Sirtuin 3 is essential for hypertension-induced cardiac fibrosis via mediating pericyte transition

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.