simvastatin re-couples dysfunctional endothelial nitric oxide synthase in experimental subarachnoid hemorrhage辛伐他汀减少失调内皮一氧化氮合酶在实验性蛛网膜下腔出血.pdfVIP

Simvastatin Re-Couples Dysfunctional Endothelial Nitric Oxide Synthase in Experimental Subarachnoid Hemorrhage Mohammed Sabri1,2,3, Jinglu Ai1,2,3, Philip A. Marsden4,5, R. Loch Macdonald 1,2,3* 1 Division of Neurosurgery, St. Michael’s Hospital, Toronto, Ontario, Canada, 2 Labatt Family Centre of Excellence in Brain Injury and Trauma Research, Keenan Research Centre, Li Ka Shing Knowledge Institute of St. Michael’s Hospital, Toronto, Ontario, Canada, 3 Department of Surgery, University of Toronto, Toronto, Ontario, Canada, 4 Renal Division, Keenan Research Centre, Li Ka Shing Knowledge Institute of St. Michael’s Hospital, Toronto, Ontario, Canada, 5 Department of Medicine, University of Toronto, Toronto, Ontario, Canada Abstract Reduced endothelial nitric oxide synthase (eNOS) function has been linked to secondary complications of subarachnoid hemorrhage (SAH). We previously found that there is increased eNOS function after SAH but that it is uncoupled, leading to secondary complications such as vasospasm, microthromboembolism and neuronal apoptosis. Here we test the hypothesis that recoupling eNOS with simvastatin can prevent these complications. SAH was created in mice that were treated with vehicle or simvastatin starting 2 weeks before or 30 minutes after SAH. SAH increased phosphorylated eNOS which was prevented by pre- or post-treatment with simvastatin. Simvastatin pre-treatment also prevented the increase in eNOS monomer formation that was associated with SAH, decreased superoxide anion radical production and increased NO. These changes were associated with decreased vasospasm, microthromboemboli and neuronal injury. The data suggest that simvastatin re-couples eNOS after SAH, leading to decreased