| First Author | Beneš H | Year | 2013 |
| Journal | Cardiovasc Toxicol | Volume | 13 |
| Issue | 4 | Pages | 347-56 |
| PubMed ID | 23690225 | Mgi Jnum | J:330981 |
| Mgi Id | MGI:6882094 | Doi | 10.1007/s12012-013-9215-1 |
| Citation | Benes H, et al. (2013) Protection from oxidative and electrophilic stress in the Gsta4-null mouse heart. Cardiovasc Toxicol 13(4):347-56 |
| abstractText | 4-Hydroxynonenal (4-HNE) mediates many pathological effects of oxidative and electrophilic stress and signals to activate cytoprotective gene expression regulated by NF-E2-related factor 2 (Nrf2). By exhibiting very high levels of 4-HNE-conjugating activity, the murine glutathione transferase alpha 4 (GSTA4-4) helps regulate cellular 4-HNE levels. To examine the role of 4-HNE in vivo, we disrupted the murine Gsta4 gene. Gsta4-null mice exhibited no cardiac phenotype under normal conditions and no difference in cardiac 4-HNE level as compared to wild-type mice. We hypothesized that the Nrf2 pathway might contribute an important compensatory mechanism to remove excess cardiac 4-HNE in Gsta4-null mice. Cardiac nuclear extracts from Gsta4-null mice exhibited significantly higher Nrf2 binding to antioxidant response elements. We also observed responses in critical Nrf2 target gene products: elevated Sod2, Cat, and Akr1b7 mRNA levels and significant increases in both cardiac antioxidant and anti-electrophile enzyme activities. Gsta4-null mice were less sensitive and maintained normal cardiac function following chronic doxorubicin treatment, known to increase cardiac 4-HNE levels. Hence, in the absence of GSTA4-4 to modulate both physiological and pathological 4-HNE levels, the adaptive Nrf2 pathway may be primed to contribute to a preconditioned cardiac phenotype in the Gsta4-null mouse. |
