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Cardioprotection of glutathione S‐transferase P against ischemia‐reperfusion injury
Author(s) -
Conklin Daniel J.,
Hill Bradford G.,
Guo Yiru,
Prough Russell A.,
Prabhu Sumanth D.,
Bolli Roberto,
Bhatnagar Aruni
Publication year - 2008
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.22.1_supplement.750.18
Subject(s) - oxidative stress , glutathione , gstp1 , glutathione peroxidase , reactive oxygen species , ischemia , glutathione s transferase , medicine , cardioprotection , chemistry , reperfusion injury , pharmacology , endocrinology , biochemistry , enzyme , superoxide dismutase
Oxidative stress is a key determinant of cardiac injury associated with acute ischemia and reperfusion (I/R). Yet, the mechanisms that regulate the outcome of redox changes in I/R‐heart remain unclear. Because glutathione‐linked metabolism is a major pathway for the detoxification of electrophiles generated during I/R, we examined the role of glutathione S‐transferase P (GSTP) – the major extrahepatic GST. To test the hypothesis that GSTP is cardioprotective, GSTP1/P2 wild‐type (WT) and null mice were subjected to left coronary artery ligation (30 min) and 4 h reperfusion in situ. Infract size due to I/R was significantly increased to 73.1 ± 3.7% of risk region (n = 8) in null mice vs WT mice (55.6 ± 3.9%; n = 8; P < 0.01). Similarly, increased levels of oxidative stress markers were observed in isolated I/R‐hearts of GSTP‐null vs WT mice. Moreover, isolated cardiomyocytes of GSTP‐null mice were more sensitive than those of WT mice to hydrogen peroxide‐ and acrolein‐induced hypercontracture. In contrast, no differences in basal levels of cardiac oxidative stress markers (e.g., GSH level), expression of the GSTs A and M, and cardiac phenotype were observed between WT and null mice, although GST and peroxidase activities were significantly decreased in null vs WT hearts. These findings indicate GSTP is a novel cardioprotective gene against I/R. This work funded by NIEHS and NIH grants ES11860 (AB) and HL78825 (RB).