Abstract 19600: Pulmonary Hypertension-Induced Right Ventricular Pressure Overload Triggers Acute Epigenetic Reprogramming of Pro-Inflammatory Cardiac Fibroblasts
Right ventricular (RV) function is a strong predictor of survival in a variety of clinical contexts including pulmonary hypertension (PH), highlighting the importance of delineating signaling pathways that contribute to RV dysfunction. We have previously demonstrated increased inflammation in PH-induced RV dysfunction and hypothesized that PH stimulates pro-inflammatory changes in RV cardiac fibroblasts (Cfibs). Further, we hypothesized that this process may be mediated by epigenetic changes in the fibroblast such as DNA methylation, which allows rapid, dynamic and sustained regulation of gene expression. We explored this hypothesis using a large animal model with significant resonance with human disease- the neonatal calf exposed to hypobaric hypoxia (HH). We assessed DNA methylation, gene expression and inflammation in control (CO) and HH RV Cfibs. Exposure to HH resulted in global DNA hypomethylation in RV Cfibs. Further, we quantified expression of regulators of global DNA methylation, DNA-methyltransferases (DNMT). DNMT3a expression was unchanged by HH. However, DNMT1 and DNMT3b expression were significantly downregulated by HH, correlating with DNA hypomethylation in these cells. RNA-seq identified 2115 genes significantly changed in HH including 193 transcriptional regulators, 21 genes involved in DNA methylation, and 105 inflammatory genes. We verified enrichment of inflammatory signaling by qRT-PCR and found HH significantly upregulated expression of Interleukin-1β and Interleukin-6. To mechanistically link inflammation and DNA methylation, we treated CO Cfib with recombinant IL-1β (rIL-1β). Chronic treatment (24-48 hours) with rIL-1β resulted in significant DNA hypomethylation. Further, DNMT1 and DNMT3b expression were significantly downregulated with rIL-1β treatment with no change in DNMT3a expression. Together, these data suggest the combination of pressure overload and hypoxia is correlated with increased inflammatory signaling and epigenetic reprogramming of Cfibs. We propose that therapies which target this acute fibroblast-mediated inflammatory process have the potential to prevent RV dysfunction.
Author Disclosures: D.R. Bruns: None. S.F. Thoemmes: None. K.R. Stenmark: None. P.M. Buttrick: Research Grant; Modest; NIH. Other Research Support; Modest; AHA. Research Grant; Significant; modest. Other Research Support; Significant; modest. L.A. Walker: None.
- © 2016 by American Heart Association, Inc.