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Human eHAND, but not dHAND, is down-regulated in cardiomyopathies
A Natarajan1, H Yamagishi, F Ahmad
1Division of Intensive Care, Department of Pediatrics, University of Texas Southwestern Medical Center, University of Texas Southwestern Medical Center, One Baylor Plaza, Dallas, Texas 75390-9148, USA.
Insights
Human dHAND and eHAND transcription factors show unique expression patterns in healthy adult hearts. Their downregulation, particularly eHAND, correlates with ischemic and dilated cardiomyopathy progression.
Area of Science:
- Cardiovascular Biology
- Molecular Cardiology
- Gene Expression Regulation
Background:
- Fetal gene expression is linked to cardiomyopathy progression.
- Basic helix-loop-helix transcription factors, dHAND and eHAND, are crucial for cardiac development in mice but downregulated in adults.
- Human HAND gene expression in cardiac chambers of healthy and diseased hearts remains uncharacterized.
Purpose of the Study:
- To map human dHAND and eHAND genes to chromosomes.
- To investigate the spatial expression patterns of dHAND and eHAND in healthy human adult cardiac chambers.
- To analyze alterations in dHAND and eHAND expression in human cardiomyopathic hearts.
Main Methods:
- Fluorescent in situ hybridization for gene mapping.
- RNA isolation from four chambers of healthy and cardiomyopathic human hearts.
- Quantitative analysis of dHAND and eHAND gene expression.
Main Results:
- Human dHAND and eHAND genes mapped to chromosomes 4q33 and 5q33.
- dHAND expressed in all four healthy adult chambers, diminished in the right atrium.
- eHAND expressed in ventricles, downregulated in atria; severely downregulated in ischemic and dilated cardiomyopathy.
- dHAND expression remained unchanged across cardiomyopathies.
Conclusions:
- Human dHAND and eHAND exhibit distinct chamber-specific expression patterns in adult hearts.
- Downregulation of eHAND in ischemic and dilated cardiomyopathy suggests a role in disease pathogenesis.
- These findings highlight unique human HAND gene regulation and potential links to heart failure progression.
Abstract:
The progression of cardiomyopathy to congestive heart failure is often associated with the expression of fetal cardiac-specific genes. In mice, the basic helix-loop-helix transcription factors, dHAND and eHAND, are expressed in a cardiac chamber-specific fashion and are essential for fetal cardiac development, but are down-regulated in the adult. Their expression in specific chambers of healthy and diseased human hearts has not been studied previously. Human dHAND and eHAND were mapped to human chromosomes 4q33 and 5q33, respectively, by fluorescent in situ hybridization. RNA from the four chambers of healthy human adult hearts, and from hearts of patients with several forms of cardiomyopathy, was obtained and assayed for dHAND and eHAND expression. Unlike in mice, dHAND expression was observed in all four chambers of the healthy human adult heart, but was diminished in the right atrium. In contrast, eHAND was expressed in the right and left ventricles, but was downregulated in both atrial chambers. We examined tissue from 15 human cardiomyopathic hearts obtained during cardiac transplantation or by endomyocardial biopsy for alterations in HAND gene expression. dHAND expression was unchanged in all forms of cardiomyopathy tested. However, cardiac expression of eHAND was severely down-regulated in six of six patients with ischemic cardiomyopathy and six of six patients with dilated cardiomyopathy. This study demonstrates that human dHAND and eHAND have unique spatial patterns of expression within human cardiac chambers. Downregulation of eHAND in ischemic and dilated cardiomyopathy suggests a correlation between eHAND dysregulation and the evolution of a subset of cardiomyopathies.