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

Abstract

BackgroundA 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 ResultsIn 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.ConclusionsThe IFN‐γ/Stat5 axis may be protective against persistent pressure overload–induced cardiac hypertrophy by activating the PI3K/Akt pathway.

Sacubitril/valsartan Inhibits Obesity-associated Diastolic Dysfunction through Suppression of Ventricular-vascular Stiffness

“…Although IFN- is implicated in immune and inflammatory responses as a component of the Th1 response, its increased expression has been shown to exert contrasting effects; promote cardiovascular dysfunction or mediate cardioprotective effects [55][56][57][58][59][60]. However, unlike in other studies [56][57][58][59][60], changes in IFN- levels did not correlate with suppression of cardiac hypertrophy in the sac/val-treated ZO rats. IL-4 levels were also elevated in ZOSV, but not in other treatment groups, suggesting that increased IL-4 levels in this treated group might have contributed to the higher impact of sac/val over val in ZO rats.…”

Signal transducer and transcriptional activation 1 protects against pressure overload‐induced cardiac hypertrophy

“…46 Kimura et al reported protective roles of IFN-γ in the pathogenesis of pressure overload-induced cardiac hypertrophy and demonstrated that bone marrow (BM)-derived CD68+ macrophages are a source of IFN-γ and infiltrating immune cells including macrophages appear to be responsible for intracardiac IFN-γ expression. 47 However, Liu et al reported that Bacillus Calmette-Guerin (BCG) and TLR4 agonists prevented pathological cardiac hypertrophy and revealed that their protective actions are mediated by IFN-γ secreted from cardiomyocytes in the left ventricle. 48 In Angioten II-induced cardiac hypertrophy, reciprocal interaction between macrophages and T cells to stimulate IFN-γ expression in the heart was reported previously.…”

Dysfunctional Insulin Resistant/mTOR Activation Is Involved In The Formation of Pulmonary Hypertension In Pressure Overload-Induced Heart Failure

“…The rats were anesthetized by a single intraperitoneal injection of pentobarbital (60 mg/kg), and echocardiography was then performed with VeVo2100 (VisualSonics, Canada). The diastolic intraventricular septum, LV end diastolic diameter, diastolic posterior wall thickness, LV internal dimension in systole, and percent LV fractional shortening were assessed from M-mode images, as previously described [11].…”