Thrombospondin-4 is required for stretch-mediated contractility augmentation in cardiac muscle short communication

Oscar H. Cingolani, Jonathan A. Kirk, Kinya Seo, Norimichi Koitabashi, Dong Lee, Genaro Ramirez-Correa, Djahida Bedja, Andreas S. Barth, An L. Moens, David A. Kass

Research output: Contribution to journalArticlepeer-review

64 Scopus citations


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.

Original languageEnglish (US)
Pages (from-to)1410-1414
Number of pages5
JournalCirculation research
Issue number12
StatePublished - Dec 9 2011


  • Anrep
  • Cardiac mechanics
  • Extracellular matrix
  • Mechano-transduction
  • Ventricular function

ASJC Scopus subject areas

  • Physiology
  • Cardiology and Cardiovascular Medicine


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