Tatsuro Minami1, Kimio Satoh2, Masamichi Nogi2, Shun Kudo2, Satoshi Miyata2, Shin-ichi Tanaka1, Hiroaki Shimokawa3. 1. Department of Cardiovascular Medicine, Tohoku University Graduate School of Medicine, Sendai, Japan Laboratory for Pharmacology, Pharmaceuticals Research Center, Asahi Kasei Pharma Corporation, Izunokuni, Japan. 2. Department of Cardiovascular Medicine, Tohoku University Graduate School of Medicine, Sendai, Japan. 3. Department of Cardiovascular Medicine, Tohoku University Graduate School of Medicine, Sendai, Japan shimo@cardio.med.tohoku.ac.jp.
Abstract
AIMS: The pleiotropic effects of HMG-CoA reductase inhibitors (statins) independent of cholesterol-lowering effects have attracted much attention. We have recently demonstrated that the pleiotropic effects of statins are partly mediated through up-regulation of small GTP-binding protein dissociation stimulator (SmgGDS) with a resultant Rac1 degradation and reduced oxidative stress. However, it remains to be elucidated what molecular mechanisms are involved. METHODS AND RESULTS: To first determine in what tissue statins up-regulate SmgGDS expression, we examined the effects of two statins (atorvastatin 10 mg/kg per day and pravastatin 50 mg/kg per day for 1 week) on SmgGDS expression in mice in vivo. The two statins increased SmgGDS expression especially in the aorta. Atorvastatin also increased SmgGDS expression in cultured human umbilical venous endothelial cells (HUVEC) and human aortic endothelial cells, but not in human aortic vascular smooth muscle cells. Furthermore, Akt phosphorylation was transiently enhanced only in HUVEC in response to atorvastatin. Then, to examine whether Akt is involved for up-regulation of SmgGDS by statins, we knocked out Akt1 by its siRNA in HUVEC, which abolished the effects by atorvastatin to up-regulate SmgGDS. Furthermore, when we knocked down β1-integrin to elucidate the upstream molecule of Akt1, the effect of atorvastatin to up-regulate SmgGDS was abolished. Finally, we confirmed that Akt activator, SC79, significantly up-regulate SmgGDS in HUVEC. CONCLUSION: These results indicate that statins selectively up-regulate SmgGDS in endothelial cells, for which the β1-integrin/Akt1 pathway may be involved, demonstrating the novel aspects of the pleiotropic effects of statins. Published on behalf of the European Society of Cardiology. All rights reserved.
AIMS: The pleiotropic effects of HMG-CoA reductase inhibitors (statins) independent of cholesterol-lowering effects have attracted much attention. We have recently demonstrated that the pleiotropic effects of statins are partly mediated through up-regulation of small GTP-binding protein dissociation stimulator (SmgGDS) with a resultant Rac1 degradation and reduced oxidative stress. However, it remains to be elucidated what molecular mechanisms are involved. METHODS AND RESULTS: To first determine in what tissue statins up-regulate SmgGDS expression, we examined the effects of two statins (atorvastatin 10 mg/kg per day and pravastatin 50 mg/kg per day for 1 week) on SmgGDS expression in mice in vivo. The two statins increased SmgGDS expression especially in the aorta. Atorvastatin also increased SmgGDS expression in cultured human umbilical venous endothelial cells (HUVEC) and human aortic endothelial cells, but not in human aortic vascular smooth muscle cells. Furthermore, Akt phosphorylation was transiently enhanced only in HUVEC in response to atorvastatin. Then, to examine whether Akt is involved for up-regulation of SmgGDS by statins, we knocked out Akt1 by its siRNA in HUVEC, which abolished the effects by atorvastatin to up-regulate SmgGDS. Furthermore, when we knocked down β1-integrin to elucidate the upstream molecule of Akt1, the effect of atorvastatin to up-regulate SmgGDS was abolished. Finally, we confirmed that Akt activator, SC79, significantly up-regulate SmgGDS in HUVEC. CONCLUSION: These results indicate that statins selectively up-regulate SmgGDS in endothelial cells, for which the β1-integrin/Akt1 pathway may be involved, demonstrating the novel aspects of the pleiotropic effects of statins. Published on behalf of the European Society of Cardiology. All rights reserved.