Introduction: Age remains the most powerful risk factor for the development of cardiovascular disease and is associated with impaired cardiac repair after myocardial infarction (MI). Sirtuin 6 (SIRT6) is an epigenetic regulator and member of the sirtuin family of NAD+ dependent deacetylases with anti-aging functions. However, its role in MI is unknown.
Methods and Results: First, to determine the role of SIRT6 in MI, we subjected Balb/c mice to LAD ligation. Significantly, 4 days after MI, SIRT6 was up-regulated in the ischemic myocardium compared with sham-operated animals. To further evaluate SIRT6 role in cardiac repair, we induced MI in 12-week old SIRT6 knock-out male mice and wild-type controls. Significantly, all SIRT6-deficient mice (5 of 5) died after MI, compared with 1 of 5 controls (p=0.04). We next induced MI in SIRT6 over-expressing (OE) and wild-type male mice (n=7-8 mice per group). Notably, 30 days after MI, SIRT6 OE mice displayed greater ejection fraction (43.82±4.2 vs. 31.26±4.17%, p=0.05), and reduced left ventricular mass (119.3±9.0 vs. 149.2±18.2 gr, p=0.12) compared with controls. Next, to determine the role of SIRT6 in macrophage polarization and function, we harvested peritoneal macrophages from SIRT6 OE and wild-type mice and incubated them in a hypoxic chamber. Flow-cytometry revealed a significant increase in reparative M2/M1 ratio in SIRT6 OE hypoxic macrophages with reduction in expression of matrix metalloproteinases.
Conclusions: We show, for the first time, that the epigenetic regulator SIRT6 is highly expressed in the ischemic myocardium and is essential for cardiac protection after MI. Furthermore, SIRT6 over-expression improves cardiac function and remodeling after MI in male mice. These beneficial effects may be partially attributed to the role of SIRT6 in shifting macrophage polarization toward an anti-inflammatory reparative phenotype. Our findings suggest that targeting SIRT6 in macrophages may be a novel therapeutic strategy to improve outcome after MI.
