Crosstalk between adipocyte-derived miRNA-802 and heart GATA4: a potential novel endocrine mechanism controlling heart remodeling and function

• Grant number: 22/00358-1
• Support Opportunities: Scholarships abroad - Research Internship - Post-doctor
• Start date: August 01, 2022
• End date: July 31, 2023
• Field of knowledge: Biological Sciences - Physiology - Physiology of Organs and Systems
• Principal Investigator: Marcelo Alves da Silva Mori
• Grantee: Henver Simionato Brunetta
• Supervisor: Alexander Bartelt
• Host Institution: Instituto de Biologia (IB). Universidade Estadual de Campinas (UNICAMP). Campinas , SP, Brazil
• Institution abroad: Ludwig Maximilian University of Munich (LMU Munich), Germany
• Associated to the scholarship: 19/21852-1 - Contribution of adipose tissue miRNAs in cardiac function, metabolism and remodeling, BP.PD

Abstract

Cardiovascular diseases (CVD) are the main cause of death worldwide, being responsible for around 31% of all deaths whereas obesity is an independent risk factor for the development of CVDs. Adipocytes extensively communicate with other organs via hormones called adipokines, and, as more recently demonstrated, via microRNAs (miRNAs). Our group has shown that the adipose tissue expression of DICER, a key protein involved in miRNA processing, is altered in obesity and aging. Indeed, adipocyte-specific Dicer deletion in mice leads to insulin resistance, metabolic alterations in remote non-adipose tissues, and premature aging. Our preliminary data show that GATA4, a fundamental pro-hypertrophic transcription factor, is increased by 15-fold in the heart of adipocyte-specific Dicer knock-out (AdicerKO) mice. Interestingly, when we fed AdicerKO mice a high-fat diet (HFD) for 20 weeks to induce obesity, these mice showed increased heart weight alongside reduced left ventricle (LV) end-systolic volume, end-diastolic volume, stroke volume, and smaller LV chamber size compared to wild-type mice on HFD, phenocopying the clinical observation of heart failure with preserved ejection fraction, which is a common complication of obesity. Next, we searched for miRNAs that target GATA4 mRNA sequence among the miRNAs reduced in the circulation of AdicerKO mice. Interestingly, we found that miR-802-5p is specifically predicted to interact with GATA4 mRNA and is reduced in circulating exosomes isolated from serum of AdicerKO mice, suggesting a possible crosstalk between adipose tissue and heart through miR-802/GATA4 interaction. Therefore, we hypothesize that miR-802 secreted from adipocytes interacts with GATA4 in cardiomyocytes, thereby controlling heart remodeling and function in obesity. (AU)