Simvastatin Reduces Endothelial NOS: Caveolin-1 Ratio but not the Phosphorylation Status of eNOS In Vivo

In vivo evidence for the pleiotropic effects of simvastatin on the nitric oxide synthase system is limited.Aims: To determine if simvastatin can affect the endothelial nitric oxide synthase cascade.Methods: New Zealand white rabbits (n=15) were divided: Group 1 (control) was fed a normal rabbit diet; Group 2 (MC) received a normal rabbit diet with 1% methionine (M) plus 0.5% cholesterol (C) and 5% peanut oil (atherogenic diet); Group 3 received the same diet as the MC group plus 5 mg/kg/ day simvastatin (S) orally (MCS). After 4 weeks, the abdominal aorta was collected and analyzed.Results: Total cholesterol (TC) and total homocysteine (tHcy) were not significantly different between MCS and MC. Endothelial function was only reduced in MC (p<0.05). Although eNOS significantly increased in MC and MCS (p<0.01), simvastatin treatment significantly reduced endothelial caveolin-1 by 35% (p=0.038), causing a 2.5-fold (p=0.026) increase in the eNOS: caveolin-1 ratio. The phosphorylation of eNOS at the threonine 495 site or serine 1177 site was not affected by diet or treatment; however, a positive correlation between the two phosphorylation sites was observed (r(2)= 0.5, p=0.01).Conclusion: in vivo pleiotropic effects of statin therapy include decreasing endothelial caveolin-1. Other therapies designed to affect eNOS phosphorylation in vivo might be useful in further preventing CVD.