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P.026 A Pivotal Role of the Anti-Angiogenetic Factor Thrombospondin-2 in the Progression of Cardiac Hypertrophy to Failure



Thrombospondin-2 has been implicated in angiogenesis during wound healing and tumour formation, but its role in cardiac hypertrophy and function during cardiac overload is unknown.


First, micro-array analysis of cardiac biopsies taken in hypertensive renin-overexpressing rats at the compensated phase (10 weeks) revealed that increased cardiac expression of the matricellular protein TSP2 identified the failure-prone hearts. Subsequently, thrombospondin-2 (TSP2) knockout and their wild type littermates were submitted to Angiontensin II infusion (0.5 µg/g/day). After detailed hemodynamic analysis, hearts were taken out and prepared for further histological and molecular analysis.


TSP2 immunostaining in WT mice revealed increased expression in areas of active remodeling after AngII infusion, with a maximum at 4 and 7 days and declining at 14 days. When TSP2 knockout (KO) mice were submitted to Ang II infusion, 70% of TSP2 KO mice succumbed due to fatal cardiac rupture. The surviving TSP2 KO mice showed severe cardiac failure, as indicated by decreased fractional shortening and increased diastolic dimensions, whereas cardiac rupture, dilatation or dysfunction were absent in TSP2 WT mice. Ultrastructural analysis of AngII treated TSP2-KO hearts revealed oedema and disruption of the extracellular matrix, associated with increased activity of the collagen degrading enzymes MMP-2 and MMP-9.

In conclusion, increased expression of the matricellular proteins TSP2 and SPARC during cardiac overload or ischemia protects against adverse cardiac remodeling, thereby preventing cardiac dilatation, failure or fatal cardiac rupture.

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Heymans, S., Vanhoutte, D. & Pinto, Y.M. P.026 A Pivotal Role of the Anti-Angiogenetic Factor Thrombospondin-2 in the Progression of Cardiac Hypertrophy to Failure. Artery Res 1 (Suppl 1), S33 (2006).

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