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

• Published in: Journal of cellular physiology Vol. 228; no. 2; pp. 380 - 392
• Main Authors: Nizamutdinova, Irina T., Guleria, Rakeshwar S., Singh, Amar B., Kendall Jr, Jonathan A., Baker, Kenneth M., Pan, Jing
• Format: Journal Article
• Language: English
• Published: Hoboken Wiley Subscription Services, Inc., A Wiley Company 01.02.2013
• Subjects: Animals; Apoptosis - drug effects; Cytokines - biosynthesis; Cytoprotection; Gene Expression Regulation - drug effects; Hyperglycemia - complications; I-kappa B Kinase - metabolism; Male; Myocytes, Cardiac - drug effects; NF-kappa B - drug effects; Phosphorylation; Protein Phosphatase 2 - drug effects; Rats; Rats, Zucker; Signal Transduction - drug effects; Tetrahydronaphthalenes - pharmacology; Tretinoin - pharmacology
• ISSN: 0021-9541; 1097-4652
• DOI: 10.1002/jcp.24142

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. J. Cell. Physiol. 228: 380–392, 2013. © 2012 Wiley Periodicals, Inc.