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. 2011 Sep;51(3):318-28.
doi: 10.1016/j.yjmcc.2011.05.010. Epub 2011 May 23.

Absence of thrombospondin-2 increases cardiomyocyte damage and matrix disruption in doxorubicin-induced cardiomyopathy

Geert C van Almen  1 , Melissa Swinnen, Paolo Carai, Wouter Verhesen, Jack P M Cleutjens, Jan D'hooge, Fons K Verheyen, Yigal M Pinto, Blanche Schroen, Peter Carmeliet, Stephane Heymans
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Absence of thrombospondin-2 increases cardiomyocyte damage and matrix disruption in doxorubicin-induced cardiomyopathy

Geert C van Almen et al. J Mol Cell Cardiol. 2011 Sep.

Abstract

Clinical use of the antineoplastic agent doxorubicin (DOX) is limited by its cardiomyocyte toxicity. Attempts to decrease cardiomyocyte injury showed promising results in vitro, but failed to reduce the adverse effects of DOX in vivo, suggesting that other mechanisms contribute to its cardiotoxicity as well. Evidence that DOX also induces cardiac injury by compromising extracellular matrix integrity is lacking. The matricellular protein thrombospondin-2 (TSP-2) is known for its matrix-preserving function, and for modulating cellular function. Here, we investigated whether TSP-2 modulates the process of doxorubicin-induced cardiomyopathy (DOX-CMP). TSP-2-knockout (TSP-2-KO) and wild-type (WT) mice were treated with DOX (2 mg/kg/week) for 12 weeks to induce DOX-CMP. Mortality was significantly increased in TSP-2-KO compared to WT mice. Surviving DOX-treated TSP-2-KO mice had depressed cardiac function compared to WT animals, accompanied by increased cardiomyocyte apoptosis and matrix damage. Enhanced myocyte damage in the absence of TSP-2 was associated with impaired activation of the Akt signaling pathway in TSP-2-KO compared to WT. The absence of TSP-2, in vivo and in vitro, reduced Akt activation both under non-treated conditions and after DOX. Importantly, inhibition of Akt phosphorylation in cardiomyocytes significantly reduced TSP-2 expression, unveiling a unique feedback loop between Akt and TSP-2. Finally, enhanced matrix disruption in DOX-treated TSP-2-KO hearts went along with increased matrix metalloproteinase-2 levels. Taken together, this study is the first to provide evidence for the implication of the matrix element TSP-2 in protecting against DOX-induced cardiac injury and dysfunction.

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