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Return to the fetal gene program protects the stressed heart: a strong hypothesis

Abstract

A common feature of the hemodynamically or metabolically stressed heart is the return to a pattern of fetal metabolism. A hallmark of fetal metabolism is the predominance of carbohydrates as substrates for energy provision in a relatively hypoxic environment. When the normal heart is exposed to an oxygen rich environment after birth, energy substrate metabolism is rapidly switched to oxidation of fatty acids. This switch goes along with the expression of “adult” isoforms of metabolic enzymes and other proteins. However, the heart retains the ability to return to the “fetal” gene program. Specifically, the fetal gene program is predominant in a variety of pathophysiologic conditions including hypoxia, ischemia, hypertrophy, and atrophy. A common feature of all of these conditions is extensive remodeling, a decrease in the rate of aerobic metabolism in the cardiomyocyte, and an increase in cardiac efficiency. The adaptation is associated with a whole program of cell survival under stress. The adaptive mechanisms are prominently developed in hibernating myocardium, but they are also a feature of the failing heart muscle. We propose that in failing heart muscle at a certain point the fetal gene program is no longer sufficient to support cardiac structure and function. The exact mechanisms underlying the transition from adaptation to cardiomyocyte dysfunction are still not completely understood.

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Abbreviations

ACC:

Acetyl-CoA carboxylase

Akt:

Protein kinase B

ANF:

Atrial natriuretic factor

CIRKO:

Specific insulin receptor knock out

COUP-TF:

Chicken ovalbumin upstream promoter transcription factor

mCPT I:

Muscle carnitine palmitoyl transferase I

4EBP1:

Eukaryotic initiation factor-4E (eIF-4E) binding protein 1

FGF-2:

Fibroblast growth factor 2

GIK:

Glucose, insulin, potassium

GLUT1:

Glucose transporter 1

GLUT4:

Glucose transporter 4

GS:

Glycogen synthase

mGS:

Muscle glycogen synthase

HIF:

Hypoxia inducible factor

IGF-1:

Insulin-like growth factor 1

JAK:

Janus kinases

MAP kinase:

Mitogen-activated protein kinase

MCD:

Malonyl-CoA decarboxylase

MCAD:

Medium chain acyl-CoA dehydrogenase

MEF2:

Myocyte enhancer factor 2

MHC:

Myosin heavy chain

mTOR:

Mammalian target of rapamycin

NFAT:

Nuclear factor of activated T cells

PDC:

Pyruvate dehydrogenase complex

PDK2:

Pyruvate dehydrogenase kinase 2

PGC-1:

Peroxisome proliferator activated receptor γ coactivator 1

PI3-kinase:

Phosphatidylinositol 3 Kinase

PPAR-α:

Peroxisome proliferator activated receptor alpha

p70S6K:

P70 ribosomal S6 kinase

SERCA:

Sarco (endo) plasmic reticulum Ca2+ATPase

Sp1/3:

Specificity protein 1/3

SRF:

Serum response factor

STAT:

Signal Transducers and Activators of Transcription

TR:

Thyroid receptor

TRα1:

Thyroid receptorα1

TRβ1:

Thyroid receptorβ1

UCP3:

Uncoupling protein 3

UPP:

Ubiquitin proteosome proteolytic

UPS:

Ubiquitin proteasome system

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Acknowledgments

The authors are grateful for the editorial assistance of Rebecca Salazar and Roxy A. Tate. This work was funded by Grant RO1 HL/AG 61483 from the National Institutes of Health, Bethesda, MD, and by the MacDonald General Research Fund, St. Luke’s Episcopal Hospital, Houston, TX.

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Correspondence to Heinrich Taegtmeyer.

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Rajabi, M., Kassiotis, C., Razeghi, P. et al. Return to the fetal gene program protects the stressed heart: a strong hypothesis. Heart Fail Rev 12, 331–343 (2007). https://doi.org/10.1007/s10741-007-9034-1

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Keywords

  • Fetal heart
  • Hypertrophy
  • Atrophy
  • Hibernating myocardium
  • Heart failure
  • Metabolism