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Myocardial Redox Hormesis Protects the Heart of Female Mice in Sepsis

Luptak, Ivan*; Croteau, Dominique*; Valentine, Catherine; Qin, Fuzhong*; Siwik, Deborah A.*; Remick, Daniel G.; Colucci, Wilson S.*; Hobai, Ion A.*,‡

doi: 10.1097/SHK.0000000000001245
Basic Science Aspects
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ABSTRACT Mice challenged with lipopolysaccharide develop cardiomyopathy in a sex and redox-dependent fashion. Here we extended these studies to the cecal ligation and puncture (CLP) model.

We compared male and female FVB mice (wild type, WT) and transgenic littermates overexpressing myocardial catalase (CAT). CLP induced 100% mortality within 4 days, with similar mortality rates in male and female WT and CAT mice. 24 h after CLP, isolated (Langendorff) perfused hearts showed depressed contractility in WT male mice, but not in male CAT or female WT and CAT mice. In WT male mice, CLP induced a depression of cardiomyocyte sarcomere shortening (ΔSS) and calcium transients (ΔCai), and the inhibition of the sarcoplasmic reticulum Ca2+ ATPase (SERCA). These deficits were associated with overexpression of NADPH-dependent oxidase (NOX)-1, NOX-2, and cyclooxygenase 2 (COX-2), and were partially prevented in male CAT mice. Female WT mice showed unchanged ΔSS, ΔCai, and SERCA function after CLP. At baseline, female WT mice showed partially depressed ΔSS, ΔCai, and SERCA function, as compared with male WT mice, which were associated with NOX-1 overexpression and were prevented in CAT female mice.

In conclusion, in male WT mice, septic shock induces myocardial NOX-1, NOX-2, and COX-2, and redox-dependent dysregulation of myocardial Ca2+ transporters. Female WT mice are resistant to CLP-induced cardiomyopathy, despite increased NOX-1 and COX-2 expression, suggesting increased antioxidant capacity. Female resistance occurred in association with NOX-1 overexpression and signs of increased oxidative signaling at baseline, indicating the presence of a protective myocardial redox hormesis mechanism.

*Cardiovascular Medicine, Department of Medicine, Boston University Medical Center, Boston, Massachusetts

Department of Pathology, Boston University Medical Center, Boston, Massachusetts

Department of Anesthesia, Critical Care and Pain Medicine, Massachusetts General Hospital and Harvard University, Boston, Massachusetts

Address reprint requests to Ion A. Hobai, MD, PhD, Department of Anesthesia, Critical Care and Pain Medicine, Massachusetts General Hospital, 55 Fruit Street, GRB 444, Boston, MA 02114. E-mail: ihobai@mgh.harvard.edu

Received 13 June, 2018

Revised 3 July, 2018

Accepted 2 August, 2018

Sources of Funding: This work was supported by National Institute of Health grants HL-061639, HL-064750 (W.S.C.) and the National Heart, Lung and Blood Institute-sponsored Boston University Cardiovascular Proteomics Center (Contract No. N01-HV-28178, W.S.C.). I.L. acknowledges American Heart Association Fellow to Faculty Award 15FTF25890062. I.A.H. acknowledges support from K08GM096082 (National Institute of General Medical Sciences) and from the Department of Anesthesia, Critical Care and Pain Medicine, Massachusetts General Hospital, Boston, MA.

The authors report no conflicts of interest.

Abstract Presentations: Preliminary results have been presented in abstract form at the Shock Society Meeting, Fort Lauderdale, FL, June 2017.

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© 2019 by the Shock Society