Chronic activation of hexosamine biosynthesis in the heart triggers pathological cardiac remodeling

Tran, Diem Hong; May, Herman I.; Li, Qinfeng; Luo, Xiang; Huang, Jian; Zhang, Guangyu; Niewold, Erica L; Wang, Xiaoding; Gillette, Thomas G.; Deng, Yingfeng; Wang, Zhao V.

doi:10.1038/s41467-020-15640-y

Cited by 66 publications

(64 citation statements)

References 57 publications

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“…We subjected wild-type C57BL/6 mice to TAC and harvested the heart 1 week later. We have shown previously that this surgical procedure leads to significant and consistent cardiac hypertrophic growth ( Tran et al, 2020 ; Wang et al, 2019 ; Zhang et al, 2019 ). Here, LDHA was augmented in the heart by TAC at protein, mRNA, and histological levels ( Figures 1I – 1L ).…”

Section: Resultsmentioning

confidence: 81%

“…Echocardiography was performed by using the Vevo 2100 High-Resolution Micro-Imaging System (VisualSonics) with a MS400C ultrasound transducer as described previously ( Tran et al, 2020 ; Wang et al, 2019 ; Zhang et al, 2019 ). The short-axis view of left ventricle at the level of the papillary muscles was captured and M-mode recordings were performed.…”

Section: Methodsmentioning

confidence: 99%

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Lactate Dehydrogenase A Governs Cardiac Hypertrophic Growth in Response to Hemodynamic Stress

Dai

May

et al. 2020

Cell Reports

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SUMMARY The heart manifests hypertrophic growth in response to high blood pressure, which may decompensate and progress to heart failure under persistent stress. Metabolic remodeling is an early event in this process. However, its role remains to be fully characterized. Here, we show that lactate dehydrogenase A (LDHA), a critical glycolytic enzyme, is elevated in the heart in response to hemodynamic stress. Cardiomyocyte-restricted deletion of LDHA leads to defective cardiac hypertrophic growth and heart failure by pressure overload. Silencing of LDHA in cultured cardiomyocytes suppresses cell growth from pro-hypertrophic stimulation in vitro, while overexpression of LDHA is sufficient to drive cardiomyocyte growth. Furthermore, we find that lactate is capable of rescuing the growth defect from LDHA knockdown. Mechanistically, lactate stabilizes NDRG3 (N-myc downregulated gene family 3) and stimulates ERK (extracellular signal-regulated kinase). Our results together suggest that the LDHA/NDRG3 axis may play a critical role in adaptive cardiomyocyte growth in response to hemodynamic stress.

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Section: Resultsmentioning

confidence: 81%

Section: Methodsmentioning

confidence: 99%

Lactate Dehydrogenase A Governs Cardiac Hypertrophic Growth in Response to Hemodynamic Stress

Dai

May

et al. 2020

Cell Reports

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“…Protein O‐GlcNAcylation affects many cellular functions including cell cycle regulation, transcriptional and translational events, metabolism, mitochondria function, protein synthesis and quality control, autophagy, epigenetic signaling, and calcium handling (Marsh et al, 2014; Wright et al, 2017). Total protein O ‐GlcNAc levels rise during cardiac pathologies including hypertrophy and heart failure in both humans and animal models (Dassanayaka et al, 2017; Gélinas et al, 2018; Lunde et al, 2012; Tran et al, 2020; Watson et al, 2010; Zhu et al, 2019). However, a lack of knowledge regarding the dynamic regulation of protein O ‐GlcNAc levels impedes our understanding of its role during cardiac hypertrophy.…”

Section: Introductionmentioning

confidence: 99%

Temporal regulation of protein O ‐GlcNAc levels during pressure‐overload cardiac hypertrophy

Zhu¹,

Ledee

Olson

2021

Physiol Rep

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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.

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“…It suggests that mTOR is activated in response to pressure overload stress. Activated mTOR phosphorylates its substrates S6K and 4EBP1 to induce protein synthesis and hypertrophy in cardiomyocytes [ 19 ]. Inhibition of mTOR activation is beneficial in pressure overload-induced myocardial hypertrophy [ 20 ].…”

Section: Discussionmentioning

confidence: 99%

Qindan Capsule Attenuates Myocardial Hypertrophy and Fibrosis in Pressure Overload-Induced Mice Involving mTOR and TGF-β1/Smad Signaling Pathway Inhibition

Bai

Ren

Cheng

et al. 2021

Evidence-Based Complementary and Alternative Medicine

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Qindan capsule (QC), a traditional Chinese medicine compound, has been used to treat hypertension in the clinic for over 30 years. It is still not known about the effects of QC on pressure overload-induced cardiac remodeling. Hence, this study aims to investigate the effects of QC on pressure overload-induced cardiac hypertrophy, fibrosis, and heart failure in mice and to determine the possible mechanisms. Transverse aortic constriction (TAC) surgery was used to induce cardiac hypertrophy and heart failure in C57BL/6 mice. Mice were treated with QC or losartan for 8 weeks after TAC surgery. Cardiac function indexes were evaluated with transthoracic echocardiography. Cardiac pathology was detected using HE and Masson’s trichrome staining. Cardiomyocyte ultrastructure was detected using transmission electron microscopy. Hypertrophy-related fetal gene expression was investigated using real-time RT-PCR. The expression of 8-OHdG and the concentration of MDA and Ang-II were assessed by immunohistochemistry stain and ELISA assay, respectively. The total and phosphorylated protein levels of mTOR, p70S6K, 4EBP1, Smad2, and Smad3 and the expression of TGF-β1 and collagen I were measured using western blot. The results showed that low- and high-dose QC improved pressure overload-induced cardiac hypertrophy, fibrosis, and dysfunction. QC inhibited ANP, BNP, and β-MHC mRNA expression in failing hearts. QC improved myocardial ultrastructure after TAC surgery. Furthermore, QC downregulated the expression of 8-OHdG and the concentration of MDA, 15-F2t-IsoP, and Ang-II in heart tissues after TAC surgery. We also found that QC inhibited the phosphorylation of mTOR, p70S6K, and 4EBP1 and the expression of TGF-β1, p-Smad2, p-Smad3, and collagen I in pressure overload-induced failing hearts. These data indicate that QC has direct benefic effects on pressure overload-induced cardiac hypertrophy, fibrosis, and dysfunction. The protective effects of QC involve prevention of increased oxidative stress injury and Ang-II levels and inhibition of mTOR and TGF-β1/Smad pathways in failing hearts.

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Chronic activation of hexosamine biosynthesis in the heart triggers pathological cardiac remodeling

Cited by 66 publications

References 57 publications

Lactate Dehydrogenase A Governs Cardiac Hypertrophic Growth in Response to Hemodynamic Stress

Lactate Dehydrogenase A Governs Cardiac Hypertrophic Growth in Response to Hemodynamic Stress

Temporal regulation of protein O ‐GlcNAc levels during pressure‐overload cardiac hypertrophy

Qindan Capsule Attenuates Myocardial Hypertrophy and Fibrosis in Pressure Overload-Induced Mice Involving mTOR and TGF-β1/Smad Signaling Pathway Inhibition

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