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Cardiomyocyte Ogt limits ventricular dysfunction in mice following pressure overload without affecting hypertrophy

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Abstract

The myocardial response to pressure overload involves coordination of multiple transcriptional, posttranscriptional, and metabolic cues. The previous studies show that one such metabolic cue, O-GlcNAc, is elevated in the pressure-overloaded heart, and the increase in O-GlcNAcylation is required for cardiomyocyte hypertrophy in vitro. Yet, it is not clear whether and how O-GlcNAcylation participates in the hypertrophic response in vivo. Here, we addressed this question using patient samples and a preclinical model of heart failure. Protein O-GlcNAcylation levels were increased in myocardial tissue from heart failure patients compared with normal patients. To test the role of OGT in the heart, we subjected cardiomyocyte-specific, inducibly deficient Ogt (i-cmOgt −/−) mice and Ogt competent littermate wild-type (WT) mice to transverse aortic constriction. Deletion of cardiomyocyte Ogt significantly decreased O-GlcNAcylation and exacerbated ventricular dysfunction, without producing widespread changes in metabolic transcripts. Although some changes in hypertrophic and fibrotic signaling were noted, there were no histological differences in hypertrophy or fibrosis. We next determined whether significant differences were present in i-cmOgt −/− cardiomyocytes from surgically naïve mice. Interestingly, markers of cardiomyocyte dedifferentiation were elevated in Ogt-deficient cardiomyocytes. Although no significant differences in cardiac dysfunction were apparent after recombination, it is possible that such changes in dedifferentiation markers could reflect a larger phenotypic shift within the Ogt-deficient cardiomyocytes. We conclude that cardiomyocyte Ogt is not required for cardiomyocyte hypertrophy in vivo; however, loss of Ogt may exert subtle phenotypic differences in cardiomyocytes that sensitize the heart to pressure overload-induced ventricular dysfunction.

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Abbreviations

HBP:

Hexosamine biosynthetic pathway

O-GlcNAc:

β-O-Linked N-acetylglucosamine

OGT:

O-GlcNAc transferase

OGA:

O-GlcNAcase

TAC:

Transverse aortic constriction

PFK1:

Phosphofructokinase-1

GFPT1:

Glutamine fructose-6-phosphate transaminase 1

GFPT2:

Glutamine fructose-6-phosphate transaminase 2

PGC1α:

Peroxisome proliferator-activated receptor gamma, co-activator 1 alpha

PGC1β:

Peroxisome proliferator-activated receptor gamma, co-activator 1 beta

CPT1b:

Carnitine palmitoyltransferase 1b

CPT2:

Carnitine palmitoyltransferase 2

MCAD:

Medium-chain acyl-CoA dehydrogenase

PPARα:

Peroxisome proliferator-activated receptor alpha

SLC2A1:

Solute carrier family 2 (facilitated glucose transporter), member 1

SLC2A4:

Solute carrier family 2 (facilitated glucose transporter), member 4

SERCA 2a:

Sarco/endoplasmic reticulum Ca2+-ATPase

CALM1:

Calmodulin 1

ANP:

Atrial natriuretic peptide

BNP:

Brain natriuretic peptide

TGFβ1:

Transforming growth factor 1

TGFβ2:

Transforming growth factor 2

TGFβ3:

Transforming growth factor 1

FGF2:

Fibroblast growth factor 2

CTGF:

Connective tissue growth factor

COL1α1:

Collagen, type I, alpha 1

COL1α2:

Collagen, type I, alpha 2

COL3α1:

Collagen, type 3, alpha 1

COL4α1:

Collagen, type 4, alpha 1

MMP2:

Matrix metallopeptidase 2

TIMP2:

Metallopeptidase inhibitor 2

ZEB1:

Zinc finger E-box-binding homeobox 1

ZEB2:

Zinc finger E-box-binding homeobox 2

SNAI1:

Snail family zinc finger1

SNAI2:

Snail family zinc finger1

TWI:

Twist basic helix-loop-helix transcription factor 1

VIM:

Vimentin

FN1:

Fibronectin 1

POSTN:

Periostin

MYH6:

Alpha myosin heavy chain

MHY7:

Beta myosin heavy chain

NKX 2-5:

NK2 homeobox 5

MEF2C:

Myocyte enhancer factor 2C

GATA4:

GATA-binding protein 4

ACTA2:

Actin, alpha 2, smooth muscle

BCL2:

B-cell lymphoma 2

VEGFA:

Vascular endothelial growth factor A

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Acknowledgements

The authors thank Linda Harrison for her expert technical assistance with neonatal cardiomyocyte isolations. In addition, we would like to thank Ms. Jessica Lan-shin Liu, Ms. Yun Shi Long, and Dr. Lakshmanan Annamalai, for their technical assistance with histology.

