TGFβ2 and TGFβ3 mediate appropriate context-dependent phenotype of rat valvular interstitial cells.

Autor:	Wang F; Discovery Toxicology Group, Bristol-Myers Squibb, Route 206 & Province Line Road, Princeton, NJ 08543, USA., Zhang C; Discovery Toxicology Group, Bristol-Myers Squibb, Route 206 & Province Line Road, Princeton, NJ 08543, USA., Kwagh J; Discovery Toxicology Group, Bristol-Myers Squibb, Route 206 & Province Line Road, Princeton, NJ 08543, USA., Strassle B; Discovery Toxicology Group, Bristol-Myers Squibb, Route 206 & Province Line Road, Princeton, NJ 08543, USA., Li J; Discovery Toxicology Group, Bristol-Myers Squibb, Route 206 & Province Line Road, Princeton, NJ 08543, USA., Huang M; Discovery Toxicology Group, Bristol-Myers Squibb, Route 206 & Province Line Road, Princeton, NJ 08543, USA., Song Y; Discovery Toxicology Group, Bristol-Myers Squibb, Route 206 & Province Line Road, Princeton, NJ 08543, USA., Lehman B; Discovery Toxicology Group, Bristol-Myers Squibb, Route 206 & Province Line Road, Princeton, NJ 08543, USA., Westhouse R; Discovery Toxicology Group, Bristol-Myers Squibb, Route 206 & Province Line Road, Princeton, NJ 08543, USA., Palanisamy K; Biocon BMS R&D Center, Syngene International Ltd., Bommasandra Industrial Area, Bengaluru, Karnataka 560099, India., Holenarsipur VK; Biocon BMS R&D Center, Syngene International Ltd., Bommasandra Industrial Area, Bengaluru, Karnataka 560099, India., Borzilleri R; Immunosciences Discovery Chemistry, Bristol-Myers Squib, Princeton, NJ 08534, USA., Augustine-Rauch K; Discovery Toxicology Group, Bristol-Myers Squibb, Route 206 & Province Line Road, Princeton, NJ 08543, USA.
Jazyk:	angličtina
Zdroj:	IScience [iScience] 2021 Feb 03; Vol. 24 (3), pp. 102133. Date of Electronic Publication: 2021 Feb 03 (Print Publication: 2021).
DOI:	10.1016/j.isci.2021.102133
Abstrakt:	This study focused on characterizing the potential mechanism of valvular toxicity caused by TGFβ receptor inhibitors (TGFβRis) using rat valvular interstitial cells (VICs) to evaluate early biological responses to TGFβR inhibition. Three TGFβRis that achieved similar exposures in the rat were assessed. Two dual TGFβRI/-RII inhibitors caused valvulopathy, whereas a selective TGFβRI inhibitor did not, leading to a hypothesis that TGFβ 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 TGFβ expression demonstrated that combined TGFβ2/β3 inhibition by small interfering RNA or neutralizing antibodies caused similar alterations as TGFβRis. Inhibition of TGFβ3 transcription was only associated with the dual TGFβRis, suggesting that TGFβRII inhibition impacts TGFβ3 transcriptional regulation, and that the potency of valvular toxicity may relate to alteration of TGFβ2/β3-mediated processes involved in maintaining proper balance of VIC phenotypes in the heart valve. Competing Interests: All authors are employees of BMS and may own shares of company stocks, but there are no conflicts of interest in regard to the disclosure of data associated with this study. (© 2021 The Author(s).)
Databáze:	MEDLINE
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