Pivotal role of activating transcription factor 6α in myocardial adaptation to chronic hypoxia

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% O2 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.