Glucosamine increases vascular contraction through activation of RhoA/Rho kinase pathway in isolated rat aorta

Kim, Do-Hyung; Seok, Young Mi; Kim, In Kyeom; Lee, Inkyu; Jeong, Seong Yun; Jeoung, Nam Ho

doi:10.5483/bmbrep.2011.44.6.415

Cited by 18 publications

(13 citation statements)

References 31 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Increased hexosamine pathway flux can result in modification of proteins (such as transcription factors) by N-acetylglucosamine and lead to pathological changes in gene expression [11]. Also the activity of RhoA, a small GTPase involved in vascular contraction, has been described to be increased by glucosamine treatment, most probably via O-GlcNAcylation [12]. Finally, fructosamine, which is generated through non-enzymatic glycation when glucose reacts with the amino group of proteins, has been found to be increased in diabetes and conditions or complications associated with diabetes (e.g., cardiovascular complications, hypertension and sleep apnea) [13]–[16].…”

Section: Discussionmentioning

confidence: 99%

A New Metabolomic Signature in Type-2 Diabetes Mellitus and Its Pathophysiology

et al. 2014

View full text Add to dashboard Cite

ObjectiveThe objective of the current study was to find a metabolic signature associated with the early manifestations of type-2 diabetes mellitus.Research Design and MethodModern metabolic profiling technology (MxP™ Broad Profiling) was applied to find early alterations in the plasma metabolome of type-2 diabetic patients. The results were validated in an independent study. Eicosanoid and single inon monitoring analysis (MxP™ Eicosanoid and MxP™ SIM analysis) were performed in subsets of samples.ResultsA metabolic signature including significantly increased levels of glyoxylate as a potential novel marker for early detection of type-2 diabetes mellitus was identified in an initial study (Study1). The signature was significantly altered in fasted diabetic and pre-diabetic subjects and in non-fasted subjects up to three years prior to the diagnosis of type-2 diabetes; most alterations were also consistently found in an independent patient group (Study 2). In Study 2 diabetic and most control subjects suffered from heart failure. In Study 1 a subgroup of diabetic subjects, with a history of use of anti-hypertensive medication further showed a more pronounced increase of glyoxylate levels, compared to a non-diabetic control group when tested in a hyperglycemic state. In the context of a prior history of anti-hypertensive medication, alterations in hexosamine and eicosanoid levels were also found.ConclusionA metabolic signature including glyoxylate was associated with type-2 diabetes mellitus, independent of the fasting status and of occurrence of another major disease. The same signature was also found to be associated with pre-diabetic subjects. Glyoxylate levels further showed a specifically strong increase in a subgroup of diabetic subjects. It could represent a new marker for the detection of medical subgroups of diabetic subjects.

show abstract

Section: Discussionmentioning

confidence: 99%

A New Metabolomic Signature in Type-2 Diabetes Mellitus and Its Pathophysiology

et al. 2014

View full text Add to dashboard Cite

show abstract

“…Scattered reports of cellular efficacy led us to investigate one of these compounds more closely. The compound was shown to operate by an interesting covalent mechanism of action, but proved too reactive to use as a selective OGT inhibitor in cells 10, 16, 32, 33 . Therefore, we reexamined the screening data to identify scaffolds amenable to optimization and a quinolinone-6-sulfonamide (Q6S) class of compounds appeared promising.…”

mentioning

confidence: 99%

A Small Molecule That Inhibits OGT Activity in Cells

et al. 2015

View full text Add to dashboard Cite

O-GlcNAc transferase (OGT) is an essential mammalian enzyme that regulates numerous cellular processes through the attachment of O-linked N-acetylglucosamine (O-GlcNAc) residues to nuclear and cytoplasmic proteins. Its targets include kinases, phosphatases, transcription factors, histones, and many other intracellular proteins. The biology of O-GlcNAc modification is still not well understood and cell-permeable inhibitors of OGT are needed both as research tools and for validating OGT as a therapeutic target. Here we report a small molecule OGT inhibitor, OSMI-1, developed from a high-throughput screening hit. It is cell-permeable and inhibits protein O-GlcNAcylation in several mammalian cell lines without qualitatively altering cell surface N- or O-linked glycans. The development of this molecule validates high-throughput screening approaches for the discovery of glycosyltransferase inhibitors, and further optimization of this scaffold may lead to yet more potent OGT inhibitors useful for studying OGT in animal models.

