Regulation of shear-induced nuclear translocation of the Nrf2 transcription factor in endothelial cells

Exposure of human umbilical vein endothelial cells (HUVECs) to laminar shear stress (12 dyne/cm2) induced Nrf2 nuclear translocation, which was inhibited by a phosphatidylinositol 3-kinase (PI3K) inhibitor, a protein kinase C (PKC) inhibitor, and an antioxidant agent N-acetyl cysteine (NAC), but not by other protein kinase inhibitors. Therefore, PI3K, PKC, and ROS are involved in the signaling pathway that leads to the shear-induced nuclear translocation of Nrf2. We also found that shear stress increased the ARE-binding activity of Nrf2 and the downstream expression of HO-1.Our data suggest that the atheroprotective effect of laminar flow is partially attributed to Nrf2 activation which results in ARE-mediated gene transcriptions, such as HO-1 expression, that are beneficial to the cardiovascular system.Vascular endothelial cells (ECs) are in direct contact with blood flow and are constantly exposed to blood flow-generated shear stresses. Accumulated data in the literature reveal that laminar shear stress is beneficial for the endothelium [1]. Numerous studies and accumulating microarray data [2-5] indicate that physiological shear stresses produce antioxidant [6], antiapoptotic [7], anti-inflammatory [8], and antiproliferative effects [9,10]. Investigations from our laboratories and others have shown that shear stress inhibits serum-, cytokine-, and hydrogen peroxide-induced responses [11-14]. Shear stresses also initiate cascades of events that are essential for endothelial function. For example, shear stress can stimulate phosphatidylinositol 3-kinase (PI3K) activity [15] which is required for Akt phosphorylation; this helps prevent endothelial apoptosis [7] and contributes to endothelial nitric oxide synthase (eNOS) activation and subsequent nitric oxide (NO) production [16,17]. NO acts as a vasodilator and exerts atheroprotective effects on the endothelium by inhibiting many atherosclerosis-prone events [18-21]. Moreover, a number of antioxidant genes, such as