Pressure Overload-induced Right Ventricular Failure is Associated with Re-expression of Myocardial Tenascin-C and Elevated Plasma Tenascin-C Levels

Abstract

Background: We investigated whether (1) monocrotaline(MCT)-induced right ventricular (RV) dilatation is associated with re-expression of myocardial tenascin-C (TNC), (2) elevated plasma TNC levels can be used as a marker of ventricular dilatation, and (3) MCT-induced RV dilatation is associated with alterations of other remodeling-related proteins. Methods: Rats were treated with MCT in low dose (30 mg/kg, MCT30, n=10) to induce compensated RV hypertrophy, in high dose (80 mg/kg, MCT80, n=11) to induce RV failure, and with saline as control (CONT, n=9). After 4 weeks, RV function was assessed. TNC gene expression, protein levels, and plasma levels were assayed. Myocardial gene expression of integrin subunit α6 and β1, and myocardial proMMP2 and proMMP9 levels were assessed. Results: TNC gene expression in the RV of MCT80 rats was significantly upregulated compared with RV of CONT (4-fold, p<0.001) and MCT30 rats (3-fold, p<0.01), whereas TNC gene expression was very low in LV and IVS of MCT80 rats, and absent in those of CONT and MCT30 rats. Myocardial TNC protein levels were only observed in MCT80 rats, and were higher in RV (0.62±0.64 ng/mg) than in LV (0.21±0.44 ng/mg) or IVS (0.21±0.09 ng/mg) (p<0.01, RV vs LV and IVS). Plasma levels of TNC were significantly elevated in MCT80 rats compared with CONT (p<0.05). RV volumes correlated positively with TNC plasma levels and RV ejection fraction correlated negatively with TNC plasma levels. MCT-induced RV failure was also associated with a significant downregulation of integrin α6 gene expression (by 48%, p<0.01). Conclusions: MCT-induced RV failure is associated with an upregulation of TNC gene expression, resulting in re-expression of myocardial TNC protein levels, and elevated TNC plasma levels. As RV ejection fraction correlated significantly with TNC plasma levels, TNC plasma levels may serve as a marker of ventricular failure. De-adhesive properties of TNC in combination with a downregulation of integrin α6 may have caused cardiomyocyte slippage, leading to adverse ventricular remodeling.

Expression profile of matricellular proteins in hypertrophied right ventricle of monocrotaline-induced pulmonary hypertensive rats

“…As with the previous reports, we confirmed that MCT induced pulmonary hypertension, RV hypertrophy and dysfunction, all of which worsened over time [11]. In hypertrophied left ventricles of various cardiac disease animal models, such as angiotensin II (Ang II)-induced and transverse aortic constriction (TAC)-induced cardiac hypertrophy model mice, expression of SPARC, TnC, TSP-1, 2 and 4, CCN1 and 5, periostin and OPN was upregulated [1, 4, 9, 10, 15, 23, 25, 30, 32, 33]. SPARC family proteins play a role in processing of procollagen to mature collagens and in collagen fibril assembly [3, 4, 27].…”

“…Hessel et al . reported that TnC expression was increased in RV from high dose (80 mg/kg, 4 weeks) MCT-treated rats [9]. They suggested that TnC caused cardiomyocyte slippage followed by RV dilatation through de-adhesive activity and integrin β6 downregulation [9].…”

“…reported that periostin expression is upregulated in in interstitial space and interstitial cells in TAC model mice [19]. In addition, TnC expression has been reported to be upregulated in interstitial space in RV of MCT-treated rats [9]. Thus, it is suggested that interstitial cells, such as cardiac fibroblasts and myofibroblasts, are the main sources for matricellular proteins in RV of MCT-treated rats.…”

“…[6]. In various heart disease models including pressure-overloaded left ventricular hypertrophy or myocardial infarction, matricellular proteins [secreted protein acidic and rich in cysteine (SPARC) family, thrombospondin (TSP) family, CCN family, tenascin (Tn) family, periostin and osteopontin (OPN)] are upregulated and involved in the progression of pathological condition [9, 16, 19, 24, 28,29,30, 33]. Kögler et al .…”

“…reported that enhanced biomechanical load is necessary to induce the changes in gene expression associated with the hypertrophic phenotype in the pressure-overloaded RV [14]. While mRNA and protein expression of TnC was reported to be upregulated in hypertrophied RV from monocrotaline (MCT)-treated pulmonary hypertensive rats [9], the expression level of other matricellular proteins has not yet been clarified. Thus, the present study aimed to clarify the mRNA expression profile of matricellular proteins in hypertrophied RV from MCT-treated pulmonary hypertensive rats.…”