부산대학교 도서관

Introduction: Interleukin-11 (IL-11) is a cytokine produced in response to tissue damage and cellular stress and is secreted from and acts on both parenchymal and stromal cells across tissues. The relative contributions of IL-11 to cardiomyocyte dysfunction and fibroblast activation in heart failure pathologies are ill-defined.Hypothesis: IL-11 causes both cardiomyocyte dysfunction and fibroblast activation that leads to distinct pathologies common to heart failure syndromes.Methods: Cardiomyocytes were isolated from adult C57BL/6 mice and treated with recombinant mouse IL-11 (rmIL-11) or control for 2 hours. Cardiomyocytes were then incubated with a calcium indicator (Fluo-4AM) and stimulated at 1Hz to allow recordings of contractility and calcium transients. In vivo studies were performed using C57BL/6 mice which were injected with rmIL-11 2 hours prior to echocardiography under isoflurane anaesthesia. HFpEF was induced in C57BL/6 mice with diet containing 60% fat and drinking water containing the nitric oxide inhibitor L-NAME. IL-11 was conditionally overexpressed in cardiomyocytes of C57BL/6 mice using a Myh6 dependent cre-loxp system. Ventricular function was measured by echocardiography and molecular analysis was performed 6 weeks following induction of overexpression.Results: Acute treatment for 2 hours with rmIL-11 impaired contractility at both a cellular level in isolated cardiomyocytes and of the whole heart in vivo, as measured by echocardiography. The impairment in systolic function was associated with reduced calcium uptake in cardiomyocytes, an effect which was rapidly reversible. In a mouse model of HFpEF, IL-11 was elevated in the ventricle of treated mice as compared to controls with an associated increase in IL-11 dependent profibrotic gene expression. IL-11 expression in cardiomyocytes results in extensive fibrotic changes in the myocardium, notably peri-vascularly, and significantly reduces systolic function, as compared to control animals.Conclusions: IL-11 is increased in a mouse model of HFpEF, is negatively inotropic in vitro and in vivo and induces fibrosis when secreted from cardiomyocytes. Hence, IL-11 contributes to heart failure pathologies across cellular compartments in the failing heart.