β1). We concluded that Ang‐II induced cardiac fibrosis partly by the mechanisms involving SIRT3‐mediated pericyte‐myofibroblast/fibroblast transition and ROS‐TGF‐β1 pathway.

中文翻译：

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Sirtuin 3通过介导周细胞过渡对高血压诱发的心脏纤维化至关重要。

高血压是心脏纤维化和舒张功能障碍发展的关键因素。我们以前的研究表明敲除瑟土因3（SIRT3）导致小鼠舒张功能障碍。在本研究中，我们探讨了SIRT3在血管紧张素II（Ang-II）诱导的心脏纤维化和周细胞-成肌纤维细胞转化中的作用。NG2追踪报告子NG2-DsRed小鼠与野生型（WT）小鼠和SIRT3KO小鼠杂交。测量心脏功能，心脏纤维化和活性氧（ROS）。注入Ang-II 28天的小鼠在小鼠心脏中显示出SIRT3表达的显着降低。敲除SIRT3可提高Ang II诱导的等容舒张时间（IVRT）升高，射血分数（EF）和分数缩短（FS）降低。Ang II诱导的心脏纤维化，敲除SIRT3进一步增强了毛细血管稀疏和肥大。注入Ang-II的NG2周细胞追踪报告基因小鼠的心脏中NG2-DsRed周细胞的数量显着增加。SIRT3的敲除进一步增强了Ang-II诱导的周细胞增加。为了检查周细胞-肌成纤维细胞/成纤维细胞的过渡，将DsRed周细胞与FSP-1和α-SMA共同染色。Ang‐II输注导致DsRed数量显着增加⁺ / FSP-1 ⁺和DsRed ⁺ /α-SMA ⁺细胞，而SIRT3KO进一步发展了周细胞-肌成纤维细胞/成纤维细胞过渡。此外，敲除SIRT3促进了Ang II诱导的NADPH氧化酶衍生的ROS形成，同时增加了转化生长因子β1（TGF-β1）的表达。我们得出的结论是，Ang-II部分地通过涉及SIRT3介导的周细胞-成肌纤维细胞/成纤维细胞过渡和ROS-TGF-β1途径的机制诱导了心脏纤维化。