Abstract 202: Thrombospondin-2 Protects Against Uncontrolled Cardiac Inflammation and Oxidative Stress During Doxorubicin-Induced Myocarditis
Background Doxorubicin is a live-saving chemotherapeutic agent in young patients affected by cancer. However, its use is limited by its cardiotoxicity caused by increased oxidative stress and exaggerated inflammation. Whether thrombospondin-2 (TSP-2) may protect against doxorubicin-induced cardiomyopathy (Dox-CMP), by limiting cardiac oxidative stress and inflammation, remains unknown.
Methods and Results Therefore, mortality, cardiac inflammation and function were investigated in TSP2 deficient (KO) (n= 10) and wild type (WT) (n=10) mice during Dox-CMP by injecting doxorubicin at 4mg/kg/week for 6 weeks. Absence of TSP-2 resulted in increased mortality after 6 weeks of Dox-injection (KO: 30% vs WT: 0%). Histological analysis of diseased hearts revealed a significantly increased influx of CD45 positive leukocytes, and increased cardiac necrosis and myocyte disarray, shown by desmin staining, in TSP2 KO mice compared to WT mice at 6 weeks of Dox-CMP. Further electron microscopic analysis of these hearts showed increased matrix disruption and mytochondrial vacuolization with membrane disruption, indicating increased oxidative injury, in TSP2 KO mice compared to WT mice. Increased inflammation and oxidative injury in absence of TSP2 resulted in significantly increased cardiac dilatation (end-diastolic dimensions, mm; 2.3 Â ± 0.2 in WT vs. 3.1 Â ± 0.3 in KO mice, P<0.05) at 6 weeks of Dox-CMP. Increased matrix disruption and cardiac dilatation in Dox-CMP in absence of TSP2 was characterized by increased MMP-2 zymographic activity and decreased tissue transglutaminase-2 activity (A.U. activity: 8.4 Â ± 3.0 in KO vs. 13.8 Â ± 4.2 in WT mice, P<0.05).
In conclusion Together, these data point towards a novel role for TSP-2 in protecting against uncontrolled cardiac inflammation, oxidative injury and dilatation in Dox-CMP.