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

Abstract

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 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.

• Authors: 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, Yigal M Pinto
• Journal: The Journal of experimental medicine (J Exp Med) Vol. 204 Issue 5 Pg. 1227-35 (May 14 2007) ISSN: 0022-1007 [Print] United States
• PMID: 17485520 (Publication Type: Comparative Study, Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• CD36 Antigens
• Cadherins
• DNA Primers
• Lysosomal Membrane Proteins
• Scarb2 protein, mouse
• beta Catenin

Topics

• Animals
• Aortic Valve Stenosis (metabolism)
• CD36 Antigens (genetics, metabolism)
• Cadherins (metabolism)
• Cardiomyopathy, Dilated (etiology, genetics, metabolism)
• DNA Primers
• Gene Expression Profiling
• Gene Expression Regulation (physiology)
• Humans
• Hypertension (complications)
• Lysosomal Membrane Proteins (genetics, metabolism)
• Mice
• Mice, Knockout
• Myocytes, Cardiac (metabolism, pathology)
• RNA Interference
• Rats
• Rats, Sprague-Dawley
• beta Catenin (metabolism)