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J Am Heart Assoc. 2018 Mar 19;7(6). pii: e008145. doi: 10.1161/JAHA.117.008145.

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

Author information

1
Department of Forensic Medicine, Wakayama Medical University, Wakayama, Japan.
2
Department of Clinical Laboratory Medicine, Wakayama Medical University, Wakayama, Japan.
3
Department of Cardiovascular Medicine, Wakayama Medical University, Wakayama, Japan.
4
Division of Molecular Bioregulation, Cancer Research Institute Kanazawa University, Kanazawa, Japan.
5
Department of Forensic Medicine, Wakayama Medical University, Wakayama, Japan kondot@wakayama-med.ac.jp.

Abstract

BACKGROUND:

A clear understanding of the molecular mechanisms underlying hemodynamic stress-initiated cardiac hypertrophy is important for preventing heart failure. Interferon-γ (IFN-γ) 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-γ in the pathogenesis of cardiac hypertrophy still remains unclear.

METHODS AND RESULTS:

In order to elucidate the roles of IFN-γ in pressure overload-induced cardiac pathology, we subjected Balb/c wild-type (WT) or IFN-γ-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-γ 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-γ antibody abrogated PI3K/Akt signal activation in WT mice during compensatory hypertrophy, while that of IFN-γ 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-γ 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-γ/Stat5 axis may be protective against persistent pressure overload-induced cardiac hypertrophy by activating the PI3K/Akt pathway.

KEYWORDS:

PI3K/Akt; cell signaling; cytokine; hypertrophy; interferon‐γ; protein kinase B; signal transducer and activator of transcription 5

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