show abstract

“…Endothelin-1-induced vasoconstriction was found to be O-GlcNAc-dependent, and the RhoA/Rho kinase pathway was a potential downstream mediator of O-GlcNAc signaling in the vasculature (60). Similarly, Kim et al (61) reported that glucosamine augmented vessel contraction in endothelium-denuded aortic rings, which was prevented by inhibition of OGT. Overall, these studies suggest that increased vascular O-GlcNAc levels may contribute to vascular dysfunction that occurs with hypertension.…”

Section: O-glcnacylation and Vascular Functionmentioning

confidence: 90%

Protein O-GlcNAcylation and Cardiovascular (Patho)physiology

Marsh

Collins

Chatham

2014

Journal of Biological Chemistry

View full text Add to dashboard Cite

Our understanding of the role of protein O-GlcNAcylation in the regulation of the cardiovascular system has increased rapidly in recent years. Studies have linked increased O-GlcNAc levels to glucose toxicity and diabetic complications; conversely, acute activation of O-GlcNAcylation has been shown to be cardioprotective. However, it is also increasingly evident that O-GlcNAc turnover plays a central role in the delicate regulation of the cardiovascular system. Therefore, the goals of this minireview are to summarize our current understanding of how changes in O-GlcNAcylation influence cardiovascular pathophysiology and to highlight the evidence that O-GlcNAc cycling is critical for normal function of the cardiovascular system.The O-linked attachment of ␤-N-acetylglucosamine (O-GlcNAc) to serine/threonine residues of proteins is a dynamic, transient, and reversible process that is an essential, metabolically regulated, signal transduction mediator in all cells (1). O-GlcNAc transferase (OGT) 3 catalyzes O-GlcNAc formation, utilizing UDP-GlcNAc as the substrate. UDPGlcNAc is the end product of the hexosamine biosynthesis pathway (HBP), which is regulated primarily by L-glutamine:Dfructose-6-phosphate amidotransferase (GFAT). GFAT catalyzes the formation of glucosamine 6-phosphate from fructose 6-phosphate. It has been estimated that 2-5% of glucose entering glycolysis is diverted through GFAT, thereby contributing to UDP-GlcNAc and O-GlcNAc synthesis (2); however, quantitative analysis of glucose flux via the HBP in the heart has yet to be performed. Although glucose availability is an important factor in O-GlcNAc synthesis, glutamine is critical as the amine donor for glucosamine 6-phosphate, whereas fatty acid metabolism is likely the primary source for the acetyl moiety. Thus, multiple nutrients contribute to both UDP-GlcNAc and protein O-GlcNAc synthesis. In addition to its synthesis, the levels of protein O-GlcNAc are also regulated by the activity of ␤-Nacetylhexosaminidase (O-GlcNAcase (OGA)), which catalyzes removal of this post-translational modification.A little over a decade following the identification of O-GlcNAc protein modification by Torres and Hart (3), the small heat shock protein ␣B-crystallin was shown to be an O-GlcNAc target in rat heart (4). Using vascular smooth muscle cells, Han and Kudlow (5) demonstrated in 1997 that O-GlcNAcylation of the transcription factor Sp1 modulated its susceptibility to proteasomal degradation, concluding that this may provide a link between nutritional status and transcriptional regulation. In the same year, reported that OGT activity was significantly higher in rat heart compared with liver, fat, and other types of striated muscle; they also hypothesized that O-GlcNAcylation could be involved in mediating glucose toxicity in insulin-responsive tissues. To our knowledge, these were the first reports of O-GlcNAcylated proteins in cardiac or vascular tissues, as well as the first to suggest that protein O-GlcNAcylation may contribute to the adverse effects of i...

show abstract

Glucosamine increases vascular contraction through activation of RhoA/Rho kinase pathway in isolated rat aorta

Cited by 18 publications

References 31 publications

A New Metabolomic Signature in Type-2 Diabetes Mellitus and Its Pathophysiology

A New Metabolomic Signature in Type-2 Diabetes Mellitus and Its Pathophysiology

A Small Molecule That Inhibits OGT Activity in Cells

Protein O-GlcNAcylation and Cardiovascular (Patho)physiology

Contact Info

Product

Resources

About