FOR 1054:  Sex-Specific Mechanisms in Myocardial Hypertrophy

• Subject Area: Medicine
• Term: from 2008 to 2016
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 60843499

Cardiovascular disease is the most common cause of death in men and women worldwide.
Nevertheless, men develop most, but not all, cardiovascular diseases at an earlier age, while women have greater risks during invasive therapies. Heart failure (HF), a mal-adaptation to myocardial hypertrophy (MH), is a common cause of cardiovascular death. The adaptations in men and women are different. Understanding these differences could result in novel therapies that would benefit both men and women.
The primary aim of this Research Unit is to investigate the protective effect of female sex in MH and HF. Female hearts develop a more favorable physiological form of myocardial remodelling when subjected to pressure or volume overload than male hearts. We hypothesise that the more favorable remodelling in female hearts involves the synergistic activity of several cellular-based protective pathways induced by estrogen signalling via estrogen receptors, thereby influencing mitochondrial function and myocardial energy metabolism. We speculate that, in contrast, testosterone induces matrix remodelling and growth factor signalling via androgen receptors and contributes to eccentric remodelling, especially in males.
We plan a series of inter-related mechanistic studies into sex differences in mitochondrial function, protein kinase B (AKT)-related signalling, fatty acid and arachidonic acid-related metabolism and matrix synthesis. Animal models for physiological and pathological MH and HF, in combination with cell-specific and/or inducible genetic deletion or over-expression of hormone receptors, will be used to analyse hormone-related and chromosome-based sex differences. The role of estrogen and androgen receptors (ER and AR) and their interaction with hypertrophic signalling will be specifically analysed.
Simultaneously, we will compare stress-induced changes in the transcriptome and proteome in female and male myocardium to detect novel sex-specific pathways. We will test new pharmacological approaches for sex-specific effects. Finally, we will investigate whether or not the mechanisms observed in animal models can be applied to the human heart. A clinical study for sex differences in human aortic stenosis is associated with our project and will facilitate our hypotheses testing. Our research, albeit basic, could contribute directly to patient-oriented research by suggesting clinical protocols. In this way, we view our research as translational in nature.

• DFG Programme: Research Units

Projects

• Administration (Verwaltungsprojekt) (Applicant Regitz-Zagrosek, Vera )
• Androgens in cardiac hypertrophy (Applicant Bader, Michael )
• Contribution of sex-specific epigenetic modifications to cardiac hypertrophy (Applicant Hübner, Norbert )
• Cytochrome P450-dependent eicosanoids in sex-specific mechanisms of cardiac hypertrophy and arrhythmia (Applicant Schunck, Wolf-Hagen )
• Estrogen and androgen-receptor crosstalk with beta-catenin signaling and sex differences in myocardial hypertrophy (Applicant Huber, Otmar )
• Sex differences in adipose tissue lipolysis and pathological cardiac hypertrophy (Applicant Kintscher, Ulrich )
• Sex differences in the cardiac proteome in myocardial hypertrophy (Applicant Klose, Joachim )
• Sex-specific functions of mTORC1 and mTORC2 in cardiac hypertrophy (Applicant Dragun, Duska )
• Sex-specific modulators of mitochondrial function (Applicant Regitz-Zagrosek, Vera )

• Spokesperson: Professorin Dr. Vera Regitz-Zagrosek
• Deputy: Professor Dr. Michael Bader