| Thrombospondin-4 is required for stretch-mediated contractility augmentation in cardiac muscle. | |
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MedLine Citation:
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PMID: 22034490 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
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RATIONALE: One of the physiological mechanisms by which the heart adapts to a rise in blood pressure is by augmenting myocyte stretch-mediated intracellular calcium, with a subsequent increase in contractility. This slow force response was first described over a century ago and has long been considered compensatory, but its underlying mechanisms and link to chronic adaptations remain uncertain. Because levels of the matricellular protein thrombospondin-4 (TSP4) rapidly rise in hypertension and are elevated in cardiac stress overload and heart failure, we hypothesized that TSP4 is involved in this adaptive mechanism. OBJECTIVE: To determine the mechano-transductive role that TSP4 plays in cardiac regulation to stress. METHODS AND RESULTS: In mice lacking TSP4 (Tsp4⁻/⁻), hearts failed to acutely augment contractility or activate stretch-response pathways (ERK1/2 and Akt) on exposure to acute pressure overload. Sustained pressure overload rapidly led to greater chamber dilation, reduced function, and increased heart mass. Unlike controls, Tsp4⁻/⁻ cardiac trabeculae failed to enhance contractility and cellular calcium after a stretch. However, the contractility response was restored in Tsp4⁻/⁻ muscle incubated with recombinant TSP4. Isolated Tsp4⁻/⁻ myocytes responded normally to stretch, identifying a key role of matrix-myocyte interaction for TSP4 contractile modulation. CONCLUSION: These results identify TSP4 as myocyte-interstitial mechano-signaling molecule central to adaptive cardiac contractile responses to acute stress, which appears to play a crucial role in the transition to chronic cardiac dilatation and failure. |
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Authors:
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Oscar H Cingolani; Jonathan A Kirk; Kinya Seo; Norimichi Koitabashi; Dong-Ik Lee; Genaro Ramirez-Correa; Djahida Bedja; Andreas S Barth; An L Moens; David A Kass |
Publication Detail:
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Type: Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't Date: 2011-10-27 |
Journal Detail:
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Title: Circulation research Volume: 109 ISSN: 1524-4571 ISO Abbreviation: Circ. Res. Publication Date: 2011 Dec |
Date Detail:
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Created Date: 2011-12-13 Completed Date: 2012-02-07 Revised Date: 2012-10-09 |
Medline Journal Info:
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Nlm Unique ID: 0047103 Medline TA: Circ Res Country: United States |
Other Details:
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Languages: eng Pagination: 1410-4 Citation Subset: IM |
Affiliation:
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Division of Cardiology, Department of Medicine, Department of Biomedical Engineering, The Johns Hopkins University Medical Institutions, Baltimore, MD 21205, USA. |
Export Citation:
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| MeSH Terms | |
Descriptor/Qualifier:
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Animals Heart Failure / physiopathology Hypertension / physiopathology MAP Kinase Signaling System / physiology Male Mice Mice, Inbred C57BL Mice, Knockout Models, Animal Myocardial Contraction / physiology* Myocytes, Cardiac / cytology, physiology* Proto-Oncogene Proteins c-akt / physiology Rats Stress, Physiological / physiology* Thrombospondins / deficiency, genetics, physiology* |
| Grant Support | |
ID/Acronym/Agency:
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HL059408/HL/NHLBI NIH HHS; HL077180/HL/NHLBI NIH HHS; HL089297/HL/NHLBI NIH HHS; K08 HL109074-01/HL/NHLBI NIH HHS; K08 HL109074-02/HL/NHLBI NIH HHS; KO8 HL109074-01/HL/NHLBI NIH HHS; T32 HL0227/HL/NHLBI NIH HHS; T32 HL0772/HL/NHLBI NIH HHS |
| Chemical | |
Reg. No./Substance:
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0/Thrombospondins; 0/thrombospondin 4; EC 2.7.11.1/Proto-Oncogene Proteins c-akt |
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
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