Targeting long non-coding RNANUDT6enhances smooth muscle cell survival and limits vascular disease progression

Abstract

AbstractLong non-coding RNAs (lncRNAs) orchestrate various biological processes and regulate the development of cardiovascular diseases. Their potential therapeutic benefit to tackle disease progression has recently been extensively explored. Our study investigates the role of lncRNA Nudix Hydrolase 6 (NUDT6)and its antisense target Fibroblast Growth Factor 2 (FGF2)in two vascular pathologies: abdominal aortic aneurysms (AAA) and carotid artery disease. Using tissue samples from both diseases, we detected a substantial increase ofNUDT6, whereasFGF2was downregulated. TargetingNudt6 in vivowith antisense oligonucleotides in three murine and one porcine animal models of carotid artery disease and AAA limited disease progression. Restoration of FGF2 uponNudt6knockdown improved vessel wall morphology and fibrous cap stability. Overexpression ofNUDT6 in vitroimpaired smooth muscle cell (SMC) migration, while limiting their proliferation and augmenting apoptosis. By employing RNA pulldown followed by mass spectrometry as well as RNA immunoprecipitation, we identified Cysteine and Glycine Rich Protein 1 (CSRP1) as another directNUDT6interaction partner, regulating cell motility and SMC differentiation. Overall, the present study identifiesNUDT6as a well-conserved antisense transcript ofFGF2. NUDT6silencing triggers SMC survival and migration and could serve as a novel RNA-based therapeutic strategy in vascular diseases.