Effects of age- and sex on inflammatory pathways, mitochondrial homeostasis, and metabolic sensing in cardiomyopathies

Abstract

Aging processes and biological sex influence physiological and pathophysiological mechanisms in the heart and may, therefore, affect the treatment effects in patients with CVD. The research projects included in this habilitation thesis contribute to better understanding of age and sex differences in inflammatory processes and mitochondrial homeostasis in cardiomyopathies (i.e., dilated cardiomyopathy and inflammatory dilated cardiomyopathy). We demonstrated age and sex-specific mechanisms in the healthy aging heart, leading to a female-specific impaired metabolic sensing and a pro-inflammatory shift due to downregulation of two key NAD+-dependent deacetylases (Sirt1 and Sirt3) in older women. In addition, we identified an impaired mitochondrial homeostasis and reduced anti-oxidative defense in older hearts of patients with end-stage DCM, which was accompanied by an enhanced pro-inflammatory response in both sex-dependent and -independent manners. To further demonstrate the role of age and biological sex in cardiomyopathies, we examined their effects on inflammation, mitochondrial homeostasis, autophagy, and cellular senescence in patients with end-stage inflammatory dilated cardiomyopathy. Our study demonstrated a compromised expression of mitochondrial proteins, which was accompanied by disturbed autophagy, pro-inflammatory shift and cellular senescence in older women with DCMI. In contrast, older male DCMI hearts showed a preserved mitochondrial homeostasis and pro-inflammatory/anti-inflammatory balance, but accelerated autophagy. The study of sex differences in autoimmune myocarditis, using the animal model of experimental autoimmune myocarditis, revealed a pro-inflammatory and pro-fibrotic phenotype in male EAM rats, which was accompanied by a severe cardiac dysfunction in males with autoimmune myocarditis. In this animal model, female rats showed less inflammation and cardiac remodeling, leading to a preserved cardiac function. Part of this thesis deals with the study of sex differences in the polarization of murine macrophages, which might influence the development and progression of myocarditis and dilated cardiomyopathy. The study suggests a stronger pro-inflammatory response to a pro-inflammatory environment in male murine bone marrow macrophages, which was accompanied by a sex-dependent pro-inflammatory and pro-fibrotic responses in male activated cardiac fibroblasts. The sex-dependent macrophage and fibroblast activation might have important effects on cardiac inflammatory diseases, e.g., myocarditis.