Abstract P046: Variable Effect Of Gstm1 Knockout In Mice

Glutathione S-transferase μ-1 (GSTM1) is an enzyme that has a role in the detoxification of electrophiles, including xenobiotics and products of oxidative stress. In humans, the GSTM1(0) null allele deletion variant is highly prevalent and is associated with both an increase in oxidative stress and an increased risk/severity of a variety of diseases, including cancers, chronic kidney disease, hypertension, and coronary artery disease.Recently, we generated a Gstm1 knockout ( Gstm1 -/- ) mouse line on a 129S6 background. Using these animals, we demonstrated that the loss of GSTM1 resulted in increased oxidative stress and greater kidney injury with either subtotal nephrectomy-induced chronic kidney disease or angiotensin II-induced hypertension, in accordance with clinical data.Following myocardial infarction, reperfusion of the heart results in additional tissue damage that is also mediated by acute oxidative stress. Here, we used an ex vivo Langendorff-perfused heart model of acute cardiac ischemia-reperfusion injury (IRI). Contrary to the expectation that hearts from Gstm1 -/- mice would be more susceptible to IRI, we found that the loss of the antioxidant enzyme GSTM1 was protective in males compared to age-matched wild-type controls. In contrast, the Gstm1 -/- genotype was deleterious in female hearts as expected.To explore the hypothesis that the loss of GSTM1 causes compensatory upregulation of other GSTs and that this effect varies based on both tissue and sex, we examined mRNA expression of α, θ, κ, μ, and π classes of Gst genes via qPCR and corresponding protein expression via HPLC and western blot. We found significant differences between male vs. female and heart vs. kidney in several GSTs both in their expression in wild-type mice and in the change in expression between wild-type and Gstm1 -/- mice. These results suggest that the severity of cardiac IRI may depend on the adaptive response mediated by genes encoding GST enzymes.