TGF2 and TGF3 mediate appropriate context-dependent phenotype of rat valvular interstitial cells

This study focused on characterizing the potential mechanism of valvular toxicity caused by TGF beta receptor inhibitors (TGF beta Ris) using rat valvular interstitial cells (VICs) to evaluate early biological responses to TGF beta R inhibition. Three TGF beta Ris that achieved similar exposures in the rat were assessed. Two dual TGF beta RI/-RII inhibitors caused valvulopathy, whereas a selective TGF beta RI inhibitor did not, leading to a hypothesis that TGF beta receptor selectivity may influence the potency of valvular toxicity. The dual valvular toxic inhibitors had the most profound effect on altering VIC phenotype including altered morphology, migration, and extracellular matrix production. Reduction of TGF beta expression demonstrated that combined TGF beta 2/beta 3 inhibition by small interfering RNA or neutralizing antibodies caused similar alterations as TGF beta Ris. Inhibition of TGF beta 3 transcription was only associated with the dual TGF beta Ris, suggesting that TGF beta RII inhibition impacts TGF beta 3 transcriptional regulation, and that the potency of valvular toxicity may relate to alteration of TGF beta 2/beta 3-mediated processes involved in maintaining proper balance of VIC phenotypes in the heart valve.