3′UTR shortening of profibrotic genes and reversibility of fibrosis in patients with end‐stage right ventricular failure

• Published in: Clinical and translational medicine 2022-09, Vol.12 (9), p.n/a
• Main Authors: Neupane, Rahul, Cieslik, Katarzyna A., Youker, Keith, Palaniyandi, Suresh Selvaraj, Guha, Ashrith, Thandavarayan, Rajarajan A.
• Format: Article
• Language: English
• Subjects: 4HNE; alternative polyadenylation; Chronic obstructive pulmonary disease; Dehydrogenases; Fibroblasts; fibrosis; Heart attacks; Heart failure; Letter to the Editor; Lipid peroxidation; MicroRNAs; Oxidative stress; Pathogenesis; Protein expression; Proteins; Pulmonary fibrosis; Regulation; right ventricle failure
• ISSN: 2001-1326; 2001-1326
• DOI: 10.1002/ctm2.1017

Previous studies have shown 4HNE as a contributor to various pathologies such as LV hypertrophy, PH-induced RV fibrosis, remodelling, myocardial infarction-induced lipid peroxidation, dilated cardiomyopathy and cardiotoxicity.2 We showed a substantial decrease in the expression and activity of aldehyde dehydrogenase 2 (ALDH2), an enzyme metabolizing 4HNE, (Figure S2A–C) and a significant accumulation of 4HNE adducts (Figure S2D and E) in cardiomyocytes and fibroblasts in RVF. The 3′UTR lengthening and downregulation of profibrotic genes correlated with the decrease in contractility of these RVF fibroblasts after Alda-1 treatment (Figure 3E and F). mRNA isoforms with longer 3′UTR are negatively regulated by miRNAs, lncRNAs and RBPs to restrict protein expression.9 Previous studies have shown selective degradation of isoforms with longer 3′UTR during recovery.3 However, the stress-induced shorter 3′UTR isoforms escape degradation and sustain their abundance post-stress.10 Hence, addressing APA and ensuring 3′UTR lengthening in shortened profibrotic genes during treatment and recovery of cardiovascular diseases, including RVF, becomes critical to ensure the reversibility of fibrosis. [...]the ALDH2 activation directly lessened oxidative stress, counteracted 4HNE adducts and reduced the tissue remodelling capabilities of the fibroblasts through 3′UTR changes in profibrotic genes.