Reactive oxygen species such as
superoxide are implicated in
cardiac hypertrophy, but their contribution to the cardiac complications of
insulin resistance is unresolved. We tested the hypothesis that the
antioxidant tempol attenuates
cardiac hypertrophy in
insulin-resistant mice. Mice with cardiac GLUT4 deletion (GLUT4-knockout), superimposed on global GLUT4 suppression (GLUT4-knockdown) were administered
tempol for 4 weeks. Age-matched GLUT4-knockdown littermates were used as controls (14 mice/group). GLUT4-knockout mice exhibited marked
cardiac hypertrophy: heart to
body weight ratio was increased 61+/-7% and expression of the hypertrophic genes
beta-myosin heavy chain and
B-type natriuretic peptide (BNP) were elevated 5.5+/-0.7- and 6.2+/-1.5-fold relative to control, respectively. Pro-fibrotic pro-
collagen III expression was also higher (3.8+/-0.7-fold) in the GLUT4-knockout myocardium (all p<0.001). Both gp91(
phox) and Nox1 subunits of
NADPH oxidase were also upregulated, 4.9+/-1.2- and 9.3+/-2.8-fold (both p<0.01).
Tempol treatment significantly attenuated all of these abnormalities in GLUT4-knockout mice. Heart to
body weight ratio was decreased, as was fold expression of
beta-myosin heavy chain (to 3.8+/-0.8), BNP (to 2.5+/-0.5), pro-
collagen III (to 1.9+/-0.4), gp91(
phox) (to 0.9+/-0.3) and Nox1 (to 2.3+/-0.1, all p<0.05 versus untreated GLUT4-knockout mice). In addition,
tempol upregulated ventricular expression of both
thioredoxin-2 (confirming an
antioxidant action) and
glycogen synthase kinase-3beta (GSK-3beta).
Tempol did not elicit any other significant changes in control mice. Cardiac
superoxide generation, however, was not altered by GLUT4-knockout or
tempol. In conclusion,
tempol treatment reduced morphological and molecular evidence of
cardiac hypertrophy in the GLUT4-knockout
insulin-resistant mouse in vivo, even at doses insufficient to lower cardiac
superoxide. Parallel reductions in pro-
collagen III and
NADPH oxidase have important implications for our understanding of the molecular basis of
cardiac hypertrophy in the setting of
insulin resistance.
Antioxidants may offer new alternatives in this disorder.