Construction of the epigenetic signature in young mice heart with heart failure induced by systemic administration of MMP-2

• Grant number: 25/00215-4
• Support Opportunities: Scholarships in Brazil - Post-Doctoral
• Start date: September 01, 2025
• End date: August 31, 2027
• Field of knowledge: Biological Sciences - Genetics
• Principal Investigator: Jose Eduardo Tanus dos Santos
• Grantee: Cezar Kayzuka Cotta Filho
• Host Institution: Faculdade de Medicina de Ribeirão Preto (FMRP). Universidade de São Paulo (USP). Ribeirão Preto , SP, Brazil

Abstract

Multicellular organisms rely on proteases to remodel tissues, adapting them to functional demands. Matrix metalloproteinases (MMPs), first discovered in the 1960s, were initially recognized for their role in tissue remodeling. However, recent research has revealed that MMPs also play critical roles in metabolic processes and the functioning of key organs, including the heart. Elevated levels of MMP-2 have been linked to cardiac dysfunction. The production of reactive oxygen species (ROS), often associated with increased MMP-2 levels, can disrupt genomic DNA methylation patterns. Since epigenetic modifications in specific genes are pivotal to the onset and progression of cardiovascular diseases, studying the epigenetic signature of hearts exposed to recombinant MMP-2 (rhMMP-2) becomes essential. This project aims to explore DNA methylation changes in young mice with rhMMP-2-induced heart failure over a five-week period, comparing these animals to healthy controls. Genome-wide methylation patterns will be analyzed to identify novel methylated regions and correlate them with cardiac function, morphology, ROS levels, and metabolic changes. Methylation analysis will be conducted using bisulfite treatment, which converts unmethylated cytosine into thymine. The study will include genome library preparation via SPLinted Adaptor Tagging (SPLAT), bioinformatics analysis, and the characterization of methylation patterns in groups treated or untreated with rhMMP-2. Preliminary findings will be integrated with data from international epigenomics databases to enhance our understanding of heart failure. Ultimately, this project seeks to develop a specific epigenetic signature for MMP-2-induced heart failure and identify potential epigenetic biomarkers for this condition. Finally, the project aims to develop a specific epigenetic signature for MMP-2-induced heart failure and identify potential epigenetic biomarkers for this condition. (AU)