Metabolomics,Unknown,Transcriptomics,Genomics,Proteomics

Dataset Information

Transcription profiling of rat Ren2 left ventricles to generate predictive heart failure expression profile

ABSTRACT: The intercalated disc of cardiac myocytes is emerging as a crucial structure in the heart. Loss of intercalated disc proteins like N-cadherin causes lethal cardiac abnormalities, mutations in intercalated disc 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 intercalated disc, where it associates with cadherin. RNAi-mediated knockdown of LIMP-2 decreases the binding of phosphorylated b-catenin to cadherin, while overexpression of LIMP-2 has the opposite effect. Taken together, our data show that lysosomal integrated membrane protein-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 intercalated disc. Experiment Overall Design: overall design: Experiment Overall Design: 3 groups of rats, 1 sample per rat: Experiment Overall Design: - compensated = Ren2 rat, hypertensive, no heart failure (N=6) Experiment Overall Design: - failure = Ren2 rat, hypertensive, no heart failure (N=4) Experiment Overall Design: - SD = control group, non-hypertensive (N=4)

ORGANISM(S): Rattus norvegicus

SUBMITTER: Arie van Erk

PROVIDER: E-GEOD-4286 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress

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Publications

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

Schroen Blanche B 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

The Journal of experimental medicine 20070507 5

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 en ...[more]

PMID: 17485520

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Project description:To identify a novel target for the treatment of heart failure, we examined gene expression in the failing heart. Among the genes analyzed, 12/15 lipoxygenase (12/15-LOX) was markedly up-regulated in heart failure. To determine whether increased expression of 12/15-LOX causes heart failure, we established transgenic mice that overexpressed 12/15-LOX in cardiomyocytes. Echocardiography showed that 12/15-LOX transgenic mice developed systolic dysfunction. Cardiac fibrosis increased in 12/15-LOX transgenic mice with advancing age, and was associated with the infiltration of macrophages. Consistent with these observations, cardiac expression of monocyte chemoattractant protein-1 (Mcp-1) was up-regulated in 12/15-LOX transgenic mice compared with wild-type mice. Treatment with 12-hydroxy-eicosatetraenotic acid, a major metabolite of 12/15-LOX, increased MCP-1 expression in cardiac fibroblasts and endothelial cells, but not in cardiomyocytes. Inhibition of Mcp-1 reduced the infiltration of macrophages into the myocardium and prevented both systolic dysfunction and cardiac fibrosis in 12/15-LOX transgenic mice. Likewise, disruption of 12/15-LOX significantly reduced cardiac Mcp-1 expression and macrophage infiltration, thereby improving systolic dysfunction induced by chronic pressure overload. Our results suggest that cardiac 12/15-LOX is involved in the development of heart failure and that inhibition of 12/15-LOX could be a novel treatment for this condition. Heart failure is still one of the leading causes of death worldwide. Therefore, it is important to elucidate the underlying mechanisms of heart failure and develop more effective treatments for this condition. To clarify the molecular mechanisms of heart failure, we performed microarray analysis using cardiac tissue samples obtained from a hypertensive heart failure model (Dahl salt-sensitive rats). ~300 genes showed significant changes of expression in the failing hearts compared with control hearts. Among the genes analyzed, 12/15-lipoxygenase (12/15-LOX) was most markedly up-regulated in failing hearts compared with control hearts .

Dataset Information

Transcription profiling of rat Ren2 left ventricles to generate predictive heart failure expression profile

Publications

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

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