Protective Roles of Interferon-c in Cardiac Hypertrophy Induced by Sustained Pressure Overload

Abstract

Background-—A clear understanding of the molecular mechanisms underlying hemodynamic stress-initiated cardiac hypertrophy is important for preventing heart failure. Interferon-c (IFN-c) has been suggested to play crucial roles in various diseases other than immunological disorders by modulating the expression of myriad genes. However, the involvement of IFN-c in the pathogenesis of cardiac hypertrophy still remains unclear. Methods and Results-—In order to elucidate the roles of IFN-c in pressure overload–induced cardiac pathology, we subjected Balb/c wild-type (WT) or IFN-c-deficient (Ifng/) mice to transverse aortic constriction (TAC). Three weeks after TAC, Ifng/ mice developed more severe cardiac hypertrophy, fibrosis, and dysfunction than WT mice. Bone marrow–derived immune cells including macrophages were a source of IFN-c in hearts after TAC. The activation of PI3K/Akt signaling, a key signaling pathway in compensatory hypertrophy, was detected 3 days after TAC in the left ventricles of WT mice and was markedly attenuated in Ifng/ mice. The administration of a neutralizing anti-IFN-c antibody abrogated PI3K/Akt signal activation in WT mice during compensatory hypertrophy, while that of IFN-c activated PI3K/Akt signaling in Ifng/ mice. TAC also induced the phosphorylation of Stat5, but not Stat1 in the left ventricles of WT mice 3 days after TAC. Furthermore, IFN-c induced Stat5 and Akt phosphorylation in rat cardiomyocytes cultured under stretch conditions. A Stat5 inhibitor significantly suppressed PI3K/Akt signaling activation in the left ventricles of WT mice, and aggravated pressure overload–induced cardiac hypertrophy. Conclusions-—The IFN-c/Stat5 axis may be protective against persistent pressure overload–induced cardiac hypertrophy by activating the PI3K/Akt pathway.