This is important because both the endothelium and the Rho-kinase pathway play a central role in the regulation of vascular tone and also modulate diverse vascular responses, including wall remodeling and inflammation-related processes, all important in hypertension-associated vascular disease

This is important because both the endothelium and the Rho-kinase pathway play a central role in the regulation of vascular tone and also modulate diverse vascular responses, including wall remodeling and inflammation-related processes, all important in hypertension-associated vascular disease. == O-GlcNAc and ET-1-Mediated Vascular Effects == ET-1 production is usually increased in the vasculature of salt-sensitive forms of hypertension, including DOCA-salt hypertensive rats. kinase) are also targets forO-GlcNAcylation. Recent experimental evidence suggests that ET-1 directly activatesO-GlcNAcylation, and this posttranslational modification mediates important vascular effects of the peptide. This review focuses on ET-1-activated signaling pathways that can be modified byO-GlcNAcylation. A brief description of theO-GlcNAcylation biology is usually presented, and its role on vascular function is usually addressed. ET-1-inducedO-GlcNAcylation and its implications for vascular function are then discussed. Finally, the interplay betweenO-GlcNAcylation andO-phosphorylation is usually resolved. Keywords:endothelin receptor, vascular signaling,O-GlcNAc modification glycosylation is the site-specific enzymatic addition of saccharides to Dapson proteins and lipids. There are many types of glycosylation, but great Dapson interest has been directed toO-GlcNAcylation, or glycosylation withO-linked -N-acetylglucosamine or -O-linked 2-acetamido-2-deoxy-d-glycopyranose (54,55,169). In this unusual form of protein glycosylation, a single sugar [-N-acetylglucosamine (O-GlcNAc)] is usually added to serine and threonine residues of nuclear or cytoplasmic proteins (54,55,169). Considering that almost every functional class of proteins is subject toO-GlcNAcylation (55,177), this specific posttranslational modification has been implicated in several biological functions, including transcription or translation, stress responses, and energy metabolism. Proteins with an important role in vascular function are also targets forO-GlcNAcylation. Examples include endothelial nitric oxide (NO) synthase (eNOS), sarcoplasmic reticulum calcium (Ca2+)-ATPase (SERCA), phospholipase C (PLC), protein kinase C (PKC), phosphatidylinositol 3-kinase (PI3K), and proteins involved in cytoskeleton regulation and microtubule assembly (22,55,177), indicating that this posttranslational modification may play an important role in vascular (dys)function. Accordingly, augmented levels ofO-GlcNAc in the vasculature increases vascular reactivity to constrictor stimuli (91) and decreases endothelium-dependent vasodilation, which is usually associated withO-GlcNAc modification of eNOS (90,91). In addition, augmented levels ofO-GlcNAc have been found in the vasculature of mineralocorticoid hypertensive animals (93) and may play a role around the vascular abnormalities in salt-sensitive hypertension. On the other hand, Xing et al. (173) have shown thatO-GlcNAc modification of proteins may inhibit acute inflammatory and neointimal responses to endoluminal arterial injury, suggesting thatO-GlcNAcylation may display cardioprotective and anti-inflammatory effects in arteries subjected to acute endoluminal injury. It is well recognized that this endothelin (ET) system plays an important role in vascular dysfunction in many diseases, including arterial hypertension, stroke/cerebral vasospasm, renal failure, and diabetes. Dapson ET-1 binds the ETAand ETBreceptors and activates intracellular signaling pathways that result in rapid and long-term alterations in cell activity and function. In the vasculature, ET-1 induces vasoconstriction through its Dapson binding to the ETAand ETBreceptors from vascular easy muscle cell, and also activates transcriptional factors responsible for the coordinated increase in many cytokines and enzymes, thus enhancing inflammation, oxidative stress, fibrosis, and tissue damage (65,139,140,155). All of these are important in the regulation of vascular tone, vascular injury, and remodeling. ET receptor activation leads to diverse cellular responses through conversation with pertussis toxin-sensitive and -insensitive pathways, indicating that multiple G proteins are involved (60,61,109). Consequently, ET-1 binding to ET receptors on vascular easy muscle cells stimulates signaling cascades that include PKC, mitogen-activated protein kinases (MAPKs), and RhoA/Rho kinase with subsequent effects on intracellular Ca2+and calmodulin-dependent pathways as well as on Ca2+-impartial pathways (12,16,47) (Fig. 1). Most recently, it has been shown that ET-1 also producesO-GlcNAcylation of vascular proteins, and this modification mediates some of the vascular effects produced by the peptide (92). Rabbit Polyclonal to IL4 == Fig. 1. == Signaling pathways activated by endothelin-1 (ET-1) in vascular easy muscle cells (VSMC). Recognition of ET-1 by the ETAand ETBreceptors in VSMCs activates intracellular signaling pathways and cascades that result in rapid alterations in cell activity and function and initiates transcriptional responses. Highlighted in the physique is the activation of PKC, MAPKs, and RhoA/Rho kinase signaling pathways, with subsequent effects on intracellular Ca2+and calmodulin-dependent pathways as well as Ca2+-impartial pathways. IP3, inositol 1,4,5-trisphosphate; SRC, sarcoma; P, phosphorylation; Pyk2, proline-rich tyrosine kinase-2; GDI, GDP dissociation inhibitors; MEK, MAPK kinase; MLC, myosin light chain; IP3R, IP3, repector; SR, sarcoplasmic reticulum. In this mini-review we will discuss how this relatively novel posttranslational modification of proteins,O-GlcNAcylation, may impact vascular function.