The general transcription factor, CREB has been shown to play an essential role in promoting cell proliferation, neuronal survival and synaptic plasticity in the nervous system. However, its function in stress response remains to be elusive. In the present study, we demonstrated that CREB plays a major role in mediating stress response. In both rat lens organ culture and mouse lens epithelial cells (MLECs), CREB promotes oxidative stress-induced apoptosis. To confirm that CREB is a major player mediating the above stress response, we established stable lines of MLECs stably expressing CREB and found that they are also very sensitive to oxidative stress-induced apoptosis. To define the underlying mechanism, RNAseq analysis was conducted. It was found that CREB significantly suppressed expression of the αB-crystallin gene to sensitize CREB-expressing cells undergoing oxidative stress-induced apoptosis. CREB knockdown via CRISPR/CAS9 technology led to upregulation of αB-crystallin and enhanced resistance against oxidative stress-induced apoptosis. Moreover, overexpression of exogenous human αB-crystallin can restore the resistance against oxidative stress-induced apoptosis. Finally, we provided first evidence that CREB directly regulates αB-crystallin gene. Together, our results demonstrate that CREB is an important transcription factor mediating stress response, and it promotes oxidative stress-induced apoptosis by suppressing αB-crystallin expression.

Apremilast is a phosphodiesterase 4 (PDE4) inhibitor used in the treatment of psoriasis and several other inflammatory diseases. Interest has been expressed in seeking out therapies that address both psoriasis and atherosclerosis. In the present study, we explored the effects of apremilast in human aortic endothelial cells (HAECs) exposed to oxidized low-density lipoprotein (ox-LDL) to simulate the atherosclerotic microenvironment in vitro. Our findings indicate that apremilast may reduce the expression of lectin-like oxidized-low-density-lipoprotein receptor-1 (LOX-1), the main ox-LDL scavenging receptor. Apremilast also inhibited the expression of tumor necrosis factor-α (TNF-α), interleukin-6 (IL-6), and interleukin-8 (IL-8), which are deeply involved in the chronic inflammatory response associated with atherosclerosis. Interestingly, we found that apremilast inhibited the attachment of U937 monocytes to HAECs by reducing the expression of the chemokine monocyte chemotactic protein 1 (MCP-1) and the cellular adhesion molecule vascular cell adhesion molecule-1 (VCAM-1). This effect was found to be mediated through the rescue of Krüppel like factor 6 (KLF6) expression, which was reduced in response to ox-LDL via increased phosphorylation of c-Jun N-terminal kinase (JNK). These findings suggest a potential role for apremilast in the treatment of atherosclerosis.