Introduction: ATF6α, is an endoplasmic reticulum (ER) transmembrane protein that senses the accumulation of toxic misfolded proteins in the ER of cardiomyocytes during ER stress. Upon ER stress, ATF6α is cleaved into an active transcription factor which increases the expression of adaptive genes. ATF6β is an isoform of ATF6α, which is also cleaved during ER stress, & binds to the same ER stress response elements as ATF6α thereby inhibiting ATF6α-mediated gene induction. Acute ATF6α activation is adaptive, however chronic ATF6α activation can be maladaptive. It is not known whether ATF6β participates in the switching of ATF6α from adaptive to maladaptive during chronic ER stress in cardiac myocytes.
Hypothesis: ATF6β enhances cardiomyocyte viability by regulating the length & strength of ATF6α mediated gene induction stressing cardiac myocytes.
Methods: The effects of knocking down ATF6α or β(ATF6α/β) on the viability of neonatal rat ventricular myocytes (NRVM) exposed to ER stress was examined. Immunobloting & qRT-PCR were performed to access the effect of loss of ATF6α/β knockdown on adaptive & maladaptive ER stress response gene expression.Results: Loss of ATF6α/β decreased the viability of NRVM during chronic ischemic condition. Knockdown of ATF6α/β downregulated a common set of known, cardioprotective genes; however, a few cardioprotective genes, including manf & herp, were upregulated upon ATF6α knockdown & downregulated upon ATF6β knockdown. Also, loss of ATF6α/β increased a common set of maladaptive genes. Interestingly, loss of ATF6α/β increased the expression of ATF6β/α , respectively showing a unique compensatory mechanism between the two isoforms.
Conclusions: Loss of endogenous ATF6β causes deleterious chronic activation of ATF6α resulting in elevated expression of maladaptive ATF6α target genes. ATF6β expression is induced when ATF6α is knocked down, which results in the balance of adaptive & maladaptive genes under the control of ATF6α to be shifted towards a maladaptive state. Thus, even though knockdown of ATF6α/β has similar effects on NRVM viability, it is through an unusual interactive mechanism that these effects are achieved, emphasizing the importance of the ratio of ATF6α to β in cardiac myocytes subjected to ER stress.