HAND1 loss-of-function within the embryonic myocardium reveals survivable congenital cardiac defects and adult heart failure
| Autor: | Rajani M. George, Ronald M Payne, Loren J. Field, Hongyu Gao, Michael Rubart-von der Lohe, Weinian Shou, Anthony B. Firulli, Wenjun Zhang, Jade Harkin, Beth A. Firulli, Ying Liu, Kevin P. Toolan, Yunlong Liu |
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| Rok vydání: | 2019 |
| Předmět: |
Heart Defects
Congenital Male Mice 129 Strain Physiology Action Potentials Biology Ventricular Function Left Diastole Heart Rate Physiology (medical) Basic Helix-Loop-Helix Transcription Factors medicine Animals Gene Regulatory Networks Genetic Predisposition to Disease Loss function Heart Failure Mice Knockout Ventricular Remodeling Myocardium Age Factors Editorials Diastolic heart failure Gene Expression Regulation Developmental Heart Isolated Heart Preparation Right bundle branch block medicine.disease Embryonic stem cell Cell biology Mice Inbred C57BL Phenotype medicine.anatomical_structure Ventricle Heart failure Female Electrical conduction system of the heart Cardiology and Cardiovascular Medicine Heart failure with preserved ejection fraction |
| Zdroj: | Cardiovasc Res |
| ISSN: | 1755-3245 0008-6363 |
| DOI: | 10.1093/cvr/cvz182 |
| Popis: | AimsTo examine the role of the basic Helix-loop-Helix (bHLH) transcription factor HAND1 in embryonic and adult myocardium.Methods and resultsHand1 is expressed within the cardiomyocytes of the left ventricle (LV) and myocardial cuff between embryonic days (E) 9.5–13.5. Hand gene dosage plays an important role in ventricular morphology and the contribution of Hand1 to congenital heart defects requires further interrogation. Conditional ablation of Hand1 was carried out using either Nkx2.5 knockin Cre (Nkx2.5Cre) or α-myosin heavy chain Cre (αMhc-Cre) driver. Interrogation of transcriptome data via ingenuity pathway analysis reveals several gene regulatory pathways disrupted including translation and cardiac hypertrophy-related pathways. Embryo and adult hearts were subjected to histological, functional, and molecular analyses. Myocardial deletion of Hand1 results in morphological defects that include cardiac conduction system defects, survivable interventricular septal defects, and abnormal LV papillary muscles (PMs). Resulting Hand1 conditional mutants are born at Mendelian frequencies; but the morphological alterations acquired during cardiac development result in, the mice developing diastolic heart failure.ConclusionCollectively, these data reveal that HAND1 contributes to the morphogenic patterning and maturation of cardiomyocytes during embryogenesis and although survivable, indicates a role for Hand1 within the developing conduction system and PM development. |
| Databáze: | OpenAIRE |
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