First Author | Cingolani OH | Year | 2011 |
Journal | Circ Res | Volume | 109 |
Issue | 12 | Pages | 1410-4 |
PubMed ID | 22034490 | Mgi Jnum | J:192717 |
Mgi Id | MGI:5466241 | Doi | 10.1161/CIRCRESAHA.111.256743 |
Citation | Cingolani OH, et al. (2011) Thrombospondin-4 is required for stretch-mediated contractility augmentation in cardiac muscle. Circ Res 109(12):1410-4 |
abstractText | 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. |