Dietary
obesity is associated with
type 2 diabetes and
cardiovascular diseases, although the underlying mechanism is unknown. This study was undertaken to elucidate the role of
angiotensin II and apoptosis signal regulating kinase-1 (ASK1) in
obesity/diabetes-associated cardiovascular complications and hepatic steatosis. Mice fed a high-fat diet were treated with
olmesartan, an
angiotensin II type 1 receptor blocker, to elucidate the role of
angiotensin II in diabetic mice. Treatment of mice fed a high-fat diet with
olmesartan markedly suppressed cardiac
inflammation and
fibrosis, as well as vascular endothelial dysfunction and remodeling, induced by
obesity/diabetes. Moreover,
olmesartan suppressed the disruption of the vascular endothelial
NO synthase dimer in diabetic mice.
Olmesartan also significantly prevented hepatic steatosis and
fibrosis in diabetic mice. These beneficial effects of
olmesartan on diabetic mice were associated with the attenuation of ASK1 activation in these mice. ASK1-deficient mice and wild-type mice were compared, regarding the effects of a high-fat diet. A comparison between ASK1-deficient and wild-type mice showed that ASK1 deficiency attenuated cardiac
inflammation and
fibrosis, as well as vascular endothelial dysfunction and remodeling induced by
obesity/diabetes. The amelioration of vascular endothelial impairment by ASK1 deficiency was attributed to the prevention of endothelial
NO synthase dimer disruption. ASK1 deficiency also significantly lessened hepatic steatosis in diabetic mice. In conclusion, our work provided the evidence that ASK1 is significantly activated in diet-induced diabetic mice and contributes to
cardiovascular diseases and hepatic steatosis in diabetic mice. Moreover, the beneficial effects of
angiotensin II inhibition on dietary diabetic mice seem to be mediated by the inhibition of ASK1 activation.