Loss of the Eukaryotic Initiation Factor 2α Kinase General Control Nonderepressible 2 Protects Mice From Pressure Overload–Induced Congestive Heart Failure Without Affecting Ventricular Hypertrophy

Abstract

In response to a number of stresses, including nutrient deprivation, General Control Nonderepressible 2 kinase (GCN2) attenuates mRNA translation by phosphorylating eukaryotic initiation factor 2 alpha (eIF2αSer51). Energy starvation is known to exacerbate congestive heart failure (CHF) and eIF2αSer51 phosphorylation is increased in the failing heart. However, the impact of GCN2 during the evolution of CHF has not been tested. In this study we examined the influence of GCN2 expression in response to a cardiac stress by inducing chronic pressure overload with Transverse Aortic Constriction (TAC) in Wild Type (WT) and GCN2 knockout (GCN2−/−) mice. Under basal conditions, GCN2−/− had normal LV structure or function but following TAC, demonstrated less contractile dysfunction, less increase of lung weight, less increase of lung inflammation and vascular remodeling, and less myocardial apoptosis and fibrosis compared with WT mice, despite an equivalent degree of LV hypertrophy. As expected, GCN2−/− attenuated TAC induced cardiac eif2αSer51 phosphorylation and preserved Sarcoplasmic reticulum Ca2+ ATPase (Serca2a) expression compared with WT mice. Interestingly, expression of the anti-apoptotic protein Bcl-2 was significantly elevated in GCN2−/− hearts, while in isolated neonatal cardiomyocytes, selective knockdown of GCN2 increased Bcl-2 protein expression and enhanced myocyte resistance to an apoptotic stress. Collectively, our data support the notion that GCN2 impairs the ventricular adaptation to chronic pressure overload by reducing Bcl-2 expression and increasing cardiomyocyte susceptibility to apoptotic stimuli. Our findings suggest that strategies to reduce GCN2 activity in cardiac tissue may be a novel approach to attenuate congestive heart failure development.

Endoplasmic Reticulum Stress Sensor Protein Kinase R–Like Endoplasmic Reticulum Kinase (PERK) Protects Against Pressure Overload–Induced Heart Failure and Lung Remodeling

“…Deletion of the PKR gene (KO) markedly attenuated Transverse Aortic Constriction (TAC)-induced CHF in mice 2 . In addition, we demonstrated that genetic disruption of the eIF2α protein kinase GCN2 also significantly attenuated TAC-induced CHF in mice 3 . However, the effect of eIF2α protein kinase PERK on TAC-induced CHF is unknown.…”

“…We previously reported that LV dysfunction causes severe lung fibrosis and lung vascular remodeling 3, 16 , which is anticipated to exacerbate the progression of CHF. Therefore, we examined TAC-induced lung fibrosis and lung vascular remodeling in wild type and PERK KO mice (Figure S10A-D).…”

“…GCN2 is mainly activated during amino-acid starvation and nutrient deficiency, and Heme-regulated inhibitor kinase limits protein synthesis in heme-deficient cells. We have recently demonstrated that genetic knockout of eIF2α kinase GCN2 significantly attenuated TAC-induced cardiac dysfunction and cardiac eIF2α phosphorylation in mice 3 , while knockout of eIF2α kinase PKR markedly attenuated TAC-induced cardiac dysfunction without affecting cardiac eIF2α phosphorylation 2 . Interestingly, both GCN2 KO and PKR KO had no detectable effect on TAC-induced LV hypertrophy.…”

“…In mammalian cells, the UPR is also mediated by ER trans-membrane proteins inositol-requiring protein-1 (IRE1) and activating transcription factor 6 (ATF6) 6 . Recently, several studies have demonstrated that development of CHF is associated with increased ER stress 7-9 , increased phosphorylation of PERK 7-9 , and increased phosphorylation of translation initiation factor eIF2α 3, 10, 11 .…”

Taxifolin protects against cardiac hypertrophy and fibrosis during biomechanical stress of pressure overload

“…Neonatal rat cardiomyocytes were collected and plated in 10% FCS/DMEM as described previously (Lu et al, 2014). After 24 h of serum starvation, Ang II (1 μM) in the presence or absence of different concentrations of TAX (0 μM, 5 μM, 10 μM, 25 μM, 50 μM) was added to the medium.…”