Protective Roles of Interferon-? 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-? (IFN-?) 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-? in the pathogenesis of cardiac hypertrophy still remains unclear. METHODS AND RESULTS:In order to elucidate the roles of IFN-? in pressure overload-induced cardiac pathology, we subjected Balb/c wild-type (WT) or IFN-?-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-? 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-? antibody abrogated PI3K/Akt signal activation in WT mice during compensatory hypertrophy, while that of IFN-? 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-? 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-?/Stat5 axis may be protective against persistent pressure overload-induced cardiac hypertrophy by activating the PI3K/Akt pathway.

SUBMITTER: Kimura A 

PROVIDER: S-EPMC5907566 | biostudies-literature | 2018 Mar

REPOSITORIES: biostudies-literature