Shear stress imposed by blood flow is crucial for maintaining vascular homeostasis. We examined the role of shear stress in regulating SIRT1, an NAD + -dependent deacetylase, and its functional relevance in vitro and in vivo. The application of laminar flow increased SIRT1 level and activity, mitochondrial biogenesis, and expression of SIRT1-regulated genes in cultured endothelial cells (ECs). When the effects of different flow patterns were compared in vitro, SIRT1 level was significantly higher in ECs exposed to physiologically relevant pulsatile flow than pathophysiologically relevant oscillatory flow. These results are in concert with the finding that SIRT1 level was higher in the mouse thoracic aorta exposed to atheroprotective flow than in the aortic arch under atheroprone flow. Because laminar shear stress activates AMP-activated protein kinase (AMPK), with subsequent phosphorylation of endothelial nitric oxide synthase (eNOS) at Ser-633 and Ser-1177, we studied the interplay of AMPK and SIRT1 on eNOS. Laminar flow increased SIRT1-eNOS association and eNOS deacetylation. By using the AMPK inhibitor and eNOS Ser-633 and -1177 mutants, we demonstrated that AMPK phosphorylation of eNOS is needed to prime SIRT1-induced deacetylation of eNOS to enhance NO production. To verify this finding in vivo, we compared the acetylation status of eNOS in thoracic aortas from AMPKα2 −/− mice and their AMPKα2 +/+ littermates. Our finding that AMPKα2 −/− mice had a higher eNOS acetylation indicates that AMPK phosphorylation of eNOS is required for the SIRT1 deacetylation of eNOS. These results suggest that atheroprotective flow, via AMPK and SIRT1, increases NO bioavailability in endothelium.NAD + -dependent deacetylase | AMP-activated protein kinase | endothelial nitric oxide synthase | NO bioavailability | endothelial homeostasis S IRT1, also known as Sirtuin 1 (silent mating type information regulation 2 homolog), contributes to the caloric restriction (CR)-induced increase in lifespan in species ranging from yeast to mammals (1-3). Functioning as an NAD + -dependent class III histone deacetylase (4), SIRT1 deacetylates multiple targets in mammalian cells, including tumor suppressor p53, Forkhead box O1 and 3 (FOXO1 and FOXO3), peroxisome proliferator-activated receptor γ (PPARγ) coactivator 1α (PGC-1α), liver X receptor, and hypoxia-inducible factor 2α (5-14). By regulating these molecules involved in cell survival and in carbohydrate and lipid metabolism, SIRT1 functions as a master regulator of stress response and energy homeostasis.SIRT1 is also an important modulator in cardiovascular functions in health and disease. The beneficial effects of SIRT1 on endothelial cell (EC) biology were demonstrated by several previous studies. Ota et al. (15) showed that overexpression of SIRT1 prevented oxidative stress-induced endothelial senescence, whereas inhibition of SIRT1 led to premature senescence. Treatment of human coronary arterial ECs with resveratrol (RSV), an SIRT1 activator, increased the mitochondrial mass and ke...

In addition, data from tumor xenografts and human cancer specimens indicate that AGO1-mediated translational desuppression of VEGF may be associated with tumor angiogenesis and poor prognosis. These findings provide evidence for an angiogenic pathway involving HRMs that target AGO1 and suggest that this pathway may be a suitable target for anti-or proangiogenesis strategies.

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Atheroprotective flow exerts antioxidative and anti-inflammatory effects on vascular endothelial cells (ECs), in part through the induction of Sirtuin 1 (SIRT1), a class III histone deacetylase. The role of Ca 2+ /calmodulin-dependent protein kinase kinase (CaMKK)β in flow induction of SIRT1 both in vitro and in vivo was investigated. Pulsatile shear stress mimicking atheroprotective flow increased the level of SIRT1 in cultured ECs by enhancing its stability, and this effect was abolished by inhibition or knockdown of CaMKKβ. Flowenhanced SIRT1 stability was primarily mediated by CaMKKβ phosphorylation of SIRT1 at Ser-27 and Ser-47, as evidenced by in vitro kinase assay, mass spectrometry, and experiments using loss-or gain-of-function SIRT1 mutants. Flow-induced CaMKKβ phosphorylation of SIRT1 Ser-27 and Ser-47 increased antioxidative and antiinflammatory capacities. Ablation of CaMKKβ or SIRT1 in mice with an apolipoprotein E-null background showed increased atherosclerosis both in athero-prone and in athero-protective areas. The results suggest that the CaMKKβ-SIRT1 axis in ECs is mechanosensitive, antioxidative, and anti-inflammatory.

Summary Diabetic peripheral neuropathy (DPN) is one of the most common diabetic chronic complications. The aim of this study was to clarify whether grape seed proanthocyanidins extracts (GSPE) are therapeutic agents against DPN. In this study, we used streptozocin (STZ) to induce diabetic rats. GSPEs (250 mg/kg body weight/d) were administrated to diabetic rats for 24 wk. Motor nerve conductive velocity (MNCV) and mechanical hyperalgesia were determined in the rats. Serum glucose, glycated hemoglobin, advanced glycation end products (AGEs), and tissue malondialdehyde (MDA) and superoxide dismutase (SOD) were determined. Light and electron microscopy were used to observe the changes of nerval ultrastructure.GSPE significantly increased the MNCV, mechanical hyperalgesia and SOD of diabetic rats ( p Ͻ 0.05) and reduced the AGEs and MDA of diabetic rats ( p Ͻ 0.05). After being treated by GSPE, the severe segmental demyelination was decreased and Schwann cells were improved. In conclusion, GSPE plays an important role against DPN. With the decreasing of AGEs and MDA, it can ameliorate oxidation-associated nerval damage. This study may provide a new recognition of natural medicine for the treatment of DPN.