The Journal of Experimental Medicine
Janeway's Immunobiology 7th Edition
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Published online May 7, 2007
doi:10.1084/jem.20070145
The Journal of Experimental Medicine, Vol. 204, No. 5, 1227-1235
The Rockefeller University Press, 0022-1007 $30.00
© 2007 Schroen et al.
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ARTICLE

 Lysosomal integral membrane protein 2 is a novel component of the cardiac intercalated disc and vital for load-induced cardiac myocyte hypertrophy

Blanche Schroen1, Joost J. Leenders1, Arie van Erk1, Anne T. Bertrand3, Mirjam van Loon1, Rick E. van Leeuwen1, Nard Kubben1, Rudy F. Duisters1, Mark W. Schellings1, Ben J. Janssen2, Jacques J. Debets2, Michael Schwake4, Morten A. Høydal5, Stephane Heymans1, Paul Saftig4, and Yigal M. Pinto1

1 Department of Experimental and Molecular Cardiology and 2 Department of Pharmacology/CARIM, University of Maastricht, 6202 AZ Maastricht, Netherlands
3 Hubrecht Laboratory and Interuniversity Cardiology Institute Netherlands, Royal Netherlands Academy of Arts and Sciences, 3584 CT Utrecht, Netherlands
4 Biochemisches Institut, Universität Kiel, 24098 Kiel, Germany
5 Department of Circulation and Medical Imaging, Norwegian University of Science and Technology, NO-7491 Trondheim, Norway

CORRESPONDENCE Yigal M. Pinto: Y.Pinto{at}cardio.azm.nl

The intercalated disc (ID) of cardiac myocytes is emerging as a crucial structure in the heart. Loss of ID proteins like N-cadherin causes lethal cardiac abnormalities, and mutations in ID proteins cause human cardiomyopathy. A comprehensive screen for novel mechanisms in failing hearts demonstrated that expression of the lysosomal integral membrane protein 2 (LIMP-2) is increased in cardiac hypertrophy and heart failure in both rat and human myocardium. Complete loss of LIMP-2 in genetically engineered mice did not affect cardiac development; however, these LIMP-2 null mice failed to mount a hypertrophic response to increased blood pressure but developed cardiomyopathy. Disturbed cadherin localization in these hearts suggested that LIMP-2 has important functions outside lysosomes. Indeed, we also find LIMP-2 in the ID, where it associates with cadherin. RNAi-mediated knockdown of LIMP-2 decreases the binding of phosphorylated ß-catenin to cadherin, whereas overexpression of LIMP-2 has the opposite effect.

Collectively, our data show that LIMP-2 is crucial to mount the adaptive hypertrophic response to cardiac loading. We demonstrate a novel role for LIMP-2 as an important mediator of the ID.

Abbreviations used: ANF, atrial natriuretic factor; Ang, angiotensin; aska, {alpha}-skeletal actin; BNP, brain natriuretic peptide; HF, heart failure; ID, intercalated disc; IP, immunoprecipitation; LIMP-2, lysosomal integral membrane protein 2; LV, left ventricle; RCM, rat ventricular cardiac myocyte; shLIMP-2, short-hairpin RNA against LIMP-2; shRNA, short-hairpin RNA; TSP, thrombospondin.


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