Abstract 79: Sex-dependent Role of Macrophage-derived Insulin-like Growth Factor-1 in Body Growth, Cardiac Homeostasis and Responses to Cardiac Tissue Stress
Biological sex is a key factor influencing the development and progression of cardiovascular disease. While sexual dimorphism has been identified in cardiac physiology and sex-based differences are observed in clinical contexts, the molecular and cellular bases for these differences are not understood.
Recently, we found for the first time that female and male hearts are different in their cellular composition. Female hearts comprise significantly greater numbers of resident mesenchymal cells, including cardiac fibroblasts, compared to male hearts, and female hearts consist of differing proportions of multiple leukocyte subsets. We found that these differences are regulated by gonadal hormones.
Extending on our previous work, this study investigates sexual dimorphism in cell-specific IGF-1 production and its impact on cardiac inflammatory responses. IGF-1 is a growth factor that is essential for development and injury responses, and that has been previously shown to function in a sex-dependent manner.
Using genetic, transcriptomic and high-dimensional flow cytometry approaches, we found that macrophages and fibroblasts are the principle IGF-1 producing cells in the heart, with macrophages from female mouse hearts producing twice as much IGF-1 as in males. This contributed to a ~20% greater level of IGF-1 found in the hearts of females compared to males. Furthermore, constitutive genetic ablation of macrophage-derived IGF-1 resulted in ~30% reduction in total IGF-1 in hearts of female mice, whereas no reduction was observed in male hearts. Surprisingly, we also found that ablation of macrophage-derived IGF-1 reduces body weight in female mice by ~10%. Finally, we found that macrophage-derived IGF-1 regulates cardiac inflammatory responses in a sex-dependent manner.
To our knowledge, this is the first study to demonstrate that a macrophage-derived growth factor is essential for normal body growth and plays a sex-dependent role in cardiac inflammatory responses. Our observations provide a cellular and molecular basis for the sexual dimorphism observed in cardiac physiology and pathology, and underscore the importance of considering biological sex in experimental models of cardiac development and disease.
Author Disclosures: A. Ilinykh: None. C. Chan: None. M.A. McLellan: None. G.T. Squiers: None. J. Branca: None. G.R. Drummond: None. N.A. Rosenthal: None. A.R. Pinto: None.
- © 2017 by American Heart Association, Inc.