Lysosomal integral membrane protein 2 is a novel component of the cardiac intercalated disc and vital for load-induced cardiac myocyte hypertrophy.
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.
Schroen
Blanche
B
Department of Experimental and Molecular Cardiology, University of Maastricht, Maastricht, Netherlands.
Leenders
Joost J
JJ
van Erk
Arie
A
Bertrand
Anne T
AT
van Loon
Mirjam
M
van Leeuwen
Rick E
RE
Kubben
Nard
N
Duisters
Rudy F
RF
Schellings
Mark W
MW
Janssen
Ben J
BJ
Debets
Jacques J
JJ
Schwake
Michael
M
Høydal
Morten A
MA
Heymans
Stephane
S
Saftig
Paul
P
Pinto
Yigal M
YM
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
D018955:CD36 Antigens; D015820:Cadherins; D017931:DNA Primers; D051907:Lysosomal Membrane Proteins; C489452:Scarb2 protein, mouse; D051176:beta Catenin