Abstract
Members of the fetal-gene-program may act as regulatory components to impede deleterious events occurring with cardiac remodeling, and constitute potential novel therapeutic heart failure (HF) targets. Mitochondrial energy derangements occur both during early fetal development and in patients with HF. Here we aim to elucidate the role of DIO2, a member of the fetal-gene-program, in pluripotent stem cell (PSC)-derived human cardiomyocytes and on mitochondrial dynamics and energetics, specifically. RNA sequencing and pathway enrichment analysis was performed on mouse cardiac tissue at different time points during development, adult age, and ischemia-induced HF. To determine the function of DIO2 in cardiomyocytes, a stable human hPSC-line with a DIO2 knockdown was made using a short harpin sequence. Firstly, we showed the selenoprotein, type II deiodinase (DIO2): the enzyme responsible for the tissue-specific conversion of inactive (T4) into active thyroid hormone (T3), to be a member of the fetal-gene-program. Secondly, silencing DIO2 resulted in an increased reactive oxygen species, impaired activation of the mitochondrial unfolded protein response, severely impaired mitochondrial respiration and reduced cellular viability. Microscopical 3D reconstruction of the mitochondrial network displayed substantial mitochondrial fragmentation. Summarizing, we identified DIO2 to be a member of the fetal-gene-program and as a key regulator of mitochondrial performance in human cardiomyocytes. Our results suggest a key position of human DIO2 as a regulator of mitochondrial function in human cardiomyocytes.
Highlights
IntroductionTo be able to counteract these increased pressures, the heart will respond with physiological cardiomyocyte hypertrophy [2,3,4]
To identify the genes and pathways associated with the cardiac fetal-gene-program, we performed RNA-sequencing using RNA from mouse whole heart at embryonic day 12 (E12), left ventricular (LV) tissue at three different stages of cardiac development [E18, postpartum day 2 (PP2), and week 20 sham], and LV tissue of ischemia/reperfusion (IR)-induced heart failure (HF) (Figure 1A)
Genes involved in the activation of the cardiac fetal gene program were defined as genes that demonstrated an inverse regulation in HF as compared to that during early development
Summary
To be able to counteract these increased pressures, the heart will respond with physiological cardiomyocyte hypertrophy [2,3,4] These long-term adaptations were found, to some extent, recapitulated as the result of cardiac injury [3]. The reoccurrence of transcriptional processes specific for early development, has been depicted as “cardiac fetal reprogramming” and is characterized by the re-activation of fetal gene transcription profiles in the diseased myocardium [5]. This adaptation is suggested to act as a dynamic mechanism in demand, counteracting detrimental processes occurring in the diseased heart during cardiac remodeling, and constitutes a pro-survival reaction.
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