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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, -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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