Abstract 3728: Angiotensin II is Involved in Hepatic Steatosis and Cardiovascular Injury in Obesity and Diabetes, via the Activation of Apoptosis Signal-Regulating Kinase 1
Objectives: This work was undertaken to investigate the role of angiotensin II (AII) in hepatic steatosis and cardiovascular injury in high fat diet (HFD)-induced obese mice.
Methods and Results:
To examine whether AT1 receptor blocker (ARB) can prevent HFD-induced hepatic steatosis and cardiovascular injury, we orally administrated olmesartan (5 mg/kg/day) to HFD-fed mice for 16 weeks. HFD treatment in mice caused impaired vascular endothelium-dependent relaxation to acethylcholine and marked cardiac macrophage infiltration and interstitial fibrosis, and olmesartan significantly prevented these cardiovascular injury in HFD-fed mice. Olmesartan also significantly prevented hepatic steatosis and fibrosis in diabetic mice. Next, we examined the molecular mechanism underlying these beneficial effects of olmesartan, focusing on the role of reactive oxygen species (ROS). HFD treatment of mice markedly increased superoxide, NADPH oxidase activity and phosphorylation of apoptosis signal-regulating kinase 1 (ASK1), a MAPKKK activated by ROS, in hepatic, cardiac and vascular tissues. Moreover, HFD caused vascular eNOS uncoupling as indicated by the increased eNOS dimer disruption in low-temperature SDS-PAGE. Olmesartan treatment significantly decreased NADPH oxidase-derived superoxide and ASK1 phosphorylation in all the above mentioned tissues, and prevented vascular eNOS uncoupling. Therefore, ASK1 might be involved in protective effect of ARB against HFD-induced hepatic steatosis and cardiovascular injury.
ASK1 −/− mice and wild type (WT) mice were compared, regarding the effects of HFD. Comparison between ASK1−/− mice and WT mice showed that ASK1 deficiency attenuated cardiac inflammation and fibrosis, and vascular endothelial dysfunction and remodeling induced by obesity/diabetes. The amelioration of vascular endothelial impairment by ASK1 deficiency was attributed to the prevention of eNOS dimer disruption. ASK1 deficiency also significantly lessened hepatic steatosis in diabetic mice.
Conclusion: AII is involved in metabolic dysfunction and cardiovascular complications caused by HFD, by ASK1 activation. ASK1 plays the key role in HFD-induced metabolic dysfunction and cardiovascular complications.