Role of CD4+ T Cells in Testosterone-Induced Cardiac Dysfunction in an Experimental Model of Gender-Affirming Hormonal Therapy (testo-GAHT)

• Grant number: 24/05161-7
• Support Opportunities: Scholarships abroad - Research Internship - Doctorate
• Start date: July 01, 2024
• End date: May 31, 2025
• Field of knowledge: Biological Sciences - Pharmacology - Cardiorenal Pharmacology
• Principal Investigator: Rita de Cassia Aleixo Tostes Passaglia
• Grantee: José Teles de Oliveira Neto
• Supervisor: Pilar Alcaide
• Host Institution: Faculdade de Medicina de Ribeirão Preto (FMRP). Universidade de São Paulo (USP). Ribeirão Preto , SP, Brazil
• Institution abroad: Tufts University, United States
• Associated to the scholarship: 22/13361-0 - Influence of the metabolic profile of CD4+ T cells on testosterone-induced heart dysfunction in an experimental model of gender affirming hormone therapy, BP.DR

Abstract

Testosterone is used in gender-affirming hormone therapy (GAHT) by transmasculine people and, although considered safe, it increases cardiovascular risk for this population. In pathophysiological contexts, testosterone causes cardiac hypertrophy and alters lipid metabolism. Changes in energy metabolism, particularly increased glycolytic metabolism, favor the differentiation of CD4+ T cells towards a pro-inflammatory phenotype. Effector CD4+ T cells contribute to adverse cardiac remodeling, characterized by increased left ventricular (LV) pressure, LV hypertrophy and fibrosis. Activated T cells release cytokines, stimulate the secretion of the extracellular matrix (ECM) components by fibroblasts and cardiomyocytes growth, processes that negatively impact cardiac function. Considering that i) testosterone promotes cardiac hypertrophy and generation of inflammatory mediators; ii) cardiovascular damage in diseases such as arterial hypertension correlates with increased Th17 lymphocytes and circulating levels of IL-17; iii) Th17 lymphocytes contribute to vascular dysfunction in an experimental model of testosterone-GAHT, this study will test the hypotheses that i) testo-GAHT promotes cardiac dysfunction, i.e. fibrosis and LV pressure overload, by stimulating the polarization of T helper lymphocytes (Th, CD4+) into IL-17-producing T cells (Th17 cells), ii) Th17 cells stimulate the transition of cardiac fibroblasts (CFB) into myofibroblasts, by integrin-integrin ligand-related mechanisms (±4 integrin of Th17 cells interacting with MHC II / ICAM-1 / VCAM-1 in CFB).