Diminished zonula occludens-1 expression in the failing human heart.
BACKGROUND
Reduced expression of the major gap junction protein connexin 43 (Cx43) in the failing human heart may lead to arrhythmias and sudden cardiac death. Cx43 interacts with the actin binding protein, zonula occludens-1 (ZO-1), and it has recently been demonstrated that ZO-1 regulates the formation and function of Cx43 gap junctions. We hypothesize that normal expression of ZO-1 and its interaction with Cx43 are required for appropriate assembly and function of Cx43 gap junctions in the heart. Here, we determined whether expression of ZO-1 is altered in patients with heart failure.


METHODS
We examined ventricular myocardium from hearts of patients in end-stage heart failure, obtained at transplant, for ZO-1 expression by immunohistochemistry. We also subjected lysates made from this tissue to immunoblotting to determine the level of ZO-1 expression.


CONCLUSIONS
ZO-1 was found at 96% of the intercalated discs in nonfailing control human hearts, where it colocalized with Cx43. In contrast, there was ZO-1 immunostaining at 5% of intercalated discs in failing hearts, coincident with a reduction in Cx43 staining in intercalated discs. Immunoblotting analysis showed that there was a 95% reduction in ZO-1 expression in human heart failure. Loss of ZO-1 at intercalated discs in heart failure may play a critical role in remodeling of Cx43 gap junctions, which may contribute to abnormal impulse propagation and arrhythmogenesis, thereby predisposing patients in heart failure to sudden cardiac death.
Laing
James G
JG
Department of Internal Medicine, Washington University School of Medicine, St. Louis, MO 63110, USA. laing@id.wustl.edu
Saffitz
Jeffrey E
JE
Steinberg
Thomas H
TH
Yamada
Kathryn A
KA
D000328:Adult; D018031:Connexin 43 / Q000378:metabolism; D005260:Female; D019084:Fluorescent Antibody Technique, Indirect; D006333:Heart Failure / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology / Q000601:surgery; D016027:Heart Transplantation; D006352:Heart Ventricles / Q000378:metabolism* / Q000473:pathology; D006801:Humans; D008297:Male; D008565:Membrane Proteins / Q000378:metabolism*; D008875:Middle Aged; D009206:Myocardium / Q000378:metabolism* / Q000473:pathology; D010750:Phosphoproteins / Q000378:metabolism*; D062826:Zonula Occludens-1 Protein
D018031:Connexin 43; C500216:GJA1 protein, human; D008565:Membrane Proteins; D010750:Phosphoproteins; C569042:TJP1 protein, human; D062826:Zonula Occludens-1 Protein