O-GlcNAcylation: a novel post-translational mechanism to alter vascular cellular signaling in health and disease: focus on hypertension

Abstract

O-Linked attachment of beta-N-acetyl-glucosamine (O-GlcNAc) on serine and threonine residues of nuclear and cytoplasmic proteins is a highly dynamic posttranslational modification that plays a key role in signal transduction pathways. Preliminary data show that O-GlcNAcylation may represent a key regulatory mechanism in the vasculature, modulating contractile and relaxant responses. Proteins with an important role in vascular function, such as endothelial nitric oxide synthase, sarcoplasmic reticulum Ca(2+)-ATPase, protein kinase C, mitogen-activated protein kinases, and proteins involved in cytoskeleton regulation and microtubule assembly are targets for O-GlcNAcylation, indicating that this posttranslational modification may play an important role in vascular reactivity. Here, we will focus on a few specific pathways that contribute to vascular function and cardiovascular disease-associated vascular dysfunction, and the implications of their modification by O-GlcNAc. New chemical tools have been developed to detect and study O-GlcNAcylation, including inhibitors of O-GlcNAc enzymes, chemoenzymatic tagging methods, and quantitative proteomics strategies; these will also be briefly addressed. An exciting challenge in the future will be to better understand the cellular dynamics of this posttranslational modification, as well as the signaling pathways and mechanisms by which O-GlcNAc is regulated on specific proteins in the vasculature in health and disease.

Figure 1

The hexosamine biosynthetic pathway (HBP), including the most well-known pharmacological inhibitors of this pathway.

Figure 2

Proteins with an important role in vascular function are targets for O-GlcNAcylation indicating that this posttranslational modification may play an important role in vascular reactivity (please refer to the text for more details).

Figure 3

Myristolated alanine rich C kinases (MARCKs) are phosphorylated demonstrating PKC activity. (A) Sprague-Dawley rat aortic rings were exposed to PUGNAc [O-(2-acetamido-2-deoxy-D-glucopyranosylidene) amino-N-phenylcarbamate; 100 μM], and inhibitor of β-N-acetylglucosaminidase (OGA), or control (methanol) for 3 hours. PUGNAc stimulates MARCKs phosphorylation. B-actin is shown for normalization of protein content. (B) Model demonstrating MARCKs as a specific substrate of protein kinase C (PKC). Nonphosphorylated MARCKs (M) is associated with the cytoplasmic side of the membrane. After PKC phosphorylates MARCKs, it is released from the membrane into the cytosol, where it remains until dephosphorylated.