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A2092 - Pharmacologic Inhibition of CtBP1 Has Multiple Beneficial Effects in the Treatment of Pulmonary Hypertension
Author Block: M. Li1, B. McKeon1, M. Frid1, A. Flockton1, C. Hu2, A. Laux2, H. Zhang1, S. Kumar1, S. Riddle1, R. Brown1, M. Fini1, K. R. Stenmark1; 1Pediatric and Critical Care, University of Colorado Denver, Aurora, CO, United States, 2Craniofacial Biology, University of Colorado Denver, Aurora, CO, United States.
Rationale: Previous work from our group showed that pulmonary artery adventitial fibroblasts isolated from calves with pulmonary hypertension (PH-Fibs), and patients with idiopathic PH (IPAH) exhibit a metabolic shift toward aerobic glycolysis to support their highly activated phenotype (hyper-proliferative, apoptotic resistant and pro-inflammatory), which is regulated in part by CtBP1, a transcriptional redox/metabolic sensor with high binding affinity for NADH. Our previous work has demonstrated that CtBP1 regulates P21, P15, NOXA, PERP and HMOX1 expression in PH-Fibs, which control cell proliferation, apoptosis and inflammation, respectively. In this study, we explored other possible targets that are regulated by CtBP1 and that are also important in the pathogenesis of PH. We focused on BMP signaling and DNA damage repair pathways because preliminary ChIP-seq studies supported these as possible targets.
Methods and Results: Dysfunction of BMP signaling pathway in pulmonary artery adventitial fibroblast cells and whole lung tissues from pulmonary hypertensive animals, using neonatal cow (exposed to hypobaric hypoxia for 2-week) and 8-wks old male wild-type B6 mice (exposed to hypobaric hypoxia for 4, 14 and 28 days), was demonstrated by down-regulated mRNA expression of BMPR2 in both bovine PH-Fibs and in hypertensive lungs (both bovine and mouse) compared to control Fibs or control lungs. No significant decrease of DNA damage repair gene expression was observed in PH-Fibs. The role of CtBP1 in regulating BMPR2 or DNA damage repair gene expression was determined by treating bovine PH-Fibs with 4-methylthio-2-oxobutyric acid (MTOB, an antagonist of CtBP transcriptional regulation) or CtBP1 siRNA. We found that treated with both CtBP1 siRNA and MTOB restored the expression of BMPR2 and genes involved in DNA damage repair in bovine PH-Fibs (NBS1, TP53BP1 and BRCA1).
Conclusion: Increased activity of CtBP1 (as a result of metabolic reprogramming) inhibited the expression of BMPR2 as well as DNA damage repair genes, both of which are critical for the development of PH. Taken together with our previous findings, this study provides evidence that CtBP1 can not only regulate pulmonary artery cell proliferation and inflammation, but also affect BMPR2 expression and DNA damage repair pathway. Small molecular inhibitor of CtBP1, such as MTOB, may target a cluster of genes involved in PH-cell function and positively impact the pathways important in PH pathogenesis.