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Chronic hypoxia down-regulates tight junction protein ZO-2 expression in children with cyanotic congenital heart defect.

Jenkins EL, Caputo M, Angelini GD, Ghorbel MT - ESC Heart Fail (2015)

Bottom Line: Tight junction protein zonula occludens protein 2 (ZO-2) is a member of the membrane-associated guanylate kinases protein family known to be expressed at tight junctions of epithelial and endothelial cells and at adherens junctions (AJs) in cardiomyocytes.This specific down-regulation can be mimicked in cultured rat cardiomyocytes by treating them with hypoxic conditions confirming that ZO-2 gene down-regulation is specifically due to cyanosis.This down-regulation suggest an involvement of ZO-2 in cardiac remodelling of AJs in cyanotic children and may explain the greater susceptibility of cyanotic patients to corrective heart surgery.

View Article: PubMed Central - PubMed

Affiliation: Bristol Heart Institute, School of Clinical Sciences University of Bristol Bristol UK.

ABSTRACT

Aims: Tight junction protein zonula occludens protein 2 (ZO-2) is a member of the membrane-associated guanylate kinases protein family known to be expressed at tight junctions of epithelial and endothelial cells and at adherens junctions (AJs) in cardiomyocytes. Little is known about ZO-2 expression and function in the human heart. Here, we examined the hypothesis that chronic hypoxia down-regulates ZO-2 expression in human myocardium and cultured rat cardiomyocytes.

Methods and results: Patients with a diagnosis of cyanotic (n = 10) or acyanotic (n = 10) Tetralogy of Fallot undergoing surgical repair were used to examine ZO-2 messenger RNA and protein expression by real time-PCR, immunohistochemistry, and western blotting. A model of cultured rat cardiomyocytes was used to measure ZO-2 and AJ proteins levels in response to hypoxia and to investigate ZO-2 cellular localization. We showed that ZO-2 is expressed in myocardial tissue in acyanotic and cyanotic children with congenital heart defects. ZO-2 was specifically down-regulated in cyanotic myocardium at both the messenger RNA and protein levels when compared with acyanotic patients. This specific down-regulation can be mimicked in cultured rat cardiomyocytes by treating them with hypoxic conditions confirming that ZO-2 gene down-regulation is specifically due to cyanosis. Furthermore, in addition to its cytoplasmic expression, ZO-2 showed nuclear expression in cultured rat cardiomyocytes suggesting potential role in transcription regulation.

Conclusions: Hypoxia down-regulates ZO-2 expression in both cyanotic patient's myocardium and cultured rat cardiomyocytes. This down-regulation suggest an involvement of ZO-2 in cardiac remodelling of AJs in cyanotic children and may explain the greater susceptibility of cyanotic patients to corrective heart surgery.

No MeSH data available.


Related in: MedlinePlus

Expression of zonula occludens protein 2 (ZO‐2) in acyanotic and cyanotic paediatric myocardium tissue. Immunohistochemical analysis of paraffin embedded heart tissue from an acyanotic and cyanotic patient using ZO‐2 specific antibody. 3,3’‐Diaminobenzidine (DAB) staining reveals expression of ZO‐2 in both tissues when compared with controls, with a visible decrease in expression in cyanotic tissue compared with acyanotic. Magnification: x200.
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ehf212081-fig-0001: Expression of zonula occludens protein 2 (ZO‐2) in acyanotic and cyanotic paediatric myocardium tissue. Immunohistochemical analysis of paraffin embedded heart tissue from an acyanotic and cyanotic patient using ZO‐2 specific antibody. 3,3’‐Diaminobenzidine (DAB) staining reveals expression of ZO‐2 in both tissues when compared with controls, with a visible decrease in expression in cyanotic tissue compared with acyanotic. Magnification: x200.

Mentions: Immunohistochemical analysis of fixed paediatric heart biopsy sections showed expression of ZO‐2 in heart tissue taken from both acyanotic and cyanotic patients undergoing corrective surgery for CHD (Figure 1).


