Temporal regulation of protein O‐GlcNAc levels during pressure‐overload cardiac hypertrophy
Abstract 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 specula...
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| Format: | Article |
| Language: | English |
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Wiley
2021-08-01
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| Series: | Physiological Reports |
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| Online Access: | https://doi.org/10.14814/phy2.14965 |
| _version_ | 1818920919931813888 |
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| author | Wei Zhong Zhu Dolena Ledee Aaron K. Olson |
| author_facet | Wei Zhong Zhu Dolena Ledee Aaron K. Olson |
| author_sort | Wei Zhong Zhu |
| collection | DOAJ |
| description | Abstract 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. |
| first_indexed | 2024-12-20T01:29:24Z |
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| id | doaj.art-7d5a8ff38b284bb7ac320dabff805568 |
| institution | Directory Open Access Journal |
| issn | 2051-817X |
| language | English |
| last_indexed | 2024-12-20T01:29:24Z |
| publishDate | 2021-08-01 |
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| series | Physiological Reports |
| spelling | doaj.art-7d5a8ff38b284bb7ac320dabff8055682022-12-21T19:58:09ZengWileyPhysiological Reports2051-817X2021-08-01915n/an/a10.14814/phy2.14965Temporal regulation of protein O‐GlcNAc levels during pressure‐overload cardiac hypertrophyWei Zhong Zhu0Dolena Ledee1Aaron K. Olson2Seattle Children’s Research Institute Seattle WA USASeattle Children’s Research Institute Seattle WA USASeattle Children’s Research Institute Seattle WA USAAbstract 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.https://doi.org/10.14814/phy2.14965Cardiac hypertrophyGFATglucose metabolismhexosamine biosynthesis pathwayO‐GlcNAcpressure‐overload hypertrophy |
| spellingShingle | Wei Zhong Zhu Dolena Ledee Aaron K. Olson Temporal regulation of protein O‐GlcNAc levels during pressure‐overload cardiac hypertrophy Physiological Reports Cardiac hypertrophy GFAT glucose metabolism hexosamine biosynthesis pathway O‐GlcNAc pressure‐overload hypertrophy |
| title | Temporal regulation of protein O‐GlcNAc levels during pressure‐overload cardiac hypertrophy |
| title_full | Temporal regulation of protein O‐GlcNAc levels during pressure‐overload cardiac hypertrophy |
| title_fullStr | Temporal regulation of protein O‐GlcNAc levels during pressure‐overload cardiac hypertrophy |
| title_full_unstemmed | Temporal regulation of protein O‐GlcNAc levels during pressure‐overload cardiac hypertrophy |
| title_short | Temporal regulation of protein O‐GlcNAc levels during pressure‐overload cardiac hypertrophy |
| title_sort | temporal regulation of protein o glcnac levels during pressure overload cardiac hypertrophy |
| topic | Cardiac hypertrophy GFAT glucose metabolism hexosamine biosynthesis pathway O‐GlcNAc pressure‐overload hypertrophy |
| url | https://doi.org/10.14814/phy2.14965 |
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