期刊
CIRCULATION RESEARCH
卷 109, 期 12, 页码 1410-1414出版社
LIPPINCOTT WILLIAMS & WILKINS
DOI: 10.1161/CIRCRESAHA.111.256743
关键词
cardiac mechanics; mechano-transduction; extracellular matrix; ventricular function; Anrep
资金
- National Health Service [HL089297, HL059408, HL-077180, T32HL-0772]
- Fondation Leducq
- Belfer Laboratory Foundation [K08-HL-109074-01, T32HL-0227]
- American Heart Association
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. (Circ Res. 2011;109:1410-1414.)
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