Abstract:
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.
journal_name
Circ Resjournal_title
Circulation researchauthors
Cingolani OH,Kirk JA,Seo K,Koitabashi N,Lee DI,Ramirez-Correa G,Bedja D,Barth AS,Moens AL,Kass DAdoi
10.1161/CIRCRESAHA.111.256743subject
Has Abstractpub_date
2011-12-09 00:00:00pages
1410-4issue
12eissn
0009-7330issn
1524-4571pii
CIRCRESAHA.111.256743journal_volume
109pub_type
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