Oxidative stress and inflammation distinctly drive molecular mechanisms of diastolic dysfunction and remodeling in female and male heart failure with preserved ejection fraction rats

Saltanat Zhazykbayeva; Roua Hassoun; Melissa Herwig; Heidi Budde; Árpád Kovács; Hans Georg Mannherz; Ibrahim El-Battrawy; Attila Tóth; Wolfgang E Schmidt; Andreas Mügge; Nazha Hamdani

doi:10.3389/fcvm.2023.1157398

Oxidative stress and inflammation distinctly drive molecular mechanisms of diastolic dysfunction and remodeling in female and male heart failure with preserved ejection fraction rats

Front Cardiovasc Med. 2023 Jun 8:10:1157398. doi: 10.3389/fcvm.2023.1157398. eCollection 2023.

Authors

Saltanat Zhazykbayeva^#^{1

2

3}, Roua Hassoun^#^{1

2

3}, Melissa Herwig^#^{1

2

3}, Heidi Budde^{1

2

3}, Árpád Kovács^{1

2

3}, Hans Georg Mannherz^{1

2

4}, Ibrahim El-Battrawy^{1

2

5}, Attila Tóth^{6

7}, Wolfgang E Schmidt⁸, Andreas Mügge^{2

3

5}, Nazha Hamdani^{1

2

3}

Affiliations

¹ Department of Cellular and Translational Physiology, Institute of Physiology, Ruhr University Bochum, Bochum, Germany.
² Institut für Forschung und Lehre (IFL), Molecular and Experimental Cardiology, Ruhr University Bochum, Bochum, Germany.
³ Department of Cardiology, St. Josef-Hospital, UK RUB, Ruhr University Bochum, Bochum, Germany.
⁴ Department of Anatomy and Molecular Embryology, Ruhr University Bochum, Bochum, Germany.
⁵ Department of Cardiology and Angiology, Bergmannsheil University Hospitals, UK RUB, Ruhr University of Bochum, Bochum, Germany.
⁶ Division of Clinical Physiology, Department of Cardiology, Faculty of Medicine, University of Debrecen, Debrecen, Hungary.
⁷ Research Centre for Molecular Medicine, University of Debrecen, Debrecen, Hungary.
⁸ Department of Medicine I, St. Josef Hospital, UK RUB, Ruhr-University Bochum, Bochum, Germany.

^# Contributed equally.

Abstract

Heart failure with preserved ejection fraction (HFpEF) is a complex cardiovascular insufficiency syndrome presenting with an ejection fraction (EF) of greater than 50% along with different proinflammatory and metabolic co-morbidities. Despite previous work provided key insights into our understanding of HFpEF, effective treatments are still limited. In the current study we attempted to unravel the molecular basis of sex-dependent differences in HFpEF pathology. We analyzed left ventricular samples from 1-year-old female and male transgenic (TG) rats homozygous for the rat Ren-2 renin gene (mRen2) characterized with hypertension and diastolic dysfunction and compared it to age-matched female and male wild type rats (WT) served as control. Cardiomyocytes from female and male TG rats exhibited an elevated titin-based stiffness (F_passive), which was corrected to control level upon treatment with reduced glutathione indicating titin oxidation. This was accompanied with high levels of oxidative stress in TG rats with more prominent effects in female group. In vitro supplementation with heat shock proteins (HSPs) reversed the elevated F_passive indicating restoration of their cytoprotective function. Furthermore, the TG group exhibited high levels of proinflammatory cytokines with significant alterations in apoptotic and autophagy pathways in both sexes. Distinct alterations in the expression of several proteins between both sexes suggest their differential impact on disease development and necessitate distinct treatment options. Hence, our data suggested that oxidative stress and inflammation distinctly drive diastolic dysfunction and remodeling in female and male rats with HFpEF and that the sex-dependent mechanisms contribute to HF pathology.

Keywords: diastolic dysfunction; inflammation; mechanisms; oxidative stress; sex differences.

Grants and funding

This research was funded by EU's Horizon 2020 research and innovation program under grant agreement No. 739593 to NH; DFG (Deutsche Forschungsgemeinschaft) HA 7512/2-4 and HA 7512/2-1 to NH; Heinrich und Alma Vogelsang Stiftung to SZ and a grant from the InnovationForum program of the Medical Faculty, RUB to NH, AM and WES. We acknowledge support by the Open Access Publication Funds of the Ruhr-Universität Bochum.