P038 A role of IFN-gamma in pressure overload-induced compensatory cardiac hypertrophy

Abstract Introduction Cardiac hypertrophy is an adaptive response of the heart to prolonged increases in hemodynamic workload. This compensatory process is initially beneficial in normalizing wall stress, and sustained left ventricular hypertrophy significantly increases the risk of developing heart failure. Although various molecules have been shown to be involved in the compensatory process, its molecular mechanism still remains unclear. We investigated roles of IFN-γ in the process of compensatory cardiac hypertrophy induced by pressure overload. Methods Male Balb/c (WT) and IFN-γ-deficient (IFN-γ-KO) mice were subjected to transverse aortic constriction (TAC).Aortic constriction was achieved by tying around the transverse thoracic aorta against a 28-gauge needle using a 7–0 silk suture, and then removing the needle. As the control, sham operation was also performed without constricting the aorta. Cardiac hypertrophy, survival rate and hypertrophy related signaling pathways were examined. Results Intracardiac gene expression for IFN-γ was rapidly increased in TAC mice. Although TAC induced rapid increase of heart weight/body weight ratio (HW/BW ratio) in WT mice even at 3 days after TAC, most mice survived for 3 weeks after TAC. On the other hand, IFN-γ-KO mice showed no significant increase of HW/BW ratio at 3 days after TAC, and about 60% of them died within 6 days after TAC. Western blotting analysis showed that AKT phosphorylation in the left ventricles of WT mice was significantly increased at 3 days after TAC, compared with sham operated mice. The downstream signal molecules, GSK-3 β and GATA4, were also highly phosphorylated in the left ventricles of WT mice, compared with sham operated mice. However, the activation of PI3K/AKT signals were significantly attenuated in the left ventricles of IFN-γ-KO mice, indicating that IFN-γ plays a crucial role in the hypertrophic response through PI3K/AKT signaling. Conclusion Our results demonstrate blunted hypertrophy with reduced survival rate and attenuated PIK3/AKT signaling following pressure overload in IFN-γ-KO mice, and suggest that IFN-γ plays a crucial role in the compensatory hypertrophic response.