Journal article
Genetic Deficiency of Glutathione S-Transferase P Increases Myocardial Sensitivity to Ischemia-Reperfusion Injury
Circulation research, Vol.117(5), pp.437-449
08/14/2015
DOI: 10.1161/CIRCRESAHA.114.305518
PMCID: PMC4854443
PMID: 26169370
Abstract
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.
We tested the hypothesis that removal of aldehydes by glutathione S-transferase P (GSTP) diminishes I/R injury.
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.
GSTP protects the heart from I/R injury by facilitating the detoxification of cytotoxic aldehydes, such as acrolein.
Details
- Title: Subtitle
- Genetic Deficiency of Glutathione S-Transferase P Increases Myocardial Sensitivity to Ischemia-Reperfusion Injury
- Creators
- Daniel J ConklinYiru GuoGanapathy JagatheesanPeter J KilfoilPetra HaberzettlBradford G HillShahid P BabaLuping GuoKarin WetzelbergerDetlef ObalD Gregg RokoshRussell A ProughSumanth D PrabhuMurugesan VelayuthamJay L ZweierJ David HoetkerDaniel W RiggsSanjay SrivastavaRoberto BolliAruni Bhatnagar
- Resource Type
- Journal article
- Publication Details
- Circulation research, Vol.117(5), pp.437-449
- DOI
- 10.1161/CIRCRESAHA.114.305518
- PMID
- 26169370
- PMCID
- PMC4854443
- ISSN
- 0009-7330
- eISSN
- 1524-4571
- Grant note
- ES14559 / NIEHS NIH HHS R01 HL055477 / NHLBI NIH HHS P20 GM103492 / NIGMS NIH HHS GM103492 / NIGMS NIH HHS T35 ES014559 / NIEHS NIH HHS R01 HL089380 / NHLBI NIH HHS HL78825 / NHLBI NIH HHS R01 HL130174 / NHLBI NIH HHS HL99014 / NHLBI NIH HHS HL55477 / NHLBI NIH HHS HL89380 / NHLBI NIH HHS P01 HL078825 / NHLBI NIH HHS R01 HL059378 / NHLBI NIH HHS
- Language
- English
- Date published
- 08/14/2015
- Academic Unit
- Anesthesia
- Record Identifier
- 9984696721402771
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