Fetal gene program cardiac hypertrophy

The heart may possess a mechanism similar to the one in the liver. In the oxygen-deprived state, glycogen stores in the heart are associated with increased survival. Secondly, switching from the highly aerobic metabolism of fatty acids to the less aerobic metabolism of glucose appears to be a necessary prerequisite for immediate cell survival.

Glycolysis, or the conversion of glucose to lactate, has been implicated as the source of ATP for fueling ion pumps, including those involved in calcium cycling. It is reasonable to assume that glycogen increases survival by acting as a fuel source during conditions of decreased substrate uptake e.

An interesting model of transient adaptation to the fetal program is hypobaric hypoxia. Exposure to in vivo hypobaric hypoxia triggers a large number of complex physiologic responses in the right ventricle. When compensatory mechanisms e. Another example of return to the fetal gene program is the heart in diabetes. During the process of adaptation, myosin isoform expression will change to maintain an appropriate contractile force.

Restricting dietary glucose prevents mhc switching in hearts of rats subjected to pressure overload—induced hypertrophy Fig.

Adapted from Young et al. In other words, glucose availability correlates with mhc isoform switching under all conditions investigated. A potential mechanism by which glucose affects gene expression is through O -linked glycosylation of specific transcription factors. The enzyme glutamine fructosephosphate amidotransferase GFAT is the rate-limiting step for flux through the hexosamine biosynthetic pathway and UDP- N -acetylglucosamine biosynthesis, the main metabolite in protein glycosylation.

Ascending aortic constriction increased intracellular levels of UDP- N -acetylglucosamine, and the expression of gfat2, but not gfat1 , in the rat heart. Although the results require further confirmation, they are in support of glucose-regulated gene expression in the heart, and the involvement of glucose metabolites in isoform switching of sarcomeric proteins characteristic for the fetal gene program. Moreover, feeding rats a high-fat, low-carbohydrate diet blocks mhc isoform switching in models of pressure overload including Dahl salt-sensitive rats 35 and rats with aortic constriction.

Myocardial hibernation is perhaps the most dramatic example of programmed cell survival, an adaptive state of reduced myocardial contractile function in response to a reduction of myocardial blood flow. As in the fetal heart, the glycogen content of hibernating myocardium is dramatically increased. This supports the idea of a direct link between metabolic pathways and pathways of both cell death and cell survival.

The fetal gene program supports the activation of innate cell-survival pathways in the heart. Akt is also a modulator of metabolic substrate use. The remodeling process of the atrophied heart also includes a return to the fetal gene program.

We propose that either increased or decreased mechanical stress induces a local environment of hypoxia and a concerted mechanism of adaptation by isoform switching in energy-providing and energy-consuming pathways, which drives the adaptation of myocardial energetics to changes in energy demand. Unloading-induced remodeling is an active metabolic process, which involves both protein synthesis and degradation.

Unloading the heart reduces cardiac mass by a self-limited process and limits energy expenditure by preserving the expression of fetal isoforms of proteins regulating myocardial energetics. In other words, opposite changes in workload result in structural adaptation remodeling , which causes induction of a similar transcriptional response.

Therefore, expression of the fetal gene program is purely adaptive and does not imply, per se , irreversible cell damage. In fact, it is cardioprotective. The prevailing opinion among the community of heart-failure physiologists remains that a return to the fetal gene program is detrimental and a hallmark for progressive decline in cardiac function. The process is associated with survival rather than destruction of the heart.

The exact mechanisms underlying the transition from adaptation to cardiomyocyte dysfunction involve isoform switches of sarcomeric proteins, which requires further investigation. Specifically, we suggest that metabolic signals arising from glucose metabolism trigger a coordinated response to stress, which includes the return to the fetal gene program.

In other words, there may be a metabolic link to gene expression in the heart. We are grateful to past and present members of the Taegtmeyer lab, especially Dr. Martin E. Young, for their many contributions to the concepts proposed and to Roxy A. Tate for her editorial assistance. Young also provided critical comments for this manuscript. Shiraj Sen is a student in the M.

Anderson Cancer Center at Houston. National Center for Biotechnology Information , U. Ann N Y Acad Sci. Author manuscript; available in PMC Apr Author information Copyright and License information Disclaimer.

Address for correspondence: Prof. Heinrich Taegtmeyer, M. Copyright notice. See other articles in PMC that cite the published article. Abstract A hallmark of cardiac metabolism before birth is the predominance of carbohydrate use for energy provision. Keywords: fetal heart, hypertrophy, atrophy, hibernating myocardium, heart failure, glucose, metabolism. Introduction A common response of the heart to hemodynamic or metabolic stress is the suppression of the post-natal gene program, resulting in a predominance of the fetal gene program.

Metabolic features of the fetal heart As the heart grows in utero it is exposed to a low oxygen environment, to a gradually increasing hemo-dynamic load, and to a changing metabolic milieu. Open in a separate window. Figure 1. Figure 2. Contractile proteins of the fetal heart The expression pattern of many sarcomeric proteins in the fetal heart also undergoes major isoform switches at birth.

Metabolic signals as regulators for a coordinated stress response in heart Metabolic remodeling The adult heart responds to a wide spectrum of stressors including pressure overload, unloading, ischemia, hypothyroidism, and metabolic dysregulation by remodeling its metabolic and contractile machinery. Figure 3. Sarcomeric remodeling During the process of adaptation, myosin isoform expression will change to maintain an appropriate contractile force.

Figure 4. Cell survival in the fetal and stressed postnatal heart Myocardial hibernation is perhaps the most dramatic example of programmed cell survival, an adaptive state of reduced myocardial contractile function in response to a reduction of myocardial blood flow.

Conclusions The prevailing opinion among the community of heart-failure physiologists remains that a return to the fetal gene program is detrimental and a hallmark for progressive decline in cardiac function. Footnotes Conflicts of interest The authors declare no conflicts of interest.

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The exact mechanisms underlying the transition from adaptation to cardiomyocyte dysfunction are still not completely understood. Abstract A common feature of the hemodynamically or metabolically stressed heart is the return to a pattern of fetal metabolism. Publication types Research Support, N. Gov't Review. Substances Fatty Acids.