Temporal regulation of protein O ‐GlcNAc levels during pressure‐overload cardiac hypertrophy
| Autor: | Dolena R Ledee, Aaron K Olson, Wei Zhong Zhu |
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| Rok vydání: | 2021 |
| Předmět: |
Gene isoform
medicine.medical_specialty Glycosylation Physiology glucose metabolism Cardiomegaly Carbohydrate metabolism Muscle hypertrophy Mice transverse aortic constriction Downregulation and upregulation Physiology (medical) Internal medicine Pressure medicine QP1-981 Animals Glycolysis pressure‐overload hypertrophy Glycoproteins Pressure overload chemistry.chemical_classification GFAT thiamet‐g Original Articles Biosynthetic Pathways Mice Inbred C57BL Blot Cardiac hypertrophy Endocrinology Enzyme chemistry Original Article hexosamine biosynthesis pathway O‐GlcNAc Protein Processing Post-Translational |
| Zdroj: | Physiological Reports Physiological Reports, Vol 9, Iss 15, Pp n/a-n/a (2021) |
| ISSN: | 2051-817X |
| Popis: | Protein posttranslational modifications (PTMs) by O‐linked β‐N‐acetylglucosamine (O‐GlcNAc) rise during pressure‐overload hypertrophy (POH) to affect hypertrophic growth. The hexosamine biosynthesis pathway (HBP) branches from glycolysis to make the moiety for O‐GlcNAcylation. It is speculated that greater glucose utilization during POH augments HBP flux to increase O‐GlcNAc levels; however, recent results suggest glucose availability does not primarily regulate cardiac O‐GlcNAc levels. We hypothesize that induction of key enzymes augment protein O‐GlcNAc levels primarily during active myocardial hypertrophic growth and remodeling with early pressure overload. We further speculate that downregulation of protein O‐GlcNAcylation inhibits ongoing hypertrophic growth during prolonged pressure overload with established hypertrophy. We used transverse aortic constriction (TAC) to create POH in C57/Bl6 mice. Experimental groups were sham, 1‐week TAC (1wTAC) for early hypertrophy, or 6‐week TAC (6wTAC) for established hypertrophy. We used western blots to determine O‐GlcNAc regulation. To assess the effect of increased protein O‐GlcNAcylation with established hypertrophy, mice received thiamet‐g (TG) starting 4 weeks after TAC. Protein O‐GlcNAc levels were significantly elevated in 1wTAC versus Sham with a fall in 6wTAC. OGA, which removes O‐GlcNAc from proteins, fell in 1wTAC versus sham. GFAT is the rate‐limiting HBP enzyme and the isoform GFAT1 substantially rose in 1wTAC. With established hypertrophy, TG increased protein O‐GlcNAc levels but did not affect cardiac mass. In summary, protein O‐GlcNAc levels vary during POH with elevations occurring during active hypertrophic growth early after TAC. O‐GlcNAc levels appear to be regulated by changes in key enzyme levels. Increasing O‐GlcNAc levels during established hypertrophy did not restart hypertrophic growth. Protein O‐GlcNAc levels temporally vary during pressure‐overload hypertrophy (POH) with the highest levels during active hypertrophic growth early after transverse aortic constriction. While it is commonly hypothesized that O‐GlcNAc levels reflect increased glucose utilization during POH, our study confirms the importance of non‐nutrient regulation through enzymes like GFAT1 and OGA. |
| Databáze: | OpenAIRE |
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