TT_I_L: Theoretical and Translational Medicine I. Lectures
Bálint András Barta1, Mihály Ruppert1, Klemens Erwin Fröhlich2, Miguel de Jesús Cosenza Contreras2, Attila Oláh1, Alex Ali Sayour1, Gellért Balázs Karvaly3, Krisztián Kovács3, Martin Werner2, Béla Merkely1, Oliver Schilling2, Tamás Radovits1
1Heart and Vascular Center, Faculty of Medicine, Semmelweis University, Budapest, Hungary
2Institute of Surgical Pathology, Faculty of Medicine, University of Freiburg Medical Center, Freiburg, Germany
3Department of Laboratory Medicine, Faculty of Medicine, Semmelweis University, Budapest, Hungary
Introduction: Myocardial infarction occurs sooner and with greater severity in men. In previous studies of the molecular background of the observed gender differences, mitochondrial function, lipid and carbohydrate metabolism, inflammation, regulation of cell death and fibrosis have emerged as potential sources of gender-related inequalities in outcomes of cardiovascular diseases. Nevertheless, an unbiased and global assessment of gender related aspects of cardiac functional and proteomic alterations following ischemia is still lacking.
Aim: Left ventricular (LV) pressure-volume analysis (P-V) and liquid chromatography-tandem mass spectrometry (LC-MS) -based proteomics was used to reveal the gender related characteristics of left ventricular function and proteomic changes following ischemic periods.
Methods: Male and female Wistar rats were injected with isoproterenol (85 mg / kg) daily for two days. Forty-eight hours after the start of the experiment, LV function was examined by P-V. Subsequently, the extent of ischemia was assessed on digitalized histological sections of LV, while peptides isolated from our frozen myocardial samples were measured by LC-MS.
Results: Mortality observed after ischemia was 55.3% lower in females than in males. In surviving rats, ischemic myocardial damage occurred to a similar extent comparing the sexes. Impairment of systolic function was more pronounced in males, while diastolic dysfunction was greater in females. Differential expression analysis found 520 proteins that showed sex-dependent regulation. The lower mortality and preserved systolic performance of females could be attributed to the sustained expression of proteins involved in fatty acid oxidation (ECI1, ETFRF1, ETFA, ETFB, ETFDH, CISD1, CPT2, ACOT2) and the increased expression of molecular chaperones (ORP-150, HSP90AA1, HSP90AB1, CALR, PDIA3 and BIP), while their impaired diastolic function could be attributed to the increased expression of proinflammatory proteins.
Conclusions: Our study revealed gender-specific aspects of functional impairment in the heart shortly after ischemia. Our proteomic analysis shed light on the gender differences in the underlying molecular processes.
Funding: ÚNKP-20-3-I-SE-1, EFOP-3.6.3-VEKOP-16-2017-00009
Semmelweis University, Doctoral School of Theoretical and Translational Medicine