Author contributions

SD performed experiments, analyzed data, generated figures, wrote draft, revised manuscript, and provided funding. REB performed experiments, analyzed data, generated figures, and wrote draft. LJW performed experiments and analyzed data. BWL performed experiments and analyzed data. KRB performed experiments and analyzed data. AMM performed experiments, generated figures, and analyzed data. AMA performed experiments and analyzed data. AMG performed experiments and analyzed data. TNA performed experiments and analyzed data. PJK performed experiments and revised manuscript. SM performed experiments and analyzed data. TH performed experiments and analyzed data. SDP designed experiments, revised manuscript, and provided funding. SPJ designed experiments, wrote draft, revised manuscript, and provided funding.

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Author notes

  1. Lewis J. Watson

    Present address: Kentucky College of Osteopathic Medicine, University of Pikeville, Pikeville, KY, USA

  2. Tariq Hamid & Sumanth D. Prabhu

    Present address: Division of Cardiovascular Disease and Comprehensive Cardiovascular Center, University of Alabama at Birmingham, Birmingham, AL, USA

Authors and Affiliations

  1. Division of Cardiovascular Medicine, Department of Medicine, Institute of Molecular Cardiology, Diabetes and Obesity Center, University of Louisville, 580 South Preston Street, Louisville, KY, 40202, USA

    Sujith Dassanayaka, Robert E. Brainard, Lewis J. Watson, Bethany W. Long, Kenneth R. Brittian, Angelica M. DeMartino, Allison L. Aird, Anna M. Gumpert, Timothy N. Audam, Peter J. Kilfoil, Senthilkumar Muthusamy, Tariq Hamid, Sumanth D. Prabhu & Steven P. Jones

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  1. Sujith Dassanayaka
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  2. Robert E. Brainard
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Correspondence to Steven P. Jones.

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Funding

Dr. Jones has been supported by Grants from the NIH (R01 HL083320, R01 HL094419, P20 RR103492, and P01 HL078825). Mr. Dassanayaka has been supported by an American Heart Association Predoctoral Fellowship—Great Rivers Affiliate (14PRE19710015).

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None.

Additional information

S. Dassanayaka and R. E. Brainard contributed equally to this work.

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Supplemental Fig. 1. Ogt deletion suppresses Oga expression. Cardiac OGA mRNA transcript and protein levels were depressed (p < 0.05) at 2 weeks in i-cmOgt −/− (A and B), but not at 4 weeks (C and D). *p <0.05 vs. WT TAC.

Supplemental Fig. 2. Ogt ablation does not alter markers of EMT progression. Markers of EMT were assessed using RT-PCR at both 2 weeks (A) and 4 weeks (B) following TAC. There were no differences in gene expression of EMT mediators; Zeb1, Zeb2, Snai1, Snai2, or Twi between i-cmOgt −/− TAC and WT TAC at any time point. In addition, there were no differences in Fn1, Vim, and Pstn expression when comparing i-cmOgt −/− TAC hearts with WT TAC hearts.

Supplemental Fig. 3. Cardiac Ogt ablation does not alter apoptosis or angiogenesis in response to pressure overload. Gene expression of GATA-4 target genes, Bcl2 and Vegfa, was measured at 2 (A) and 4 (B)-week post-TAC. LV apoptosis (via TUNEL) was measured at 4-week post-TAC (C). LV capillary density (via isolectin B4) was measured 4-week post-TAC (D). *p <0.05 vs. WT TAC.

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Dassanayaka, S., Brainard, R.E., Watson, L.J. et al. Cardiomyocyte Ogt limits ventricular dysfunction in mice following pressure overload without affecting hypertrophy. Basic Res Cardiol 112, 23 (2017). https://doi.org/10.1007/s00395-017-0612-7

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