Hypoxic states are generally associated with
cardiovascular disease. Adaptation to chronic
hypoxia is one well-defined means of improving cardiac tolerance to certain kinds of stresses. However, the details of the mechanisms underlying myocardial adaptation to chronic
hypoxia are still poorly understood.
Hypoxia stresses the endoplasmic reticulum and activates unfolded protein response. However, the behavior of individual signaling pathways can vary markedly over time. By examining myocardial samples from patients with cyanotic congenital cardiac defects, we detected endoplasmic reticulum stress and found that, out of all the components of the unfolded protein response, only activating
transcription factor 6α limb was activated in cyanotic patients. The activation of activating
transcription factor 6α and expression of
glucose regulated
protein 78 were notably induced in cardiac myocytes cultured for prolonged
hypoxia (1% O(2) for 48 h). When the activation of activating
transcription factor 6α under prolonged
hypoxia was blocked by chemical inhibitor
Brefeldin A, the rate of apoptosis among cardiac myocytes increased and levels of cleaved
caspase 3 and cleaved
poly ADP ribose polymerase also increased significantly. After the expression of activating
transcription factor 6α was knocked down, the activity of cardiac myocytes under prolonged
hypoxia decreased and the phosphorylation of c-Jun NH2-terminal
kinases increased during the re-oxygenation process (after 72 h of
hypoxia). Together, these results indicate that activating
transcription factor 6α plays a pivotal role in myocardial adaptation to chronic
hypoxia and that the activation of activating
transcription factor 6α is one possible mechanism of myocardial preconditioning.