Overexpression of the Longevity Gene SIRT6 in Myeloid Cells Reduced Left Ventricular Hypertrophy After Myocardial Infraction

Background and Aim: The longevity gene SIRT6 provides anti-ageing, anti-inflammatory, and anti-hypertrophic properties that might protect against several cardiovascular diseases. Because macrophages are involved in every stage of infarct repair, we aimed to test the hypothesis that activation of SIRT6 in macrophages could improve the outcome after acute myocardial infarction (MI).
Methods and Results: First, to determine whether macrophages-SIRT6 is involved in cardiac repair after MI, we induced MI in 12-week old SIRT6 overexpressing (SIRT6-OE) mice and their wild-type littermates (WT). At day 4 after MI, the M2 (CD206+) /M1 (CD86+) macrophages ratio was 3-fold higher in SIRT6-OE cardiac macrophages than in WT controls (p=0.02). Next, to determine the role of macrophage-SIRT6 in infarct repair, we irradiated WT recipient mice and 24h later performed bone marrow transplantation (BMT) from either SIRT6-OE donors (n=8) or WT donors (n=7). Thirty days after BMT, we induced MI in BMT mice and evaluated cardiac function by serial echocardiography studies. Thirty days after MI, echocardiography studies did not reveal a significant difference in cardiac function between SIRT6-OE BMT and WT BMT mice. However, heart/body weight ratio in SIRT6-OE BMT mice was smaller by 2-folds than in WT BMT mice (p=0.03). Postmortem morphometric assessment revealed that left ventricular hypertrophy (LVH), indicated by muscle area, septal wall thickness, and scar thickness were smaller in SIRT6-OE BMT compared with WT BMT mice (7.428±0.6 vs. 9.663±0.8mm², p=0.06, 0.7±0.05 vs. 0.85±0.02mm, p=0.08, 0.2±0.02 vs. 0.3±0.04mm, p=0.05). Finally, SIRT6-OE BMT reduced post-MI cardiomyocyte hypertrophy compared with WT BMT mice (11.2±0.11 vs. 12.3±0.13um, p<0.001).

Conclusions: The longevity gene SIRT6 regulates macrophages activation and promotes their anti-inflammatory and anti-hypertrophy properties. Overexpression of SIRT6 in myeloid cells prevents LVH and improves cardiac remodeling after myocardial infraction. Our data suggest that stimulating macrophage-SIRT6 could be a novel therapeutic strategy to reduce LVH after myocardial infraction.