Early life stress induces vascular expression of pro‐oxidant, proinflammatory genes in adulthood in an HDAC9‐dependent manner

Abstract

Early life stress (ELS) has been correlated with an increased risk of developing cardiovascular disease (CVD) in adulthood; however, mechanisms linking ELS and CVD risk are unknown. Toll‐like receptor (TLR) activation, specifically TLR4, has been implicated as a key link between inflammation and CVD. TLR4 signaling can activated NADPH oxidases (NOXs) that produce superoxide to increase CVD risk. Further, multiple studies have found that NF‐kB activation, an important downstream step in the TLR4 signaling pathway, requires the activation of certain NOX isoforms, including NOX2 and NOX4. We utilized a mouse model of maternal separation with early weaning (MSEW) to investigate the effect of ELS on the expression and activation of genes encoding these pro‐oxidant, proinflammatory proteins. MSEW mice were separated 4hr/day during postnatal day (PD)2–5, 8 hr/day during PD6‐16, and weaned at PD17. Normally‐reared control mice were left undisturbed and weaned at PD21. Experiments were conducted on 3–6 month old male mice. We have previously shown that MSEW induces NOX‐dependent superoxide production and vascular endothelial dysfunction. We also found increased gene expression of NOX2, NOX4, and TLR4 in the aorta of MSEW mice. Recent immunohistochemical studies have also revealed increased aortic TLR4 protein expression in MSEW mice (n=5/group). Due to similar patterns of expression of genes involved in the TLR4 signaling pathway, we further hypothesized that a common upstream transcription factor could be a driver of these ELS‐induced gene changes. We focused this study on histone deacetylases (HDACs), as numerous studies have implicated HDACs in the modulation of proinflammatory responses and the progression of a variety of CVDs. Interestingly, we found that MSEW induced aortic HDAC9 protein expression, exclusive of other HDAC isoforms. A 3‐hr ex vivo pretreatment with trichostatin A (TSA), a pan‐inhibitor of HDACs, improved vascular endothelial function in MSEW mice (n=5/group, p=0.047). Further, ex vivo TSA treatment led to a trend of decreased expression of NOX2, NOX4, and TLR4 genes (n=4–8/group). These results suggest that ELS leads to HDAC9‐dependent pro‐oxidative and proinflammatory gene expression that increase CVD risk in adulthood. They also further emphasize the role of TLR4 signaling on superoxide production and vascular endothelial function. Future studies aim to clarify the role of TLR4 signaling in these phenotypes, as well as the effect of increased HDAC9 expression on the transcriptional regulation of TLR4 and other genes that could confer CVD risk in adulthood.Support or Funding InformationThis research was funded by PO1HL69999 and the UAB PREP Program.This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.