Abstract 767: Pressure Overload-Induced Right Ventricular Dilatation is Associated with Re-Expression of Myocardial Tenascin-C and Increased Plasma Levels of Tenascin-C
Purpose: Tenascin-C (TNC) contributes to myocardial remodeling by weakening the binding between cardiomyocytes and extracellular matrix (ECM). TNC is primarily expressed in fetal myocardium but reappears in adult myocardium under various pathological conditions, where extensive tissue remodeling occurs. The purpose of this study was to test whether monocrotaline (MCT)-induced right ventricular (RV) dilatation in the rat is associated with re-expression of myocardial TNC and increased plasma levels of TNC.
Methods: Rats were treated with MCT in low dose (30 mg/kg s.c., MCT30, n=10) to induce compensated RV hypertrophy, in high dose (80 mg/kg s.c., MCT80, n=11) to induce RV failure, and with saline as control (CONT, n=9). After 4 weeks, RV function was characterized by pressure-volume loop analyses (conductance catheter). Subsequently, blood samples were collected and rats were sacrificed. Hearts were dissected, the RV, left ventricle (LV) and interventricular septum (IVS) were cut free and homogenized. TNC mRNA levels were determined by RT-PCR, myocardial TNC levels by ELISA and immunohistochemistry, and plasma levels of TNC by ELISA.
Results: Relative RV mRNA levels of TNC were significantly upregulated in MCT80 rats (≈412±82% p<0.01) compared to CONT (100%) and MCT30 rats (≈135±125%). Myocardial TNC protein levels were detectable in MCT80 rats (RV: 0.62±0.64 ng/mg; LV: 0.21±0.44 ng/mg; IVS:0.18±0.11 ng/mg), but not in CONT or MCT30 rats. Myocardial TNC was located in the ECM only. Plasma levels of TNC were 23.9±8.5 ng/ml in CONT, 30.8±5.3 ng/ml in MCT30, and 37±16 ng/ml in MCT80 rats (p<0.05 vs CONT), and correlated positively with RV end-systolic and end-diastolic volumes (r=0.526, p=0.008 and r=0.458, p=0.05, respectively.) and negatively with RV ejection fraction (r=−0.59, p=0.002).
Conclusions: RV dilatation as a result of MCT-induced pressure-overload is associated with upregulation of TNC mRNA levels, resulting in re-expression of myocardial TNC protein levels and increased TNC plasma levels. TNC may cause cardiomyocyte slippage during remodeling and the specific expression suggests that elevated plasma levels of TNC can be used as marker for ventricular remodeling.