Differential Changes in TGF-β/BMP Signaling Pathway in the Right Ventricular Myocardium of Newborns With Hypoplastic Left Heart Syndrome

Marco Ricci; Bhagyalaxmi Mohapatra; Arnel Urbiztondo; Rhea J Birusingh; Micaela Morgado; Maria M Rodriguez; Joy Lincoln; Matteo Vatta

doi:10.1016/j.cardfail.2010.03.007

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Differential Changes in TGF-β/BMP Signaling Pathway in the Right Ventricular Myocardium of Newborns With Hypoplastic Left Heart Syndrome

Journal article

Peer reviewed

Differential Changes in TGF-β/BMP Signaling Pathway in the Right Ventricular Myocardium of Newborns With Hypoplastic Left Heart Syndrome

Marco Ricci, Bhagyalaxmi Mohapatra, Arnel Urbiztondo, Rhea J Birusingh, Micaela Morgado, Maria M Rodriguez, Joy Lincoln and Matteo Vatta

Journal of cardiac failure, Vol.16(8), pp.628-634

2010

DOI: 10.1016/j.cardfail.2010.03.007

PMID: 20670841

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Abstract

Hypoplastic left heart syndrome (HLHS) is characterized by underdevelopment of the left ventricle (LV) and increased biomechanical stress on the right ventricle (RV) from single ventricle physiology. Despite the clinical significance, the signaling pathways active during RV remodeling and disease progression are not known. To address this, we examined differential changes in expression of genes associated with transforming growth factor-β (TGF-β)/bone morphogenetic protein (BMP) signaling in RV tissue isolated from HLHS patients relative to RV and LV tissue from control subjects. Quantitative real-time polymerase chain reaction was used to detect changes in expression of 84 genes involved in TGF-β/BMP-mediated cardiac development, cell growth, and differentiation in RV tissue collected from 6 neonates with HLHS undergoing stage 1 Norwood procedure (age, 1-7 days; mean, 4 days) and RV and LV tissue obtained from 5 infants with noncardiac pathology (age range, 1-135 days: mean, 85 days) that served as controls. Analysis of gene expression profiles between control-LV and control-RV revealed significant depression of TGF-β/BMP signaling in RV compared with LV. Of the 84 genes analyzed, 38 were differentially expressed between HLHS-RV and control-RV, whereas only 22 compared with control-LV. Significant changes were observed in: tissue remodeling genes including Activin receptor type IIA ( ACVR2A) (+2.13) and Activin receptor-like kinase 1 ( ACVRL1) (+2.22); and cell survival, growth, and differentiation genes including CDC25A (+2.18), p21 (−3.64), p15 (+2.15), BMP5 (+4.58), BMP3 (+2.16), GDF3 (+8.59), NODAL (+2.32), and BMP binding endothelial regulator (BMPER) (+4.58). The most significant changes common to HLHS-RV versus control-RV and control-LV sample groups is observed for Anti müllerian hormone receptor 2 ( AMHR2) (+18.79 control-RV, +3.38 control-LV), and the BMP antagonist Inhibin alpha ( INHA) (+11.47 control-RV, +5.73 control-LV). Although this descriptive study does not allow cause-effect inferences, our results suggest changes in cardiac development pathways and upregulation of genes associated with cell growth and differentiation in the neonatal RV of children with HLHS. These molecular profiles are more closely related to those observed in the normal LV rather than normal RV at similar maturational age. This work provides the basis for future mechanistic studies to elucidate the molecular mechanisms regulating RV remodeling in HLHS.

Hypoplastic left heart

heart failure

gene expression

Details

Title: Subtitle: Differential Changes in TGF-β/BMP Signaling Pathway in the Right Ventricular Myocardium of Newborns With Hypoplastic Left Heart Syndrome
Creators: Marco Ricci - Division of Cardiothoracic Surgery, University of Miami Miller School of Medicine and Holtz Children's Hospital, Miami, FL
Bhagyalaxmi Mohapatra - Cytogenetics Laboratory, Department of Zoology, BHU, Varanasi, India
Arnel Urbiztondo - Department of Pathology, University of Miami Miller School of Medicine and Holtz Children's Hospital, Miami, FL
Rhea J Birusingh - Department of Pathology, University of Miami Miller School of Medicine and Holtz Children's Hospital, Miami, FL
Micaela Morgado - Division of Pediatric Cardiology, Texas Children's Hospital/Baylor College of Medicine, Houston, TX
Maria M Rodriguez - Department of Pathology, University of Miami Miller School of Medicine and Holtz Children's Hospital, Miami, FL
Joy Lincoln - Department of Molecular and Cellular Pharmacology, University of Miami Miller School of Medicine, Miami, FL
Matteo Vatta - Division of Pediatric Cardiology, Texas Children's Hospital/Baylor College of Medicine, Houston, TX
Resource Type: Journal article
Publication Details: Journal of cardiac failure, Vol.16(8), pp.628-634
DOI: 10.1016/j.cardfail.2010.03.007
PMID: 20670841
NLM abbreviation: J Card Fail
ISSN: 1071-9164
eISSN: 1532-8414
Publisher: Elsevier Inc
Grant note: Jonathan and Eileen Otto Research Fund DeWitt Daughtry Family Department of Surgery of the University of Miami
Language: English
Date published: 2010
Academic Unit: Surgery; Cardiothoracic Surgery
Record Identifier: 9984051783602771

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