Thrombospondin-4 Is Required for Stretch-Mediated Contractility Augmentation in Cardiac Muscle

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

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review

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Abstract

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.To determine the mechano-transductive role that TSP4 plays in cardiac regulation to stress.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.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
Pages (from-to)1410-1414
JournalCirculation Research
Volume109
Issue number12
DOIs
Publication statusPublished - 9 Dec 2011

Keywords

  • cardiac mechanics
  • mechano-transduction
  • extracellular matrix
  • ventricular function
  • Anrep

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