Chronic treatment of mice with leukemia inhibitory factor does not cause adverse cardiac remodeling but improves heart function

Recent evidence suggests that the IL-6 family cytokine, leukemia inhibitory factor (LIF) is produced by cardiac cells under stress conditions including myocardial infarction and heart failure. Additionally, short-term delivery of LIF has been shown to have preconditioning effects on the heart and to limit infarct size. However, cell culture studies have suggested that LIF may exert harmful effects on cardiac myocytes, including pathological hypertrophy and contractile dysfunction. Long-term effects of LIF on the heart in vivo have not been reported and were the focus of this study. Adult male mice were injected daily with LIF (2 mu g/30 g) or saline for 10 days. LIF treatment caused an approximate 11% loss in body weight. Cardiac function as assessed by echocardiography was improved in LIF-treated mice. Ejection fraction and fractional shortening were increased by 21% and 32%, respectively. No cardiac hypertrophy was seen on histology in LIF-treated mice, there was no change in the heart-to-tibia length ratio, and no cardiac fibrosis was observed. STAT3 was markedly activated by LIF in the left ventricle. Different effects of LIF were seen in protein levels of genes associated with STAT3 in the left ventricle: levels of SOD2 and Bcl-xL were unchanged, but levels of total STAT3 and MCP-1 were increased. There was a trend towards increased expression of miR-17, miR-21, and miR-199 in the left ventricle of LIF-treated mice, but these changes were not statistically significant. In conclusion, effects of chronic LIF treatment on the heart, although modest, were positive for systolic function: adverse cardiac remodeling was not observed. Our findings thus lend further support to recent proposals that LIF may have therapeutic utility in preventing injury to or repairing the myocardium.