Master of Science

thesisWe examined mice with cardiac specific deletion of the gene encoding glucose transporter 4 (GLUT4, G4H-/-). These mice develop moderate cardiac hypertrophy with normal basal cardiac function and show signs of mitochondrial and whole cell oxidative stress as evidenced by increased concentration of oxidized glutathione (GSSG). Preliminary research in our laboratory has shown that treatment with the antioxidant tempol (a whole cell antioxidant), but not MnTBAP (a mitochondrial targeted superoxide 2 mimetic), can attenuate cardiac hypertrophy. Furthermore, GSSG concentrations were not altered by tempol, but reduced by MnTBAP. Based on these preliminary data, we hypothesized that 1) glutathione peroxidase (Gpx) was elevated and glutathione reductase (Gsr) was lower in hearts of G4H-/- mice. Both Gpx and Gsr are important components of glutathione cycle. 2) MnTBAP treatment increases Gsr and lowers Gpx expression, but tempol did not affect either of them. 3) Tempol treatment can decrease GSK3? phosphorylation and increase Txn2 expression. In contrast to our hypothesis, Gpx was not elevated in G4H-/- mice and Gsr levels were similar between G4H-/- and control. Treatment with either tempol or MnTBAP did not affect Gpx protein levels. On the other hand, tempol reduced Gsr in G4H-/- mice vs. untreated G4H-/- and controls. GSK3? activity was similar between G4H-/- mice and controls and remained unchanged after tempol and MnTBAP. Txn2 expression was also similar between controls and G4H-/-. Tempol treatment increased Txn2 mRNA expression in controls only, but MnTBAP did not affect Txn2 in any group. Additionally, after tempol treatment, mRNA level of Gpx was not elevated in G4H-/- mice but actually lower, whereas Gsr was unchanged. To sum up, the reduction of hypertrophy after tempol treatment was not associated with changes in; a) GSK3? phosphorylation, b) enzymes used in the glutathione oxidation and reduction cycle, or c) Txn2 expression. Additionally, though preliminary studies found a reduction of GSSG after MnTBAP treatment, the present study found this was not accompanied by any change in Gpx or Gsr. Therefore, we conclude that the attenuation of cardiac hypertrophy is unrelated to the modulation of oxidative stress by these enzymes, or a change in GSK3? phosphorylation