Remodeling of the hypertrophied human myocardium by cardiac bHLH transcription factors.
The basic helix-loop-helix transcription factors eHAND and dHAND are involved in developmental cardiac growth and differentiation. We investigated HAND gene expression in the normal and in the hypertrophied right and left ventricle of patients with tetralogy of Fallot (ToF) and hypertrophic obstructive cardiomyopathy (HOCM). HAND mRNA was constitutively expressed in the hypertrophied heart and increased in the hypertrophic tissue of both patient groups. HAND genes had a complementary left-right cardiac asymmetry of expression with dHAND predominantly in the right and eHAND in the left ventricle. The two cardiac bHLH factors have the ability to form heterodimers with the ubiquitous bHLH protein E12, subsequently recognizing E-boxes in the promoter region of target genes like ALC-1. We found a highly significant positive correlation between HAND and ALC-1 mRNA. The total ALC-1 protein level in ToF was smaller than in HOCM, although ALC-1 mRNA as well as HAND mRNA levels were significantly higher. ToF patients expressed around four times more ALC-1 mRNA for similar amounts of ALC-1 than HOCM patients. Suggesting disturbed ALC-1 translation in ToF, we found ALC-1 antisense mRNA expression in the hypertrophied, but not in the normal, ventricles. The higher the antisense/sense ALC-1 mRNA ratio, the lower ALC-1 protein was expressed.
Ritter
O
O
Max Delbrück Center for Molecular Medicine, 13122 Berlin, Germany.
Haase
H
H
Schulte
H D
HD
Lange
P E
PE
Morano
I
I
D001483:Base Sequence; D051792:Basic Helix-Loop-Helix Proteins; D002312:Cardiomyopathy, Hypertrophic / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D017931:DNA Primers / Q000235:genetics; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D015870:Gene Expression; D006352:Heart Ventricles / Q000378:metabolism; D018257:Helix-Loop-Helix Motifs / Q000235:genetics / Q000502:physiology; D006801:Humans; D009206:Myocardium / Q000378:metabolism* / Q000473:pathology; D018994:Myosin Light Chains / Q000235:genetics / Q000378:metabolism; D016372:RNA, Antisense / Q000235:genetics / Q000378:metabolism; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D013771:Tetralogy of Fallot / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism*; D029961:Zebrafish Proteins
D051792:Basic Helix-Loop-Helix Proteins; D017931:DNA Primers; D004268:DNA-Binding Proteins; D018994:Myosin Light Chains; D016372:RNA, Antisense; D012333:RNA, Messenger; D014157:Transcription Factors; D029961:Zebrafish Proteins; C498765:HAND2 protein, human; C410915:hand2 protein, zebrafish; C097341:helix-loop-helix protein, eHAND