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Comparative Study
Lysosomal integral membrane protein 2 is a novel component of the cardiac intercalated disc and vital for load-induced cardiac myocyte hypertrophy.
- Blanche Schroen, Joost J Leenders, Arie van Erk, Anne T Bertrand, Mirjam van Loon, Rick E van Leeuwen, Nard Kubben, Rudy F Duisters, Mark W Schellings, Ben J Janssen, Jacques J Debets, Michael Schwake, Morten A Høydal, Stephane Heymans, Paul Saftig, and Yigal M Pinto.
- Department of Experimental and Molecular Cardiology, University of Maastricht, Maastricht, Netherlands.
- J. Exp. Med. 2007 May 14; 204 (5): 1227-35.
AbstractThe 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 beta-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.
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