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01.07.2006 | ORIGINAL CONTRIBUTION

LAMP-2 deficient mice show depressed cardiac contractile function without significant changes in calcium handling

verfasst von: Dr. med. Jörg Stypmann, Paul M.L. Janssen, Jürgen Prestle, Markus A. Engelen, Harald Kögler, Renate Lüllmann-Rauch, Lars Eckardt, Kurt von Figura, Jobst Landgrebe, Anna Mleczko, Paul Saftig

Erschienen in: Basic Research in Cardiology | Ausgabe 4/2006

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Abstract

Objective

Mutations in the highly glycosylated lysosome associated membrane protein-2 (LAMP-2) cause, as recently shown, familial Danon disease with mental retardation, mild myopathy and fatal cardiomyopathy. Extent and basis of the contractile dysfunction is not completely understood.

Methods

In LAMP-2 deficient mice, we investigated cardiac function in vivo using Doppler-echocardiography and contractile function in vitro in isolated myocardial trabeculae.

Results

LAMP-2 deficient mice displayed reduced ejection fraction (EF) (58.9±3.4 vs. 80.7±5.1%, P<0.05) and reduced cardiac output (8.3±3.1 vs. 14.7±3.6 ml/min, P<0.05) as compared to wild-type controls. Isolated multicellular muscle preparations from LAMP-2 deficient mice confirmed depressed force development (3.2±0.6 vs. 8.4±0.9 mN/mm², P<0.01). All groups showed similar force-frequency behaviour when normalised to baseline force. Post-rest potentiation was significantly depressed at intervals >15 s in LAMP-2 deficient mice (P<0.05). Although attenuated in absolute force development, the normalised inotropic response to increased calcium and β-adrenoreceptor stimulation was unaltered. Electron microscopic analysis revealed autophagic vacuoles in LAMP-2 deficient cardiomyocytes. Protein analysis showed unaltered levels of SERCA2a, calsequestrin and phospholamban.

Conclusions

Cardiac contractile function in LAMP-2 deficient mice as a model for Danon disease is significantly attenuated. The occurrence of autophagic vacuoles in LAMP-2 deficient myocytes is likely to be causal for the depressed contractile function resulting in an attenuated cardiac pump reserve.

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Titel: LAMP-2 deficient mice show depressed cardiac contractile function without significant changes in calcium handling
verfasst von: Dr. med. Jörg Stypmann
Paul M.L. Janssen
Jürgen Prestle
Markus A. Engelen
Harald Kögler
Renate Lüllmann-Rauch
Lars Eckardt
Kurt von Figura
Jobst Landgrebe
Anna Mleczko
Paul Saftig
Publikationsdatum: 01.07.2006
Verlag: Steinkopff-Verlag
Erschienen in: Basic Research in Cardiology / Ausgabe 4/2006
Print ISSN: 0300-8428
Elektronische ISSN: 1435-1803
DOI: https://doi.org/10.1007/s00395-006-0591-6

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LAMP-2 deficient mice show depressed cardiac contractile function without significant changes in calcium handling