title: 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.affiliation: Department of Experimental and Molecular Cardiology, University of Maastricht, Maastricht, Netherlands.
authors.forename: Blanche
authors.initials: B
authors.lastname: Schroen
authors.forename: Joost J
authors.initials: JJ
authors.lastname: Leenders
authors.forename: Arie
authors.initials: A
authors.lastname: van Erk
authors.forename: Anne T
authors.initials: AT
authors.lastname: Bertrand
authors.forename: Mirjam
authors.initials: M
authors.lastname: van Loon
authors.forename: Rick E
authors.initials: RE
authors.lastname: van Leeuwen
authors.forename: Nard
authors.initials: N
authors.lastname: Kubben
authors.forename: Rudy F
authors.initials: RF
authors.lastname: Duisters
authors.forename: Mark W
authors.initials: MW
authors.lastname: Schellings
authors.forename: Ben J
authors.initials: BJ
authors.lastname: Janssen
authors.forename: Jacques J
authors.initials: JJ
authors.lastname: Debets
authors.forename: Michael
authors.initials: M
authors.lastname: Schwake
authors.forename: Morten A
authors.initials: MA
authors.lastname: Høydal
authors.forename: Stephane
authors.initials: S
authors.lastname: Heymans
authors.forename: Paul
authors.initials: P
authors.lastname: Saftig
authors.forename: Yigal M
authors.initials: YM
authors.lastname: Pinto
mesh_terms: D000818:Animals; D001024:Aortic Valve Stenosis / Q000378:metabolism; D018955:CD36 Antigens / Q000235:genetics / Q000378:metabolism*; D015820:Cadherins / Q000378:metabolism; D002311:Cardiomyopathy, Dilated / Q000209:etiology / Q000235:genetics / Q000378:metabolism*; D017931:DNA Primers; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation / Q000502:physiology; D006801:Humans; D006973:Hypertension / Q000150:complications*; D051907:Lysosomal Membrane Proteins / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D032383:Myocytes, Cardiac / Q000378:metabolism* / Q000473:pathology; D034622:RNA Interference; D051381:Rats; D017207:Rats, Sprague-Dawley; D051176:beta Catenin / Q000378:metabolism
chemical_list: D018955:CD36 Antigens; D015820:Cadherins; D017931:DNA Primers; D051907:Lysosomal Membrane Proteins; C489452:Scarb2 protein, mouse; D051176:beta Catenin