Abstract
Hemodynamic stress on the mammalian heart results in compensatory hypertrophy and activation of the unfolded protein response through activating transcription factor 6α (ATF6α) in cardiac myocytes, but the roles of ATF6α or the related transcription factor ATF6β in regulating this hypertrophic response are not well-understood. Here we examined the effects of loss of ATF6α or ATF6β on the cardiac response to pressure overload. Mice gene-deleted for Atf6 or Atf6b were subjected to 2 weeks of transverse aortic constriction, and each showed a significant reduction in hypertrophy with reduced expression of endoplasmic reticulum (ER) stress-associated proteins compared with controls. However, with long-term pressure overload both Atf6 and Atf6b null mice showed enhanced decompensation typified by increased heart weight, pulmonary edema and reduced function compared to control mice. Our subsequent studies using cardiac-specific transgenic mice expressing the transcriptionally active N-terminus of ATF6α or ATF6β revealed that these factors control overlapping gene expression networks that include numerous ER protein chaperones and ER associated degradation components. This work reveals previously unappreciated roles for ATF6α and ATF6β in regulating the pressure overload induced cardiac hypertrophic response and in controlling the expression of genes that condition the ER during hemodynamic stress.
Highlights
Hemodynamic stress, such as that caused by chronic hypertension or aortic stenosis leads to activation of signaling pathways such as calcineurin/nuclear factor of activated T-cells and calcium-calmodulin-dependent protein kinase II that result in hypertrophy of the heart[1]
We previously demonstrated that mice lacking Thbs[4], which is required for proper activating transcription factor 6α (ATF6α) activation in the heart, showed increased mortality after transverse aortic constriction (TAC) surgery[2]
These mice were subjected to 2 weeks of pressure overload produced by TAC surgery, our results showed that Thbs[4] overexpression did not alter this TAC-induced hypertrophic response in either the Atf[6] or Atf6b null backgrounds (Fig. S1)
Summary
Hemodynamic stress, such as that caused by chronic hypertension or aortic stenosis leads to activation of signaling pathways such as calcineurin/nuclear factor of activated T-cells and calcium-calmodulin-dependent protein kinase II that result in hypertrophy of the heart[1] This growth initially serves as an adaptive response that allows for the maintenance of cardiac output but if the stress is prolonged the heart can decompensate leading to failure and death. Microarray studies using cardiac-specific transgenic mice expressing the transcriptionally-active ATF6α or ATF6β N-terminus revealed partially-overlapping gene expression programs including ER protein chaperones and ERAD components. These data suggest that the increased demand on protein production and folding machinery associated with the hypertrophic response requires ATF6α and ATF6β signaling and we hypothesize that failure to activate these effectors compromises ER protein production resulting in heart failure
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