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The central hypothesis of this study is that restraint stress induces sex-specific changes in gene expression in the heart, which leads to an intensified response to ischemia\/reperfusion injury due to the development of a pro-oxidative environment in female hearts. We challenged male and female C57BL\/6 mice in a restraint stress model to mimic the effects of mental stress. Exposure to restraint stress led to sex differences in the expression of genes involved in cardiac hypertrophy, inflammation, and iron-dependent cell death (ferroptosis). Among those genes, we identified tumor protein p53 and cyclin-dependent kinase inhibitor 1A (p21), which have established controversial roles in ferroptosis. The exacerbated response to I\/R injury in restraint-stressed females correlated with downregulation of p53 and nuclear factor erythroid 2\u2013related factor 2 (Nrf2, a master regulator of the antioxidant response system-ARE). S-female hearts also showed increased superoxide levels, lipid peroxidation, and prostaglandin-endoperoxide synthase 2 (Ptgs2) expression (a hallmark of ferroptosis) compared with those of their male counterparts. Our study is the first to test the sex-specific impact of restraint stress on the heart in the setting of I\/R and its outcome.<\/jats:p>","DOI":"10.3390\/ijms241310994","type":"journal-article","created":{"date-parts":[[2023,7,3]],"date-time":"2023-07-03T00:34:08Z","timestamp":1688344448000},"page":"10994","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":10,"title":["Exposure to Stress Alters Cardiac Gene Expression and Exacerbates Myocardial Ischemic Injury in the Female Murine Heart"],"prefix":"10.3390","volume":"24","author":[{"given":"Hemangini A.","family":"Dhaibar","sequence":"first","affiliation":[{"name":"Department of Molecular and Cellular Physiology, Louisiana State University Health Sciences Center at Shreveport, Shreveport, LA 71103, USA"},{"name":"Center for Cardiovascular Diseases and Sciences and Center for Redox Biology and Cardiovascular Disease, LSU Health Sciences Center, Shreveport, LA 71103, 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University William Beaumont School of Medicine, Rochester, MI 48309, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Xinggui","family":"Shen","sequence":"additional","affiliation":[{"name":"Center for Cardiovascular Diseases and Sciences and Center for Redox Biology and Cardiovascular Disease, LSU Health Sciences Center, Shreveport, LA 71103, USA"},{"name":"Department of Pathology and Translational Pathobiology, Louisiana State University Health Sciences Center at Shreveport, Shreveport, LA 71103, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Hyung","family":"Nam","sequence":"additional","affiliation":[{"name":"Center for Cardiovascular Diseases and Sciences and Center for Redox Biology and Cardiovascular Disease, LSU Health Sciences Center, Shreveport, LA 71103, USA"},{"name":"Pharmacology, Toxicology and Neuroscience, Louisiana State University Health Sciences Center at Shreveport, Shreveport, LA 71103, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"A. Wayne","family":"Orr","sequence":"additional","affiliation":[{"name":"Center for Cardiovascular Diseases and Sciences and Center for Redox Biology and Cardiovascular Disease, LSU Health Sciences Center, Shreveport, LA 71103, USA"},{"name":"Department of Pathology and Translational Pathobiology, Louisiana State University Health Sciences Center at Shreveport, Shreveport, LA 71103, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Tanja","family":"Dudenbostel","sequence":"additional","affiliation":[{"name":"Center for Cardiovascular Diseases and Sciences and Center for Redox Biology and Cardiovascular Disease, LSU Health Sciences Center, Shreveport, LA 71103, USA"},{"name":"LSU Health Sciences Center, Department of Internal Medicine, Louisiana State University Health Sciences Center at Shreveport, Shreveport, LA 71103, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5792-6926","authenticated-orcid":false,"given":"Steven R.","family":"Bailey","sequence":"additional","affiliation":[{"name":"Center for Cardiovascular Diseases and Sciences and Center for Redox Biology and Cardiovascular Disease, LSU Health Sciences Center, Shreveport, LA 71103, USA"},{"name":"LSU Health Sciences Center, Department of Internal Medicine, Louisiana State University Health Sciences Center at Shreveport, Shreveport, LA 71103, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Christopher G.","family":"Kevil","sequence":"additional","affiliation":[{"name":"Center for Cardiovascular Diseases and Sciences and Center for Redox Biology and Cardiovascular Disease, LSU Health Sciences Center, Shreveport, LA 71103, USA"},{"name":"Department of Pathology and Translational Pathobiology, Louisiana State University Health Sciences Center at Shreveport, Shreveport, LA 71103, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2827-7162","authenticated-orcid":false,"given":"Luca","family":"Cucullo","sequence":"additional","affiliation":[{"name":"Department of Biological Sciences, Oakland University, Rochester, MI 48309, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Diana","family":"Cruz-Topete","sequence":"additional","affiliation":[{"name":"Department of Molecular and Cellular Physiology, Louisiana State University Health Sciences Center at Shreveport, Shreveport, LA 71103, USA"},{"name":"Center for Cardiovascular Diseases and Sciences and Center for Redox Biology and Cardiovascular Disease, LSU Health Sciences Center, Shreveport, LA 71103, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2023,7,1]]},"reference":[{"key":"ref_1","unstructured":"Reinert, M., Theresa, N., and Fritze, D. 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