Genetic Deficiency of Glutathione S-Transferase P Increases Myocardial Sensitivity to Ischemia-Reperfusion Injury

Daniel J Conklin; Yiru Guo; Ganapathy Jagatheesan; Peter J Kilfoil; Petra Haberzettl; Bradford G Hill; Shahid P Baba; Luping Guo; Karin Wetzelberger; Detlef Obal; D Gregg Rokosh; Russell A Prough; Sumanth D Prabhu; Murugesan Velayutham; Jay L Zweier; J David Hoetker; Daniel W Riggs; Sanjay Srivastava; Roberto Bolli; Aruni Bhatnagar

doi:10.1161/CIRCRESAHA.114.305518

Genetic Deficiency of Glutathione S-Transferase P Increases Myocardial Sensitivity to Ischemia-Reperfusion Injury

Circ Res. 2015 Aug 14;117(5):437-49. doi: 10.1161/CIRCRESAHA.114.305518. Epub 2015 Jul 13.

Authors

Daniel J Conklin¹, Yiru Guo², Ganapathy Jagatheesan², Peter J Kilfoil², Petra Haberzettl², Bradford G Hill², Shahid P Baba², Luping Guo², Karin Wetzelberger², Detlef Obal², D Gregg Rokosh², Russell A Prough², Sumanth D Prabhu², Murugesan Velayutham², Jay L Zweier², J David Hoetker², Daniel W Riggs², Sanjay Srivastava², Roberto Bolli², Aruni Bhatnagar²

Affiliations

¹ From the Diabetes and Obesity Center (D.J.C., G.J., P.J.K., P.H., B.G.H., S.P.B., L.G., K.W., D.O., D.G.R., J.D.H., D.W.R., S.S., R.B., A.B.), Institute of Molecular Cardiology (D.J.C., Y.G., P.J.K., P.H., B.G.H., S.P.B., D.O., D.G.R., S.S., R.B., A.B.), Division of Cardiovascular Medicine, Department of Medicine (D.J.C., Y.G., G.J., P.J.K., P.H., B.G.H., S.P.B., L.G., D.O., D.G.R., J.D.H., D.W.R., S.S., R.B., A.B), Department of Anesthesiology and Perioperative Medicine (D.O.), and Department of Biochemistry and Molecular Genetics (P.J.K., R.A.P., A.B.), University of Louisville, KY; Division of Cardiovascular Disease, University of Alabama at Birmingham (S.D.P.); and Center for Biomedical EPR Spectroscopy and Imaging, Davis Heart and Lung Research Institute, and Division of Cardiovascular Medicine, Department of Internal Medicine, The Ohio State University College of Medicine, Columbus (M.V., J.L.Z.). dj.conklin@louisville.edu.
² From the Diabetes and Obesity Center (D.J.C., G.J., P.J.K., P.H., B.G.H., S.P.B., L.G., K.W., D.O., D.G.R., J.D.H., D.W.R., S.S., R.B., A.B.), Institute of Molecular Cardiology (D.J.C., Y.G., P.J.K., P.H., B.G.H., S.P.B., D.O., D.G.R., S.S., R.B., A.B.), Division of Cardiovascular Medicine, Department of Medicine (D.J.C., Y.G., G.J., P.J.K., P.H., B.G.H., S.P.B., L.G., D.O., D.G.R., J.D.H., D.W.R., S.S., R.B., A.B), Department of Anesthesiology and Perioperative Medicine (D.O.), and Department of Biochemistry and Molecular Genetics (P.J.K., R.A.P., A.B.), University of Louisville, KY; Division of Cardiovascular Disease, University of Alabama at Birmingham (S.D.P.); and Center for Biomedical EPR Spectroscopy and Imaging, Davis Heart and Lung Research Institute, and Division of Cardiovascular Medicine, Department of Internal Medicine, The Ohio State University College of Medicine, Columbus (M.V., J.L.Z.).

Abstract

Rationale: Myocardial ischemia-reperfusion (I/R) results in the generation of oxygen-derived free radicals and the accumulation of lipid peroxidation-derived unsaturated aldehydes. However, the contribution of aldehydes to myocardial I/R injury has not been assessed.

Objective: We tested the hypothesis that removal of aldehydes by glutathione S-transferase P (GSTP) diminishes I/R injury.

Methods and results: In adult male C57BL/6 mouse hearts, Gstp1/2 was the most abundant GST transcript followed by Gsta4 and Gstm4.1, and GSTP activity was a significant fraction of the total GST activity. mGstp1/2 deletion reduced total GST activity, but no compensatory increase in GSTA and GSTM or major antioxidant enzymes was observed. Genetic deficiency of GSTP did not alter cardiac function, but in comparison with hearts from wild-type mice, the hearts isolated from GSTP-null mice were more sensitive to I/R injury. Disruption of the GSTP gene also increased infarct size after coronary occlusion in situ. Ischemia significantly increased acrolein in hearts, and GSTP deficiency induced significant deficits in the metabolism of the unsaturated aldehyde, acrolein, but not in the metabolism of 4-hydroxy-trans-2-nonenal or trans-2-hexanal; on ischemia, the GSTP-null hearts accumulated more acrolein-modified proteins than wild-type hearts. GSTP deficiency did not affect I/R-induced free radical generation, c-Jun N-terminal kinase activation, or depletion of reduced glutathione. Acrolein exposure induced a hyperpolarizing shift in INa, and acrolein-induced cell death was delayed by SN-6, a Na(+)/Ca(++) exchange inhibitor. Cardiomyocytes isolated from GSTP-null hearts were more sensitive than wild-type myocytes to acrolein-induced protein crosslinking and cell death.

Conclusions: GSTP protects the heart from I/R injury by facilitating the detoxification of cytotoxic aldehydes, such as acrolein.

Keywords: acrolein; glutathione transferase; lipid peroxidation; myocardial infarction; myocardial ischemia; oxidative stress; reperfusion injury.

Publication types

Research Support, N.I.H., Extramural
Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

Animals
Glutathione Transferase / deficiency*
Glutathione Transferase / genetics*
Male
Mice
Mice, Inbred C57BL
Mice, Knockout
Myocardial Reperfusion Injury / enzymology*
Myocardial Reperfusion Injury / genetics*
Myocardial Reperfusion Injury / pathology
Myocardium / metabolism*
Myocardium / pathology

Substances

Glutathione Transferase

Abstract

Publication types

MeSH terms

Substances

Grants and funding