Genetic Deficiency of Glutathione S -Transferase P Increases Myocardial Sensitivity to Ischemia–Reperfusion Injury
| Autor: | Sanjay K. Srivastava, Detlef Obal, Aruni Bhatnagar, Yiru Guo, Jay L. Zweier, D. Gregg Rokosh, Daniel J. Conklin, Luping Guo, Ganapathy Jagatheesan, J. David Hoetker, Sumanth D. Prabhu, Bradford G. Hill, Roberto Bolli, Murugesan Velayutham, Shahid P Baba, Karin Wetzelberger, Daniel W. Riggs, Petra Haberzettl, Russell A. Prough, Peter J. Kilfoil |
|---|---|
| Rok vydání: | 2015 |
| Předmět: |
Male
medicine.medical_specialty Antioxidant Physiology medicine.medical_treatment Myocardial Reperfusion Injury medicine.disease_cause Article GSTA4 Lipid peroxidation Mice chemistry.chemical_compound GSTP1 Internal medicine medicine Animals Glutathione Transferase Mice Knockout Chemistry Myocardium Acrolein Glutathione medicine.disease Mice Inbred C57BL Endocrinology Biochemistry Cardiology and Cardiovascular Medicine Reperfusion injury Oxidative stress |
| Zdroj: | Circulation Research. 117:437-449 |
| ISSN: | 1524-4571 0009-7330 |
| Popis: | 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 I Na , 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. |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|