Activation of the hexosamine biosynthesis pathway and protein O-GlcNAcylation modulate hypertrophic and cell signaling pathways in cardiomyocytes from diabetic mice

Susan A Marsh; Louis J Dell'Italia; John C Chatham

doi:10.1007/s00726-010-0699-8

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Activation of the hexosamine biosynthesis pathway and protein O-GlcNAcylation modulate hypertrophic and cell signaling pathways in cardiomyocytes from diabetic mice

Journal article

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Peer reviewed

Activation of the hexosamine biosynthesis pathway and protein O-GlcNAcylation modulate hypertrophic and cell signaling pathways in cardiomyocytes from diabetic mice

Susan A Marsh, Louis J Dell'Italia and John C Chatham

Amino acids, Vol.40(3), pp.819-828

03/2011

DOI: https://doi.org/10.1007/s00726-010-0699-8

Handle:

https://hdl.handle.net/2376/105521

PMCID: PMC3025273

PMID: 20676904

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Abstract

Gene Expression

Signal Transduction

Diabetes Mellitus, Type 2 - genetics

Humans

Mice, Inbred C57BL

Cells, Cultured

Biosynthetic Pathways

Glycosylation

Diabetes Mellitus, Type 2 - metabolism

Acetylglucosamine - metabolism

Myocytes, Cardiac - pathology

Animals

Proteins - metabolism

Myocytes, Cardiac - metabolism

Mice

Diabetes Mellitus, Type 2 - pathology

Hexosamines - biosynthesis

Hypertrophy

Patients with diabetes have a much greater risk of developing heart failure than non-diabetic patients, particularly in response to an additional hemodynamic stress such as hypertension or infarction. Previous studies have shown that increased glucose metabolism via the hexosamine biosynthesis pathway (HBP) and associated increase in O-linked-β-N-acetylglucosamine (O-GlcNAc) levels on proteins contributed to the adverse effects of diabetes on the heart. Therefore, in this study we tested the hypothesis that diabetes leads to impaired cardiomyocyte hypertrophic and cell signaling pathways due to increased HBP flux and O-GlcNAc modification on proteins. Cardiomyocytes isolated from type 2 diabetic db/db mice and non-diabetic controls were treated with 1 μM ANG angiotensin II (ANG) and 10 μM phenylephrine (PE) for 24 h. Activation of hypertrophic and cell signaling pathways was determined by assessing protein expression levels of atrial natriuretic peptide (ANP), α-sarcomeric actin, p53, Bax and Bcl-2 and phosphorylation of p38, ERK and Akt. ANG II and PE significantly increased levels of ANP and α-actin and phosphorylation of p38 and ERK in the non-diabetic but not in the diabetic group; phosphorylation of Akt was unchanged irrespective of group or treatment. Constitutive Bcl-2 levels were lower in diabetic hearts, while there was no difference in p53 and Bax. Activation of the HBP and increased protein O-GlcNAcylation in non-diabetic cardiomyocytes exhibited a significantly decreased hypertrophic signaling response to ANG or PE compared to control cells. Inhibition of the HBP partially restored the hypertrophic signaling response of diabetic cardiomyocytes. These results suggest that activation of the HBP and protein O-GlcNAcylation modulates hypertrophic and cell signaling pathways in type 2 diabetes.

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Title: Activation of the hexosamine biosynthesis pathway and protein O-GlcNAcylation modulate hypertrophic and cell signaling pathways in cardiomyocytes from diabetic mice
Creators: Susan A Marsh - Division of Cardiovascular Disease, Department of Medicine, University of Alabama at Birmingham, Birmingham, AL 35294-0007, USA
Louis J Dell'Italia
John C Chatham
Publication Details: Amino acids, Vol.40(3), pp.819-828
Academic Unit: Pharmaceutical Sciences, Department of
Publisher: Austria
Grant note: R01 HL101192 / NHLBI NIH HHS P50 HL077100 / NHLBI NIH HHS R01 HL067464 / NHLBI NIH HHS HL-101192 / NHLBI NIH HHS R01 HL067464-06 / NHLBI NIH HHS P50 HL077100-04 / NHLBI NIH HHS HL-77100 / NHLBI NIH HHS HL-67464 / NHLBI NIH HHS
Identifiers: 99900546753201842
Language: English
Resource Type: Journal article