DOI: 10.1161/01.res.0000156274.72390.2c. Induced Deletion of the <i>N-Cadherin</i> Gene in the Heart Leads to Dissolution of the Intercalated Disc Structure [Penn]

Induced Deletion of the N-Cadherin Gene in the Heart Leads to Dissolution of the Intercalated Disc Structure

10.1161/01.res.0000156274.72390.2c

Crossref journal-article

Ovid Technologies (Wolters Kluwer Health)

Circulation Research (276)

Abstract

The structural integrity of the heart is maintained by the end-to-end connection between the myocytes called the intercalated disc. The intercalated disc contains different junctional complexes that enable the myocardium to function as a syncytium. One of the junctional complexes, the zonula adherens or adherens junction, consists of the cell adhesion molecule, N-cadherin, which mediates strong homophilic cell–cell adhesion via linkage to the actin cytoskeleton. To determine the function of N-cadherin in the working myocardium, we generated a conditional knockout containing loxP sites flanking exon 1 of the N-cadherin ( Cdh2 ) gene. Using a cardiac-specific tamoxifen-inducible Cre transgene, N-cadherin was deleted in the adult myocardium. Loss of N-cadherin resulted in disassembly of the intercalated disc structure, including adherens junctions and desmosomes. The mutant mice exhibited modest dilated cardiomyopathy and impaired cardiac function, with most animals dying within two months after tamoxifen administration. Decreased sarcomere length and increased Z-line thickness were observed in the mutant hearts consistent with loss of muscle tension because N-cadherin was no longer available to anchor myofibrils at the plasma membrane. Ambulatory electrocardiogram monitoring captured the abrupt onset of spontaneous ventricular tachycardia, confirming that the deaths were arrhythmic in nature. A significant decrease in the gap junction protein, connexin 43, was observed in the N-cadherin–depleted hearts. This animal model provides the first demonstration of the hierarchical relationship of the structural components of the intercalated disc in the working myocardium, thus establishing N-cadherin’s paramount importance in maintaining the structural integrity of the heart.

Bibliography

Kostetskii, I., Li, J., Xiong, Y., Zhou, R., Ferrari, V. A., Patel, V. V., Molkentin, J. D., & Radice, G. L. (2005). Induced Deletion of the N-Cadherin Gene in the Heart Leads to Dissolution of the Intercalated Disc Structure. Circulation Research, 96(3), 346â354.

Authors 8

Igor Kostetskii (first)
Jifen Li (additional)
Yanming Xiong (additional)
Rong Zhou (additional)
Victor A. Ferrari (additional)
Vickas V. Patel (additional)
Jeffery D. Molkentin (additional)
Glenn L. Radice (additional)

References 37 Referenced 289

Dates

Type	When
Created	20 years, 7 months ago (Jan. 20, 2005, 8:25 p.m.)
Deposited	1 year, 3 months ago (May 12, 2024, 2:14 p.m.)
Indexed	3 weeks, 2 days ago (Aug. 7, 2025, 4:54 a.m.)
Issued	20 years, 6 months ago (Feb. 18, 2005)
Published	20 years, 6 months ago (Feb. 18, 2005)
Published Print	20 years, 6 months ago (Feb. 18, 2005)

Funders 0

None

BibTeX

@article{Kostetskii_2005, title={Induced Deletion of the N-Cadherin Gene in the Heart Leads to Dissolution of the Intercalated Disc Structure}, volume={96}, ISSN={1524-4571}, url={http://dx.doi.org/10.1161/01.res.0000156274.72390.2c}, DOI={10.1161/01.res.0000156274.72390.2c}, number={3}, journal={Circulation Research}, publisher={Ovid Technologies (Wolters Kluwer Health)}, author={Kostetskii, Igor and Li, Jifen and Xiong, Yanming and Zhou, Rong and Ferrari, Victor A. and Patel, Vickas V. and Molkentin, Jeffery D. and Radice, Glenn L.}, year={2005}, month=feb, pages={346–354} }

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  "abstract": "<jats:p>\n            The structural integrity of the heart is maintained by the end-to-end connection between the myocytes called the intercalated disc. The intercalated disc contains different junctional complexes that enable the myocardium to function as a syncytium. One of the junctional complexes, the zonula adherens or adherens junction, consists of the cell adhesion molecule, N-cadherin, which mediates strong homophilic cell\u2013cell adhesion via linkage to the actin cytoskeleton. To determine the function of N-cadherin in the working myocardium, we generated a conditional knockout containing loxP sites flanking exon 1 of the\n            <jats:italic>N-cadherin</jats:italic>\n            (\n            <jats:italic>Cdh2</jats:italic>\n            ) gene. Using a cardiac-specific tamoxifen-inducible Cre transgene,\n            <jats:italic>N-cadherin</jats:italic>\n            was deleted in the adult myocardium. Loss of N-cadherin resulted in disassembly of the intercalated disc structure, including adherens junctions and desmosomes. The mutant mice exhibited modest dilated cardiomyopathy and impaired cardiac function, with most animals dying within two months after tamoxifen administration. Decreased sarcomere length and increased Z-line thickness were observed in the mutant hearts consistent with loss of muscle tension because N-cadherin was no longer available to anchor myofibrils at the plasma membrane. Ambulatory electrocardiogram monitoring captured the abrupt onset of spontaneous ventricular tachycardia, confirming that the deaths were arrhythmic in nature. A significant decrease in the gap junction protein, connexin 43, was observed in the N-cadherin\u2013depleted hearts. This animal model provides the first demonstration of the hierarchical relationship of the structural components of the intercalated disc in the working myocardium, thus establishing N-cadherin\u2019s paramount importance in maintaining the structural integrity of the heart.\n          </jats:p>",
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