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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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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DOI: https://doi.org/10.1007/s10741-007-9034-1