Altered connexin expression in human congestive heart failure.
Congestive heart failure is associated with a high risk of life-threatening ventricular re-entrant arrhythmias. Down-regulation of the principal gap-junctional protein of the ventricular myocytes, connexin43, has previously been implicated in arrhythmia in ischaemic heart disease, but it is not known whether connexin43 is similarly reduced in heart failure due to idiopathic dilated cardiomyopathy, whether disease-related connexin43 down-regulation occurs at the level of transcription or translation, or whether the expression of other connexin isotypes is altered in congestive heart failure. We therefore investigated the expression of the four connexins expressed in the heart-connexins 43, 40, 45 and 37-at the mRNA and protein levels in explanted hearts from transplant patients with end-stage heart failure (NYHA class 4) by immunoconfocal analysis, and northern and western blotting. Connexin43 mRNA and protein were markedly downregulated in the left ventricle in end-stage heart failure due both to ischaemic cardiomyopathy and idiopathic dilated cardiomyopathy. Connexin43 content was spatially heterogeneous in the diseased ventricle. Connexin40 mRNA was increased in the ischaemic group, more so in the left ventricle than the right. This correlated with an increased depth of connexin40 protein expression in myocytes at the endocardial surface. Connexin45 mRNA and protein, present only in very low quantities, followed a similar trend to connexin43, while connexin37 (exclusively expressed in endothelium) showed no change. Our findings show that congestive heart failure is associated with significantly reduced levels of the principal gap junction protein, connexin43, in the left ventricle, potentially contributing to enhanced arrhythmogenicity and contractile dysfunction. This down-regulation is due predominantly to a reduced transcript steady-state level. Elevated connexin40 may represent a compensatory response that improves the spread of depolarization in the otherwise compromised ischaemic ventricle.
Dupont
E
E
National Heart and Lung Institute, Imperial College of Science, Technology and Medicine, London, UK.
Matsushita
T
T
Kaba
R A
RA
Vozzi
C
C
Coppen
S R
SR
Khan
N
N
Kaprielian
R
R
Yacoub
M H
MH
Severs
N J
NJ
D000328:Adult; D015152:Blotting, Northern; D015153:Blotting, Western; D009202:Cardiomyopathies / Q000378:metabolism; D002311:Cardiomyopathy, Dilated / Q000378:metabolism; D018031:Connexin 43 / Q000096:biosynthesis; D017630:Connexins / Q000096:biosynthesis*; D015536:Down-Regulation; D005260:Female; D006333:Heart Failure / Q000378:metabolism*; D016027:Heart Transplantation; D006801:Humans; D008297:Male; D018613:Microscopy, Confocal; D008856:Microscopy, Fluorescence; D008875:Middle Aged; D009206:Myocardium / Q000378:metabolism*; D014176:Protein Biosynthesis; D012333:RNA, Messenger / Q000378:metabolism; D014158:Transcription, Genetic; D000097003:Gap Junction alpha-5 Protein; D000097006:Gap Junction alpha-4 Protein
D018031:Connexin 43; D017630:Connexins; D012333:RNA, Messenger; D000097003:Gap Junction alpha-5 Protein; D000097006:Gap Junction alpha-4 Protein; C082920:connexin 45