title: Absence of thrombospondin-2 increases cardiomyocyte damage and matrix disruption in doxorubicin-induced cardiomyopathy.
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.
authors.affiliation: Center for Heart Failure Research, Cardiovascular Research Institute Maastricht, Maastricht University, PO Box 5800, 6202 AZ Maastricht, The Netherlands.
authors.forename: Geert C
authors.initials: GC
authors.lastname: van Almen
authors.forename: Melissa
authors.initials: M
authors.lastname: Swinnen
authors.forename: Paolo
authors.initials: P
authors.lastname: Carai
authors.forename: Wouter
authors.initials: W
authors.lastname: Verhesen
authors.forename: Jack P M
authors.initials: JP
authors.lastname: Cleutjens
authors.forename: Jan
authors.initials: J
authors.lastname: D'hooge
authors.forename: Fons K
authors.initials: FK
authors.lastname: Verheyen
authors.forename: Yigal M
authors.initials: YM
authors.lastname: Pinto
authors.forename: Blanche
authors.initials: B
authors.lastname: Schroen
authors.forename: Peter
authors.initials: P
authors.lastname: Carmeliet
authors.forename: Stephane
authors.initials: S
authors.lastname: Heymans
mesh_terms: D000818:Animals; D000903:Antibiotics, Antineoplastic / Q000633:toxicity*; D009202:Cardiomyopathies / Q000139:chemically induced* / Q000378:metabolism / Q000473:pathology; D004317:Doxorubicin / Q000633:toxicity*; D005109:Extracellular Matrix / Q000187:drug effects* / Q000378:metabolism; D005260:Female; D005355:Fibrosis / Q000235:genetics; D005786:Gene Expression Regulation / Q000187:drug effects; D008297:Male; D020778:Matrix Metalloproteinase 2 / Q000235:genetics / Q000378:metabolism; D051379:Mice; D057507:Mice, 129 Strain; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D032383:Myocytes, Cardiac / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D018384:Oxidative Stress / Q000235:genetics; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D051381:Rats; D011917:Rats, Inbred Lew; D015398:Signal Transduction / Q000187:drug effects / Q000235:genetics; D013482:Superoxide Dismutase / Q000235:genetics / Q000378:metabolism; D019699:Thrombospondins / Q000235:genetics* / Q000378:metabolism; D000099262:Thrombospondin 2; D000099156:Superoxide Dismutase 2
chemical_list: D000903:Antibiotics, Antineoplastic; D004317:Doxorubicin; D020778:Matrix Metalloproteinase 2; D051057:Proto-Oncogene Proteins c-akt; D013482:Superoxide Dismutase; D019699:Thrombospondins; D000099262:Thrombospondin 2; D000099156:Superoxide Dismutase 2