Retinoic acid protects cardiomyocytes from high glucose‐induced apoptosis through inhibition of NF‐κB signaling Pathway

Abstract

We have previously shown that retinoic acid (RA) has protective effects on high glucose (HG)-induced cardiomyocyte apoptosis. To further elucidate the molecular mechanisms of RA effects, we determined the interaction between nuclear factor (NF)-κB and RA signaling. HG induced a sustained phosphorylation of IKK/IκBα and transcriptional activation of NF-κB in cardiomyocytes. Activated NF-κB signaling has an important role in HG-induced cardiomyocyte apoptosis and gene expression of interleukin-6 (IL-6), tumor necrosis factor (TNF)-α and monocyte chemoattractant protein-1 (MCP-1). All-trans RA (ATRA) and LGD1069, through activation of RAR/RXR-mediated signaling, inhibited the HG-mediated effects in cardiomyocytes. The inhibitory effect of RA on NF-κB activation was mediated through inhibition of IKK/IκBα phosphorylation. ATRA and LGD1069 treatment promoted protein phosphatase 2A (PP2A) activity, which was significantly suppressed by HG stimulation. The RA effects on IKK and IκBα were blocked by okadaic acid or silencing the expression of PP2Ac-subunit, indicating that the inhibitory effect of RA on NF-κB is regulated through activation of PP2A and subsequent dephosphorylation of IKK/IκBα. Moreover, ATRA and LGD1069 reversed the decreased PP2A activity and inhibited the activation of IKK/IκBα and gene expression of MCP-1, IL-6 and TNF-α in the hearts of Zucker diabetic fatty rats. In summary, our findings suggest that the suppressed activation of PP2A contributed to sustained activation of NF-κB in HG-stimulated cardiomyocytes; and that the protective effect of RA on hyperglycemia-induced cardiomyocyte apoptosis and inflammatory responses is partially regulated through activation of PP2A and suppression of NF-κB-mediated signaling and downstream targets.

Stress-induced NF-κB activation differentiates promyelocytic leukemia cells to macrophages in response to all-trans-retinoic acid

“…2), indicating NF-κB activation. However, it has been reported that ATRA-induced NF-κB activation is largely cellular context dependent [35][36][37][38][39]. Our present study showed that ATRA enhanced macrophage differentiation of HL-60 and NB4 cells along with NF-κB activation under serum deprived condition.…”

Differential Regulation of Bcl‐xL Gene Expression by Corticosterone, Progesterone, and Retinoic Acid

“…Retinoic acids have been shown to mediate cell survival response in neuroblastoma cells, neural crest cells, myeloid leukemia blasts, lung cancer cells, islet-epithelial cells, and olfactory sensory neurons [46–51]. In cardiomyocytes, high glucose induced apoptosis can be inhibited by RA in NF-κB dependent manner [52]. …”

Dexamethasone Suppresses Neurosteroid Biosynthesis <i>via</i> Downregulation of Steroidogenic Enzyme Gene Expression in Human Glioma GI-1 Cells

“…Although direct cross-talk between GR and RAR/RXR or VDR is not well documented, accumulating evidence indicates that glucocorticoids can influence the activity of other transcription factors, such as activator protein 1 (AP-1), NF-κB, and cAMP response element binding protein (CREB). [22][23][24] In addition, several studies indicate that GR associates with other transcription factors through direct protein-protein interactions to mutually repress or stimulate each protein's transcriptional activities. [25][26][27] Recently glucocorticoid-mediated modulation of miRNA has been reported.…”