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

Research output: Contribution to journalArticle

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.

Original languageEnglish (US)
Pages (from-to)437-449
Number of pages13
JournalCirculation Research
Volume117
Issue number5
DOIs
StatePublished - Aug 14 2015
Externally publishedYes

Fingerprint

Glutathione Transferase
Reperfusion Injury
Acrolein
Aldehydes
Ischemia
Free Radicals
Myocardial Ischemia
Cell Death
Myocardial Reperfusion Injury
Myocardial Reperfusion
JNK Mitogen-Activated Protein Kinases
Coronary Occlusion
Inbred C57BL Mouse
Cardiac Myocytes
Muscle Cells
Lipid Peroxidation
Reperfusion
Glutathione
Proteins
Antioxidants

Keywords

  • acrolein
  • glutathione transferase
  • lipid peroxidation
  • myocardial infarction
  • myocardial ischemia
  • oxidative stress
  • reperfusion injury

ASJC Scopus subject areas

  • Physiology
  • Cardiology and Cardiovascular Medicine
  • Medicine(all)

Cite this

Conklin, D. J., Guo, Y., Jagatheesan, G., Kilfoil, P. J., Haberzettl, P., Hill, B. G., ... Bhatnagar, A. (2015). Genetic Deficiency of Glutathione S-Transferase P Increases Myocardial Sensitivity to Ischemia-Reperfusion Injury. Circulation Research, 117(5), 437-449. https://doi.org/10.1161/CIRCRESAHA.114.305518

Genetic Deficiency of Glutathione S-Transferase P Increases Myocardial Sensitivity to Ischemia-Reperfusion Injury. / Conklin, Daniel J.; Guo, Yiru; Jagatheesan, Ganapathy; Kilfoil, Peter J.; Haberzettl, Petra; Hill, Bradford G.; Baba, Shahid P.; Guo, Luping; Wetzelberger, Karin; Obal, Detlef; Gregg Rokosh, D.; Prough, Russell A.; Prabhu, Sumanth D.; Velayutham, Murugesan; Zweier, Jay L.; David Hoetker, J.; Riggs, Daniel W.; Srivastava, Sanjay; Bolli, Roberto; Bhatnagar, Aruni.

In: Circulation Research, Vol. 117, No. 5, 14.08.2015, p. 437-449.

Research output: Contribution to journalArticle

Conklin, DJ, Guo, Y, Jagatheesan, G, Kilfoil, PJ, Haberzettl, P, Hill, BG, Baba, SP, Guo, L, Wetzelberger, K, Obal, D, Gregg Rokosh, D, Prough, RA, Prabhu, SD, Velayutham, M, Zweier, JL, David Hoetker, J, Riggs, DW, Srivastava, S, Bolli, R & Bhatnagar, A 2015, 'Genetic Deficiency of Glutathione S-Transferase P Increases Myocardial Sensitivity to Ischemia-Reperfusion Injury', Circulation Research, vol. 117, no. 5, pp. 437-449. https://doi.org/10.1161/CIRCRESAHA.114.305518
Conklin, Daniel J. ; Guo, Yiru ; Jagatheesan, Ganapathy ; Kilfoil, Peter J. ; Haberzettl, Petra ; Hill, Bradford G. ; Baba, Shahid P. ; Guo, Luping ; Wetzelberger, Karin ; Obal, Detlef ; Gregg Rokosh, D. ; Prough, Russell A. ; Prabhu, Sumanth D. ; Velayutham, Murugesan ; Zweier, Jay L. ; David Hoetker, J. ; Riggs, Daniel W. ; Srivastava, Sanjay ; Bolli, Roberto ; Bhatnagar, Aruni. / Genetic Deficiency of Glutathione S-Transferase P Increases Myocardial Sensitivity to Ischemia-Reperfusion Injury. In: Circulation Research. 2015 ; Vol. 117, No. 5. pp. 437-449.
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T1 - Genetic Deficiency of Glutathione S-Transferase P Increases Myocardial Sensitivity to Ischemia-Reperfusion Injury

AU - Conklin, Daniel J.

AU - Guo, Yiru

AU - Jagatheesan, Ganapathy

AU - Kilfoil, Peter J.

AU - Haberzettl, Petra

AU - Hill, Bradford G.

AU - Baba, Shahid P.

AU - Guo, Luping

AU - Wetzelberger, Karin

AU - Obal, Detlef

AU - Gregg Rokosh, D.

AU - Prough, Russell A.

AU - Prabhu, Sumanth D.

AU - Velayutham, Murugesan

AU - Zweier, Jay L.

AU - David Hoetker, J.

AU - Riggs, Daniel W.

AU - Srivastava, Sanjay

AU - Bolli, Roberto

AU - Bhatnagar, Aruni

PY - 2015/8/14

Y1 - 2015/8/14

N2 - 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.

AB - 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.

KW - acrolein

KW - glutathione transferase

KW - lipid peroxidation

KW - myocardial infarction

KW - myocardial ischemia

KW - oxidative stress

KW - reperfusion injury

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