Summary AMPK has emerged as a critical mechanism for salutary effects of polyphenols on lipid metabolic disorders in type 1 and type 2 diabetes. We demonstrate that AMPK interacts with and directly phosphorylates sterol regulatory element binding proteins (SREBP-1c and −2). Ser372 phosphorylation of SREBP-1c by AMPK is sufficient and necessary for inhibition of proteolytic processing and transcriptional activity of SREBP-1c in response to polyphenols and metformin. AMPK stimulates Ser372 phosphorylation, suppresses SREBP-1c cleavage and nuclear translocation, and represses SREBP-1c target gene expression in hepatocytes exposed to high glucose, leading to reduced lipogenesis and lipid accumulation. Hepatic activation of AMPK by the synthetic polyphenol S17834 protects against hepatic steatosis, hyperlipidemia, and accelerated atherosclerosis in diet-induced insulin resistant LDL receptor deficient mice in part through phosphorylation of SREBP-1c Ser372 and suppression of SREBP-1c and −2-dependent lipogenesis. AMPK-dependent phosphorylation of SREBP may offer novel therapeutic strategies to combat insulin resistance, dyslipidemia, and atherosclerosis.

Abstract-The focal pattern of atherosclerotic lesions in arterial vessels suggests that local blood flow patterns are important factors in atherosclerosis. Although disturbed flows in the branches and curved regions are proatherogenic, laminar flows in the straight parts are atheroprotective. Results from in vitro studies on cultured vascular endothelial cells with the use of flow channels suggest that integrins and the associated RhoA small GTPase play important roles in the mechanotransduction mechanism by which shear stress is converted to cascades of molecular signaling to modulate gene expression. By interacting dynamically with extracellular matrix proteins, the mechanosensitive integrins activate RhoA and many signaling molecules in the focal adhesions and cytoplasm. Through such mechanotransduction mechanisms, laminar shear stress upregulates genes involved in antiapoptosis, cell cycle arrest, morphological remodeling, and NO production, thus contributing to the atheroprotective effects. This review summarizes some of the recent findings relevant to these mechanotransduction mechanisms. These studies show that integrins play an important role in mechanosensing in addition to their involvement in cell attachment and migration. Key Words: shear stress Ⅲ mechanotransduction Ⅲ endothelium Ⅲ integrins Ⅲ Rho L ocated between the circulating blood and the vessel wall, vascular endothelial cells (ECs) are the primary cell type exposed to the shear stress resulting from blood flow. During the last 2 decades, the mechanotransduction mechanisms by which ECs convert shear stress stimulation to biochemical signals have been studied intensively with both in vivo and in vitro approaches. Experiments with the use of cultured ECs in flow channels, which allow the control of chemical and mechanical factors, facilitate the investigation of specific cellular responses to the applied mechanical forces. Knowledge emerging from interdisciplinary research involving vascular biology and bioengineering has demonstrated that mechanical sensing of shear stress can occur on both the abluminal and luminal sides of the EC membrane.Integrins are membrane-associated glycoproteins composed of ␣ and ␤ subunits. To date, 18 ␣ and 8 ␤ subunits have been identified in mammalian cells. Each subunit has a large extracellular domain, a transmembrane spanning region, and a short cytoplasmic domain (see review 1 ). The extracellular domain binds directly to extracellular matrix (ECM) proteins, such as vitronectin, fibronectin, laminin, and collagen. The cytoplasmic domains of both the ␣ and ␤ subunits interact with signaling molecules and cytoskeletal proteins to regulate cellular events, such as signal transduction, cytoskeletal organization, and cell motility via the modulation of integrin affinity and/or avidity. Affinity modulation involves changes in integrin heterodimer conformation that lead to an increased binding effectiveness for their ligands, whereas Integrin activation is directly associated with members of the Rho small GTPase famil...

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Fluid shear stress and circumferential stretch play important roles in maintaining the homeostasis of the blood vessel, and they can also be pathophysiological factors in cardiovascular diseases such as atherosclerosis and hypertension. The uses of flow channels and stretch devices as in vitro models have helped to elucidate the mechanisms of signal transduction and gene expression in cultured endothelial cells in response to shear stress, which is a function of blood flow and vascular geometry, or mechanical strain, which is a function of transmural pressure and the mechanical properties and geometry of the vessel. Shear stress has been found to increase the activities of a number of kinases to modulate the phosphorylation of many signaling proteins in endothelial cells, eg, the proteins in focal adhesion sites and the proteins in the mitogen-activated protein kinase pathways. Downstream to such signaling cascades, multiple transcription factors such as AP-1, NF-kappaB, Sp-1, and Egr-1 are activated. The actions of these transcription factors on the corresponding cis-elements result in the induction of genes encoding for vasoactivators, adhesion molecules, monocyte chemoattractants, and growth factors in endothelial cells, thus modulating vascular structure and function. Some of the effects of mechanical strain on endothelial cells are similar to those by shear stress, eg, the signaling pathways and the genes activated, but there are differences, eg, the time course of the responses. Studies on the effects of mechanical forces on signal transduction and gene expression provide insights into the molecular mechanisms by which hemodynamic factors regulate vascular physiology, and pathophysiology.