Abstract 15145: Aldehyde Dehydrogenase 2 Agonist Reverses Fibroblast Activation in the End Stage Human Right Ventricle Failure via 3’Utr Regulation of Profibrotic Genes

Abstract

Background: Cardiac fibrosis, a prominent feature of pressure overloaded right ventricle (RV) in pulmonary hypertension (PH), is fundamental to the development of right ventricle failure (RVF). We found that a defect in alternative polyadenylation (APA) of profibrotic genes is a driving factor that induces fibrosis. Oxidative stress-mediated reactive aldehydes, such as 4-hydroxy-2-nonenal (4HNE) contribute to fibrosis and extracellular matrix (ECM) remodeling. However, the role of 4HNE in APA is unknown. Methods: We compared isolated cardiac fibroblasts from the RVs of explanted transplanted hearts of recipients with pulmonary hypertension patients to control hearts. Results: Compared to controls, tissue and fibroblasts derived from failing RV human hearts have greater deposition of extracellular matrix (ECM) proteins, such as collagen type I alpha (COL1A) and fibronectin (FN1), the expression of alpha smooth muscle actin (α-SMA), indicative of myofibroblast differentiation, and nuclear factor kappa B subunit (NFκB), a transcription factor critical for profibrotic genes transcriptional activation. Moreover, alternative polyadenylation (APA) isoforms of mRNA for COL1A, FN1, NFκB, TGF-β1 and its receptor - transforming growth factor beta receptor 1 (TGFβR1) are associated with shortened 3’UTR in RVF tissues or fibroblasts. Likewise, reduced expression and activity of aldehyde dehydrogenase 2 (ALDH2) expression, a 4HNE detoxifying enzyme, correlated with increased 4HNE adduction in tissues and cardiac fibroblasts derived from RVF hearts. Moreover, ALDH2 activation by its agonist, Alda-1, decreased 4HNE adduction and oxidative stress and most importantly downregulated the gene and protein expression of profibrotic genes, simultaneously lengthening the 3’UTR of the previously shortened profibrotic genes. Conclusion: In RVF, fibroblasts express mRNA of profibrotic genes with shortened 3'UTRs, suggesting the feasibility of developing antifibrotic therapies targeting 3'UTRs in myofibroblasts. Furthermore, our findings suggest that Alda-1 has a therapeutic role in mitigating cardiac fibrosis in RVF hearts by attenuating 4HNE-mediated dysregulation of APA.