Document Detail


Thrombospondin-4 is required for stretch-mediated contractility augmentation in cardiac muscle.
MedLine Citation:
PMID:  22034490     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
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.
Authors:
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:
Type:  Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't     Date:  2011-10-27
Journal Detail:
Title:  Circulation research     Volume:  109     ISSN:  1524-4571     ISO Abbreviation:  Circ. Res.     Publication Date:  2011 Dec 
Date Detail:
Created Date:  2011-12-13     Completed Date:  2012-02-07     Revised Date:  2013-06-27    
Medline Journal Info:
Nlm Unique ID:  0047103     Medline TA:  Circ Res     Country:  United States    
Other Details:
Languages:  eng     Pagination:  1410-4     Citation Subset:  IM    
Affiliation:
Division of Cardiology, Department of Medicine, Department of Biomedical Engineering, The Johns Hopkins University Medical Institutions, Baltimore, MD 21205, USA.
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MeSH Terms
Descriptor/Qualifier:
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:
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:
0/Thrombospondins; 0/thrombospondin 4; EC 2.7.11.1/Proto-Oncogene Proteins c-akt
Comments/Corrections

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