The Longevity Gene Sirtuin 6 Switches Macrophages into an Anti-Inflammatory Phenotype and Improves Cardiac Function After Myocardial Infarction in Mice.

Background and Purpose:Ageing has been implicated in macrophage (MQ) dysfunction, deterioration of myocardial homeostasis, chronic inflammation, adverse remodeling and fibrosis. The longevity gene Sirtuin 6 (SIRT6) regulates anti-ageing and anti-inflammatory properties that protect against several cardiovascular risk factors. However, the role of SIRT6 in cardiac repair, and its role in MQ remain unknown. Therefore, we aimed to determine the role of MQ SIRT6 in acute myocardial infarction (MI).

Methods and Results: First, we aimed to determine whether SIRT6 is involved in cardiac repair after MI. We induced MI in 12-week old SIRT6-overexpressing (SIRT6-OE) male mice and their wild-type (WT) litter mates as controls. Thirty days after MI, SIRT6-OE mice developed higher left ventricular (LV) fractional shortening (46%, p=0.05) and smaller LV mass (25%, p=0.12), compared with WT controls. Then, to determine whether SIRT6 influences cardiac MQ phenotype after MI, we induced MI in 12-week old SIRT6-OE male mice and their WT litter-mates, and analyzed cardiac MQ phenotype by flow cytometry using CD206 (M2 marker) and CD86 (M1 marker). At day 4 after MI, the M2/M1 ratio was 3-fold greater in cardiac MQs from SIRT6-OE mice vs. controls (p=0.02). Furthermore, we found reduced expression of the pro-fibrotic gene TGFβ (p=0.02) and higher expression of MMP12 (p=0.05) in MQs extracted from SIRT6-OE mice, compared with WT.

Conclusions: Over expression of the longevity gene SIRT6 improves cardiac remodeling and function after MI. SIRT6 regulates MQ activation and promotes anti-inflammatory and anti-fibrotic properties. Our results suggest that targeting macrophage SIRT6 could be a novel therapeutic strategy for acute MI.