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Glutathione peroxidase deficiency exacerbates ischemia-reperfusion injury in male but not female myocardium: insights into antioxidant compensatory mechanisms

Lim, Chee Chew, Bryan, Nathan S., Jain, Mohit, Garcia-Saura, Maria F., Fernandez, Bernadette O., Sawyer, Douglas B., Handy, Diane E., Loscalzo, Joseph, Feelisch, Martin and Liao, Ronglih (2009) Glutathione peroxidase deficiency exacerbates ischemia-reperfusion injury in male but not female myocardium: insights into antioxidant compensatory mechanisms American Journal of Physiology: Heart and Circulatory Physiology, 297, (6), H2144-H2153. (doi:10.1152/ajpheart.00673.2009). (PMID:19801492).

Record type: Article


The female sex has been associated with increased resistance to acute myocardial ischemia-reperfusion (I/R) injury. While enhanced antioxidant capacity has been implicated in female cardioprotection, there is little evidence to support this assumption. Previous studies have shown an important role of cellular glutathione peroxidase (GPx1) in protection of the myocardium from I/R injury. Whether GPx1 is mechanistic in the protection of female myocardium, post-I/R, has not been examined. We utilized a murine model with homozygous deletion of GPx1 and examined its impact on postischemic myocardial recovery in male and female mice. Following I/R, male GPx1(-/-) hearts were more susceptible to contractile and diastolic dysfunction, and this was associated with increased protein carbonyls, a marker of oxidative stress. In contrast, GPx1 deficiency in female hearts did not exacerbate dysfunction or oxidative stress post-I/R. Both wild-type and GPx1(-/-) female hearts exhibited reduced creatine kinase leakage and a more favorable ascorbate redox status compared with males. Following I/R, female GPx1(-/-) hearts showed a comparable decrease in glutathione redox status as their male counterparts; however, they exhibited a greater decrease in nitrate-to-nitrite ratio, suggesting a higher consumption of nitrate in female GPx1(-/-) hearts. Our findings demonstrate that GPx1 is critical for cardioprotection during I/R in male, but not female, mice. The maintenance of cardioprotection in female mice lacking GPx1 post-I/R may be due to an improved ascorbate redox homeostasis and enhanced nitrate-to-nitrite conversion, which would predictably be accompanied by enhanced production of cardioprotective nitric oxide.

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e-pub ahead of print date: 2 October 2009
Published date: 1 December 2009
Keywords: ischemia, reperfusion, gender, free radicals, antioxidants, ascorbate, nitric oxide, nitrite
Organisations: Clinical & Experimental Sciences


Local EPrints ID: 337702
ISSN: 0363-6135
PURE UUID: 01f0650b-5cb5-49a8-9e69-54a75eb54c41
ORCID for Martin Feelisch: ORCID iD

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Date deposited: 02 May 2012 13:09
Last modified: 18 Jul 2017 06:01

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Author: Chee Chew Lim
Author: Nathan S. Bryan
Author: Mohit Jain
Author: Maria F. Garcia-Saura
Author: Bernadette O. Fernandez
Author: Douglas B. Sawyer
Author: Diane E. Handy
Author: Joseph Loscalzo
Author: Martin Feelisch ORCID iD
Author: Ronglih Liao

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