Abstract
BackgroundReduced cardiovascular risk in premenopausal women has been the focus of research in recent decades. Previous hypothesis-driven experiments have highlighted the role of sex hormones on distinct inflammatory responses, mitochondrial proteins, extracellular remodeling and estrogen-mediated cardioprotective signaling pathways related to post-ischemic recovery, which were associated with better cardiac functional outcomes in females. We aimed to investigate the early, sex-specific functional and proteomic changes following myocardial ischemia in an unbiased approach.MethodsIschemia was induced in male (M-Isch) and female (F-Isch) rats with sc. injection of isoproterenol (85 mg/kg) daily for 2 days, while controls (M-Co, F-Co) received sc. saline solution. At 48 h after the first injection pressure–volume analysis was carried out to assess left ventricular function. FFPE tissue slides were scanned and analyzed digitally, while myocardial proteins were quantified by liquid chromatography–tandem mass spectrometry (LC–MS/MS) using isobaric labeling. Concentrations of circulating steroid hormones were measured with LC–MS/MS. Feature selection (PLS and PLS-DA) was used to examine associations among functional, proteomic and hormonal datasets.ResultsInduction of ischemia resulted in 38% vs 17% mortality in M-Isch and F-Isch respectively. The extent of ischemic damage to surviving rats was comparable between the sexes. Systolic dysfunction was more pronounced in males, while females developed a more severe impairment of diastolic function. 2224 proteins were quantified, with 520 showing sex-specific differential regulation. Our analysis identified transcriptional, cytoskeletal, contractile, and mitochondrial proteins, molecular chaperones and the extracellular matrix as sources of disparity between the sexes. Bioinformatics highlighted possible associations of estrogens and their metabolites with early functional and proteomic alterations.ConclusionsOur study has highlighted sex-specific alterations in systolic and diastolic function shortly after ischemia, and provided a comprehensive look at the underlying proteomic changes and the influence of estrogens and their metabolites. According to our bioinformatic analysis, inflammatory, mitochondrial, chaperone, cytoskeletal, extracellular and matricellular proteins are major sources of intersex disparity, and may be promising targets for early sex-specific pharmacologic interventions.Graphical
Highlights
Sex has been shown to have a major impact on the pathophysiology, presentation and outcomes of cardiovascular diseases [1]
The induction of ischemia on two consecutive days has resulted in 38% and 17% mortality in M-Isch and F-Isch rats respectively
left ventricular (LV) functional characterization 48 h after the first injection, LV end-systolic pressure (LVESP) was significantly lowered in both Isch groups, MAP, systolic arterial blood pressure (SABP), SADP and stroke work (SW) were found to be markedly diminished only in M-Isch
Summary
Sex has been shown to have a major impact on the pathophysiology, presentation and outcomes of cardiovascular diseases [1]. This phenomenon is apparent in coronary artery diseases (CAD). A majority of these investigations have found higher survival rates as well as faster recovery of contractility and relaxation in females in the first few days after MI (as reviewed by Regitz-Zagrosek and Kararigas [1]). Previous hypothesis-driven experiments have highlighted the role of sex hormones on distinct inflammatory responses, mitochondrial proteins, extracellular remodeling and estrogen-mediated cardioprotective signaling path‐ ways related to post-ischemic recovery, which were associated with better cardiac functional outcomes in females. We aimed to investigate the early, sex-specific functional and proteomic changes following myocardial ischemia in an unbiased approach
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