title: Mechanisms of transthyretin cardiomyocyte toxicity inhibition by resveratrol analogs.
abstract: The transthyretin amyloidoses are a subset of protein misfolding diseases characterized by the extracellular deposition of aggregates derived from the plasma homotetrameric protein transthyretin (TTR) in peripheral nerves and the heart. We have established a robust disease-relevant human cardiac tissue culture system to explore the cytotoxic effects of amyloidogenic TTR variants. We have employed this cardiac amyloidosis tissue culture model to screen 23 resveratrol analogs as inhibitors of amyloidogenic TTR-induced cytotoxicity and to investigate their mechanisms of protection. Resveratrol and its analogs kinetically stabilize the native tetramer preventing the formation of cytotoxic species. In addition, we demonstrate that resveratrol can accelerate the formation of soluble non-toxic aggregates and that the resveratrol analogs tested can bring together monomeric TTR subunits to form non-toxic native tetrameric TTR.
authors.affiliation: Department of Molecular and Experimental Medicine, The Scripps Research Institute, MEM-230, 10550 North Torrey Pines Road, La Jolla, CA 92037, USA.
authors.forename: Steve
authors.initials: S
authors.lastname: Bourgault
authors.forename: Sungwook
authors.initials: S
authors.lastname: Choi
authors.forename: Joel N
authors.initials: JN
authors.lastname: Buxbaum
authors.forename: Jeffery W
authors.initials: JW
authors.lastname: Kelly
authors.forename: Joshua L
authors.initials: JL
authors.lastname: Price
authors.forename: Natàlia
authors.initials: N
authors.lastname: Reixach
mesh_terms: D000686:Amyloidosis / Q000378:metabolism*; D000975:Antioxidants / Q000737:chemistry* / Q000494:pharmacology*; D002460:Cell Line; D006801:Humans; D032383:Myocytes, Cardiac / Q000187:drug effects* / Q000378:metabolism; D011228:Prealbumin / Q000037:antagonists & inhibitors* / Q000378:metabolism / Q000633:toxicity; D000077185:Resveratrol; D013267:Stilbenes / Q000737:chemistry* / Q000494:pharmacology*
chemical_list: D000975:Antioxidants; D011228:Prealbumin; D013267:Stilbenes; D000077185:Resveratrol