Thrombospondin-4 is required for stretch-mediated contractility augmentation in cardiac muscle.
BACKGROUND
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.


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.


CONCLUSIONS
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.
Division of Cardiology, Department of Medicine, Department of Biomedical Engineering, The Johns Hopkins University Medical Institutions, Baltimore, MD 21205, USA.
Oscar H
OH
Cingolani
Jonathan A
JA
Kirk
Kinya
K
Seo
Norimichi
N
Koitabashi
Dong-Ik
DI
Lee
Genaro
G
Ramirez-Correa
Djahida
D
Bedja
Andreas S
AS
Barth
An L
AL
Moens
David A
DA
Kass
D000818:Animals; D006333:Heart Failure / Q000503:physiopathology; D006973:Hypertension / Q000503:physiopathology; D020935:MAP Kinase Signaling System / Q000502:physiology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D023421:Models, Animal; D009200:Myocardial Contraction / Q000502:physiology*; D032383:Myocytes, Cardiac / Q000166:cytology / Q000502:physiology*; D051057:Proto-Oncogene Proteins c-akt / Q000502:physiology; D051381:Rats; D013312:Stress, Physiological / Q000502:physiology*; D019699:Thrombospondins / Q000172:deficiency / Q000235:genetics / Q000502:physiology*
D019699:Thrombospondins; C101864:thrombospondin 4; D051057:Proto-Oncogene Proteins c-akt