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.

Endothelin receptor B, a candidate gene from human studies at high altitude, improves cardiac tolerance to hypoxia in genetically engineered heterozygote mice

“…These three genes are differentially expressed in normoxia as well as hypoxia, and we believe that they are involved in the phenotypic difference between the EdnrB +/+ and EdnrB −/+ . Of interest, we note that these genes are expressed in the fetal heart (49, 50), possibly adding some evidence to a role in hypoxia, because gene expression of fetal transcripts can often show up during stress (51). As anticipated, the top-scoring networks for these genes were all related to cardiovascular function ranging from heart contraction, blood circulation, and the cGMP metabolic process to Ca 2+ homeostasis (Fig.…”

Taurine Depletion-Related Cardiomyopathy in Animals

“…Moreover, detailed functional analysis on Langendorff perfused heart also demonstrated the age-dependent cardiac dysfunction, such as a decrease in peak positive dp/dt and an increase in negative dp/dt as well as decreased ejection fraction in TauTKO mice (unpublished data). It is well established that the expression of fetal genes, including atrial natriuretic peptide (ANP), brain natriuretic peptide (BNP) and β-myosin heavy chain (β-MHC), is reactivated in heart failure (Rajabi et al, 2007). These cardiac failure markers were significantly elevated in TauTKO mice.…”

Cardinal roles of miRNA in cardiac development and disease

“…Pathological hypertrophy is mainly caused by hypertension, loss of myocytes subsequent to myocardial infarction (MI) or ischemic/reperfusion (I/R) injury, and genetic alterations that lead to enlargement of the left ventricles, such as dilated cardiomyopathy. Moreover, metabolic abnormality or stress can also lead to hypertrophy [17]. Currently, there is great interest in determining the molecular mechanisms, including the roles of miRNAs, in pathological hypertrophy ( Figure 1).…”