The Atheroprotective Mechanism of Triterpenoids from Ganoderma Tsugae in the Carotid-Artery-Ligation Mouse Model

Abstract

Atherosclerosis is a chronic inflammatory vascular disease and is prone to occur at the sites encountering blood flow turbulence Neointima formation is a distinct feature of atherosclerosis at the initial stage Triterpenoid extract from Ganoderma containing a variety of ganoderic acids and alcohols (GAs) alleviates cardiac injury in a work-overload mouse model through its anti-inflammatory and anti-oxidant activities However the protective potential of GAs against atherosclerosis was unclear We hypothesized that GAs may prevent atherosclerosis through its anti-inflammation and anti-oxidant activities We tested this hypothesis using a complete-carotid-artery-ligation mouse model to create flow turbulence and induce neointima formation We found that either subcutaneous (300 mg/kg/day) or oral (500 mg/kg/day) GAs treatment significantly inhibited neointima formation 14 days after ligation We found elevated levels of monocytes/macrophages infiltration endothelial reactive oxygen species accumulation apoptosis and proliferation in the lesion sites 14 days after ligation GAs treatment prevented the monocytes/macrophages infiltration endothelial ROS accumulation apoptosis and proliferation induced by disturbed flow The endothelial dysfunction induced by disturbed flow initiates the atherogenesis Thus we examined the arterial endothelium 3 days after surgery while there was still no structural changes being detected We found that the levels of endothelial oxidative stress monocyte chemoattractant protein-1 endothelin-1 and von Willebrand factor were up-regulated by disturbed blood flow and these inductions were blocked by subcutaneous GAs (300 mg/kg/day) treatment In addition we tested the therapeutic potential of GAs by delaying the treatment 3 days after surgery The delayed GAs treatment remained effective in preventing intimal hyperplasia demonstrating its therapeutic activities on existing vascular conditions To assess the anti-oxidant activities of GAs we treated HUVECs with H2O2 in combination with GAs for 30 min GAs successfully ameliorated the oxidative stress and prevented the cells death induced by H2O2 in HUVECs indicating that GAs protect arteries against atherosclerosis via restoring endothelial function by their anti-oxidant activities

Date of Award	2016 Aug 31
Original language	English
Supervisor	Fan-E Mo (Supervisor)