Chronic hypoxia down-regulates tight junction protein ZO-2 expression in children with cyanotic congenital heart defect.

Jenkins EL, Caputo M, Angelini GD, Ghorbel MT - ESC Heart Fail (2015)

Expression of zonula occludens protein 2 (ZO‐2) in acyanotic and cyanotic paediatric myocardium tissue. Immunohistochemical analysis of paraffin embedded heart tissue from an acyanotic and cyanotic patient using ZO‐2 specific antibody. 3,3’‐Diaminobenzidine (DAB) staining reveals expression of ZO‐2 in both tissues when compared with controls, with a visible decrease in expression in cyanotic tissue compared with acyanotic. Magnification: x200.
© Copyright Policy - creativeCommonsBy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4933037&req=5

ehf212081-fig-0001: Expression of zonula occludens protein 2 (ZO‐2) in acyanotic and cyanotic paediatric myocardium tissue. Immunohistochemical analysis of paraffin embedded heart tissue from an acyanotic and cyanotic patient using ZO‐2 specific antibody. 3,3’‐Diaminobenzidine (DAB) staining reveals expression of ZO‐2 in both tissues when compared with controls, with a visible decrease in expression in cyanotic tissue compared with acyanotic. Magnification: x200.
Mentions: Immunohistochemical analysis of fixed paediatric heart biopsy sections showed expression of ZO‐2 in heart tissue taken from both acyanotic and cyanotic patients undergoing corrective surgery for CHD (Figure 1).

Bottom Line: Tight junction protein zonula occludens protein 2 (ZO-2) is a member of the membrane-associated guanylate kinases protein family known to be expressed at tight junctions of epithelial and endothelial cells and at adherens junctions (AJs) in cardiomyocytes.This specific down-regulation can be mimicked in cultured rat cardiomyocytes by treating them with hypoxic conditions confirming that ZO-2 gene down-regulation is specifically due to cyanosis.This down-regulation suggest an involvement of ZO-2 in cardiac remodelling of AJs in cyanotic children and may explain the greater susceptibility of cyanotic patients to corrective heart surgery.

View Article: PubMed Central - PubMed

Affiliation: Bristol Heart Institute, School of Clinical Sciences University of Bristol Bristol UK.

ABSTRACT

Aims: Tight junction protein zonula occludens protein 2 (ZO-2) is a member of the membrane-associated guanylate kinases protein family known to be expressed at tight junctions of epithelial and endothelial cells and at adherens junctions (AJs) in cardiomyocytes. Little is known about ZO-2 expression and function in the human heart. Here, we examined the hypothesis that chronic hypoxia down-regulates ZO-2 expression in human myocardium and cultured rat cardiomyocytes.

Methods and results: Patients with a diagnosis of cyanotic (n = 10) or acyanotic (n = 10) Tetralogy of Fallot undergoing surgical repair were used to examine ZO-2 messenger RNA and protein expression by real time-PCR, immunohistochemistry, and western blotting. A model of cultured rat cardiomyocytes was used to measure ZO-2 and AJ proteins levels in response to hypoxia and to investigate ZO-2 cellular localization. We showed that ZO-2 is expressed in myocardial tissue in acyanotic and cyanotic children with congenital heart defects. ZO-2 was specifically down-regulated in cyanotic myocardium at both the messenger RNA and protein levels when compared with acyanotic patients. This specific down-regulation can be mimicked in cultured rat cardiomyocytes by treating them with hypoxic conditions confirming that ZO-2 gene down-regulation is specifically due to cyanosis. Furthermore, in addition to its cytoplasmic expression, ZO-2 showed nuclear expression in cultured rat cardiomyocytes suggesting potential role in transcription regulation.

Conclusions: Hypoxia down-regulates ZO-2 expression in both cyanotic patient's myocardium and cultured rat cardiomyocytes. This down-regulation suggest an involvement of ZO-2 in cardiac remodelling of AJs in cyanotic children and may explain the greater susceptibility of cyanotic patients to corrective heart surgery.

No MeSH data available.


Related in: MedlinePlus