Return to the fetal gene program

Abstract

A hallmark of cardiac metabolism before birth is the predominance of carbohydrate use for energy provision. After birth, energy substrate metabolism rapidly switches to the oxidation of fatty acids. This switch accompanies the expression of “adult” isoforms of metabolic enzymes and other proteins. However, in a variety of pathophysiologic conditions, including hypoxia, ischemia, hypertrophy, atrophy, diabetes, and hypothyroidism, the postnatal heart returns to the “fetal” gene program. These adaptive mechanisms are also a feature of the failing heart muscle, where at a certain point this fetal-like reprogramming no longer suffices to support cardiac structure and function. We advance the hypothesis that in the postnatal heart, metabolic remodeling triggers the process through glycosylation of transcription factors, potentially protecting the stressed heart from irreversible functional impairment and programmed cell death. In other words, we propose a metabolic link to gene expression in the heart.

Changes in myofilament proteins, but not Ca2+ regulation, are associated with a high-fat diet-induced improvement in contractile function in heart failure

“…Okere et al (30) also reported that a high-fat diet prevented a Mhc-␣ to Mhc-␤ isoform switch that was accompanied by reductions in LV remodeling and contractile dysfunction in hypertensioninduced hypertrophy. In addition, increased glucose availability has been reported to promote the Mhc-␣ to Mhc-␤ isoform switch, whereas high fatty acid levels blocked the changes in myosin isoforms (41,49) considered a hallmark for a progressive decline in cardiac function. Thus, there may be a metabolic link that functions to protect the heart under pathological conditions through alterations in gene and protein expression involved in regulating contractile function; however, a potential cardioprotective effect may be unique to our model of mild-moderate HF/LV dysfunction.…”

“…Similarly, at the myofilament level, the composition and phosphorylation of contractile proteins also impact contractility. The relative abundance of myosin heavy chain (MHC) ␣-and ␤-isoforms correlates with in vivo contractile function (41). Specifically, an increase in MHC-␤ contributes to decreased in vivo contractile function as a result of lower intrinsic ATPase activity and reduced myofilament shortening velocity (46).…”

Therapeutic Molecular Phenotype of β-Blocker–Associated Reverse-Remodeling in Nonischemic Dilated Cardiomyopathy

“…Many β-blocker-associated gene expression changes in responders versus nonresponders represent a partial reversal of the cardiac fetal/adult gene program, 3,34,35 but they may also be consistent with alternative regulatory mechanisms including inhibition of β 1 -AR signaling 5,6,36 or enhanced thyroid hormone receptor (TR-α) activity (Table 5). 7 We previously reported changes in TR-α1 and TR-α2 expression in IDC LVs consistent with hypothyroidism at the TR-α level.…”

Investigations into the role of the ErbB4 receptor in cardiomyocyte hypertrophy and adult cardiac function

“…Sarcomere reorganisation resulting in the remodelling of the cardiomyocytes, affecting the ability of the cardiomyocytes to contract (Telley et al, 2007). The activation of the "fetal gene program" involves the re-expression (in the adult) of genes normally only expressed during fetal development including of α-skeletal actin, β-myosin heavy chain (β-MHC), atrial natriuretic peptide (ANP) and myosin light chain-2v (MLC-2V) (Parker et al, 1990;Taegtmeyer et al, 2010). Some of the induced fetal genes code for contractile proteins.…”

“…handling proteins potentially contributes to alterations in the contractile ability of cardiomyocytes (Razeghi et al, 2001;Taegtmeyer et al, 2010).…”