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HER-2 as a Prognostic and Predictive Biomarker in Cancer
Published in Sherry X. Yang, Janet E. Dancey, Handbook of Therapeutic Biomarkers in Cancer, 2021
Alexandra S. Zimmer, Suparna B. Wedamb, Stanley Lipkowitza
Homozygous deletion of HER-2 in mice results in embryonic lethality due to defective development ofcardiac trabeculae [22]. Also, HER-2 null mice have abnormal development of the nervous system and the neuromuscular junction [22–25]. Homozygous deletion of neuregulin, which binds to HER-3 and HER-4 and stimulates heterodimerization of these receptors with HER-2 and activation of the HER-2 kinase activity, causes similar developmental defects in the heart and nervous system [26]. In the developing heart, HER-2 is expressed in embryonic myocytes while the ligand neuregulin is expressed in the adjacent endocardium, consistent with a paracrine developmental signal (reviewed in [27]). Thus, HER-2 is essential for cardiac and neural development. Also, HER-2 serves important functions in the adult heart. Mice with conditional deletion of HER-2 targeted to cardiomyocytes have normal embryonic heart development but develop dilated cardiomyopathy at 3 months of age [28]. Doxorubicin treatment of mice with a heterozygous deletion of neuregulin-1 results in increased cardiac damage and mortality and induces less phosphorylation of HER-2, HER-4, ERK 1 and 2, AKT, and 70S6K in the heterozygous neuregulin deficient mice compared to wild type mice [29]. Together these data demonstrate a role for HER-2 in normal homeostasis and response to damage in the adult heart. This is likely to explain the cardiac toxicity observed in breast cancer patients treated with the anti-HER-2 antibody trastuzumab (reviewed in [30]).
Metabolomics and perinatal cardiology
Published in Moshe Hod, Vincenzo Berghella, Mary E. D'Alton, Gian Carlo Di Renzo, Eduard Gratacós, Vassilios Fanos, New Technologies and Perinatal Medicine, 2019
Roberta Pintus, Angelica Dessì, Vassilios Fanos
There are several crucial time points for heart development in fetuses and neonates. From 16 up to 35 weeks, the linear increase in heart tissue volume is due entirely to cardiomyocite proliferation (9). Furthermore, during late prenatal or early postnatal life, there is a switch from hyperplastic to hypertrophic cellular growth (10).
Regeneration of Cardiomyocytes from Bone Marrow Stem Cells and Application to Cell Transplantation Therapy
Published in Richard K. Burt, Alberto M. Marmont, Stem Cell Therapy for Autoimmune Disease, 2019
Various cardiac specific transcription factors have been cloned, and their genes are serially expressed in the developing heart during myogenesis and morphogenesis. Figure 4 shows the time course of the expression of cardiomyocyte-specific transcription factors in fetal developing heart and CMG cells. The genes coding Nkx2.515 (homeobox type transcription factor specifically expressed beginning in the early developing heart), GATA416 (GATA-motif-binding Zinc finger type transcription factor expressed beginning in the early stage developing heart), HAND 1/2 (basic helix-loop-helix type transcription factor expressed in the heart and autonomic nervous system), and MEF2-B/C17 (muscle enhancement factor: a MADS box family transcription factor expressed in the myocytes) were expressed in the early stage of heart development, and MEF2A and MEF2-D in the middle stage. The CMG cells already expressed GATA4, TEF-118(transcription enhancement factor 2), Nkx2.5, HAND, and MEF2-C before exposure to 5-azacytidine, and they expressed MEF2-A and MEF2-D after exposure to 5-azacytidine. This pattern of gene expression in CMG cells was similar to that of developing cardiomyocytes in vivo,11 and indicated that the developmental stage of the undifferentiated CMG cells is close to that of cardiomyoblasts or the early stages of heart development. We estimated that the stage of differentiation of the CMG cells lies between the cardiomyocyte-progenitor stage and the differentiated cardiomyocyte stage.
MiR-23b targets GATA6 to down-regulate IGF-1 and promote the development of congenital heart disease
Published in Acta Cardiologica, 2022
Guo-Jin Huang, Xue-Liang Xie, Yong Zou
Congenital heart disease is the most common birth defect. The process of heart development involves the spatiotemporal specific expression of many related genes and the activation and precise regulation of many signal pathways (such as Notch, Wnt, and BMP pathway) to ensure the correct migration, proliferation, and differentiation of cardiomyocytes [24–26]. Abnormalities in any link of heart development will lead to the occurrence of CHD. MiR-23b possesses a variety of cellular functions, inclusive of cell proliferation, differentiation, and migration. Although studies have shown that the expression of miR-23b in the myocardium of CHD patients is up-regulated and may affect cardiomyocyte proliferation and apoptosis, the specific mechanism has not been elucidated before. In this research, we demonstrated that miR-23b can affect cardiomyocyte proliferation and apoptosis by regulating the expression of downstream genes.
Hypoplastic left heart syndrome (HLHS): molecular pathogenesis and emerging drug targets for cardiac repair and regeneration
Published in Expert Opinion on Therapeutic Targets, 2021
Anthony T Bejjani, Neil Wary, Mingxia Gu
Other cardiac cell types besides cardiomyocytes are also instrumental for proper cardiogenesis, including endocardial cells, fibroblasts, and epicardial cells. These cells provide necessary signals that direct different aspects of the heart development and cardiomyocyte maturation. Endocardial cells are a source of mesenchymal cells that contribute to parts of the valves and septa of the heart [55]. Moreover, they produce signals that mediate the trabeculation of the chambers during development [21,56]. This cell population was shown to be reduced in patients with HLHS [57]. Recently, Miao et al. characterized an impaired endocardial cell population in HLHS patients using single-cell RNA sequencing and showed that several transcription factors were downregulated in patient iPSC derived endocardial cells compared to controls such as ETS proto-oncogene 1 (ETS1), which is known to be associated with HLHS [30]. Additionally, chromatin remodelers such as Chromodomain-helicase-DNA-binding including protein (CHD7) were also downregulated [58]. Fibronectin 1 (FN1) was downstream of the ETS1 in the endocardium, which decreased cardiomyocyte proliferation and possibly contributed to the ventricular hypoplasia [58,59]. More studies are needed to assess the roles of non-cardiomyocyte cell populations in CHDs.
MST1-Hippo pathway regulates inflammation response following myocardial infarction through inhibiting HO-1 signaling pathway
Published in Journal of Receptors and Signal Transduction, 2020
Yanan Tian, Haijiu Song, Dapeng Jin, Na Hu, Lixian Sun
ROS are essential for heart development and regeneration. The level of ROS increases in the first week after birth, and the increased ROS induce the DNA damage response of the cells in the heart that play a role in the transition from the regenerative to the nonregenerative stage. Reduced ROS level or inhibition of the DNA damage response may prolong the regenerative window of cardiomyocytes. Interestingly, a recent study reported that PITX2 interacts with YAP and induces the expression of antioxidant genes such as Ldha, Ndufb3, and Oxnad1. By performing PITX2 and YAP ChIP-seq in mouse hearts, they showed that PITX2 and YAP directly regulate the expression of these antioxidant genes. Deletion of Pitx2 in cardiomyocytes is detrimental to neonatal mouse heart regeneration [44]. However, when Pitx2 conditional knockout mice were treated with the antioxidant N-acetyl-l-cysteine, the scar size was decreased. In addition, these authors reported that NRF2, a regulator of the antioxidant response, activates PITX2 expression and also promotes PITX2 nuclear translocation [45].