Abstract 13408: Tumor Endothelial Marker 1 is Upregulated in Cardiomyocytes and Participates in Cardiac Remodeling After Cardiac Injury

Background: Tumor endothelial marker 1 (TEM1), also known as endosialin or CD248, is a transmembrane protein that expresses in mesenchymal lineage-derived cells only during embryogenesis and becomes undetectable in normal tissues after birth. Re-expression of TEM1 is found on activated cells of mesenchymal lineage during pathological conditions, such as stroma cells in cancer, fibroblasts in organ fibrosis and wound healing, indicating its potential role in tissue remodeling and repair. The expression levels and physiological functions of TEM1 in heart are unknown. Methods and Results: All data were presented as mean ± standard error. In 2 explanted hearts from patients with heart failure (HF) received heart transplantation, immunofluorescence staining showed TEM1 was highly expressed in cardiomyocytes (CMs) and also in cardiac fibroblasts. In mouse HF models induced by intraperitoneal doxorubicin injection (5 mg/kg/wk for 4 wks) or coronary ligation, immunohistochemistry study showed TEM1 expression in hearts. Western blot showed 1.23±0.02 and 1.56±0.04-fold increase of cardiac TEM1 expression compared to controls, respectively. In vitro studies showed TEM1 expression increased in cultured CMs (H9C2 cells) treated with: (1) mechanical stretch (10% elongation at 60 cycles/min) (0 vs 0.5 vs 1 vs 3 hr, Western blot ratio: 1 vs 1.86±0.20 vs 1.87±0.20 vs 1.21±0.21, p<0.05), (2) doxorubicin (100 nM) (0 vs 0.5 vs 2 vs 4 hr: 1 vs 0.70±0.22 vs 1.75±0.26 vs 1.84±0.24, p<0.05) and (3) hypoxia (1% O2) (0 vs 0.5 vs 2 vs 4 hr: 1 vs 1.70±0.06 vs 1.49±0.22 vs 2.07±0.35, p<0.05). Recombinant TEM1 (rTEM1) promoted proliferation of H9C2 cells (saline vs rTEM1 50 vs 100 vs 250 nM, BrdU absorbance: 1.23±0.03 vs 1.36±0.03 vs 1.37±0.05 vs 1.38±0.02, p<0.05), reduced doxorubicin (1uM)-induced apoptosis (apoptosis ratio: 1 vs 0.89±0.02 vs 0.91±0.01 vs 0.88±0.05, p<0.05), increased cell hypertrophy (cell area ratio: 1 vs 1.11±0.21 vs 1.51±0.18 vs 1.63±0.13, p<0.05) and increased collagen production from CMs (collagen 3 Western blot ratio: 1 vs 1.49±0.15 vs 1.53±0.19 vs 1.29±0.24, p<0.05). Conclusions: Our study results indicate that TEM1 is upregulated in CMs after cardiac injury and influences the cell behaviors of CMs that related to cardiac remodeling.