Membrane-Repairing Long Noncoding RNA Masir as a Novel Therapeutic for Ischemic Heart Injury

About This Grant

Project Summary Heart disease remains the leading cause of death worldwide, with cardiomyocyte (CM) loss in diseased hearts ultimately leading to heart failure. The plasma membrane––particular the sarcolemma in CMs––is crucial for maintaining cell viability under mechanical and metabolic stress. Because CMs continuously contract, they frequently experience transient membrane injuries even under physiological conditions, and this vulnerability increases with aging and disease. Indeed, compromised sarcolemma structural integrity is a key contributor to the progression of heart failure. Strengthening cardiac membrane repair mechanisms therefore represents a promising strategy to protect the heart and prevent disease progression. However, whether RNA molecules can directly participate in membrane repair remains unknown. Non-coding RNAs, including microRNAs and long non-coding RNAs (lncRNAs), play crucial roles in regulating cardiac development, function, and pathology. Building on our recent discovery that microRNAs can exert biophysical effects beyond classical gene regulation, we identified a sarcolemma-enriched lncRNA, termed Masir (MG53-associated sarcolemma injury repair lncRNA), that promotes endocytosis/exocytosis and enhances membrane repair via a noncanonical biophysical mechanism. In vivo administration of Masir significantly preserved myocardial tissue, improved cardiac hemodynamic function, reduced fibrosis, and potentially attenuated arrhythmic vulnerability in mouse hearts subjected to ischemic injury. Furthermore, extracellular Masir markedly attenuated laser-induced membrane injury in human induced pluripotent stem cell (iPSC)-derived CMs, supporting its translational potential. We hypothesize that Masir protects cardiac cells from ischemia injury by enhancing membrane repair, without notable safety concerns, making it a promising RNA-based therapeutic for preventing heart failure and arrhythmia after myocardial ischemia. To rigorously assess Masir’s translational potential, we will investigate the molecular and cellular mechanisms, evaluate its efficacy and safety in mouse models, a preclinical pig model, and human CMs/tissues. Two specific aims are proposed: Aim 1) Characterize Masir’s cardioprotective mechanisms and safety in mice; Aim 2) Assess Masir’s cardioprotective efficacy in a preclinical pig model and human CMs. This project will elucidate the mechanisms underlying Masir’s cardioprotective actions and determine its effective and safe therapeutic dose to protect the heart from ischemic injury and prevent ischemia-induced arrhythmia across species. The proposed studies will significantly advance our understanding of membrane- repairing lncRNAs and establish the foundation for developing first-in-class RNA-based therapeutic strategies for ischemic heart disease and heart failure.