Atherosclerosis is the main cause of heart disease, which in turn is the most common cause of death worldwide. A team led by Professor Christian Weber from the Institute for Cardiovascular Prevention (IPEK) at LMU University Hospital demonstrated that a snippet of microRNA known as miR-126-5p can protect against atherosclerosis by inhibiting the enzyme caspase-3 in the cell nucleus, which triggers programmed cell death. In this way, the researchers discovered a completely unknown function of microRNAs. The German Research Foundation (DFG) has now awarded funding of around 1.5 million euros to Weber’s plan to investigate in detail the interactions between key components of the new signaling pathway as part of the project, “Influencing non-canonical functions of microRNAs in atherosclerosis.”

Before now, it was generally assumed that microRNAs operate in the cytoplasm, where they contribute to the silencing of genes by binding to messenger RNA and blocking the translation of genetic information into proteins. “The discovery that miR-126-5p binds directly to a protein – the enzyme Caspase-3 – in the cell nucleus significantly expands our understanding of microRNA functions and adds a new level to the mechanisms set in train by microRNAs,” says Weber. The RNA-binding protein MEX3A, which facilitates the binding of miR-126-5p to the enzyme, plays an important role in this new signaling pathway.

The goal of the new interdisciplinary project is to characterize the cell-specific functions of MEX3A in relation to atherosclerosis and discover potential therapeutic options. Furthermore, the researchers intend to analyze further microRNAs that are influenced by MEX3A and shed light on the structural foundations of the interactions. “Our project promises groundbreaking insights into an uninvestigated area of molecular biology and could yield new selective therapeutics for vascular medicine,” summarizes Weber.