lgk974 and Myocardial-Infarction

The secreted Wnt signaling molecules are essential to the coordination of cell-fate decision making in multicellular organisms. In adult animals, the secreted Wnt proteins are critical for tissue regeneration and frequently contribute to cancer. Small molecules that disable the Wnt acyltransferase Porcupine (Porcn) are candidate anticancer agents in clinical testing. Here we have systematically assessed the effects of the Porcn inhibitor (WNT-974) on the regeneration of several tissue types to identify potentially unwanted chemical effects that could limit the therapeutic utility of such agents. An unanticipated observation from these studies is proregenerative responses in heart muscle induced by systemic chemical suppression of Wnt signaling. Using in vitro cultures of several cell types found in the heart, we delineate the Wnt signaling apparatus supporting an antiregenerative transcriptional program that includes a subunit of the nonfibrillar collagen VI. Similar to observations seen in animals exposed to WNT-974, deletion of the collagen VI subunit,

Topics: Acyltransferases; Animals; Atrial Remodeling; Cells, Cultured; Collagen Type VI; Enzyme Inhibitors; Gene Expression; HEK293 Cells; Humans; Membrane Proteins; Mice, Inbred C57BL; Molecular Structure; Myocardial Infarction; Pyrazines; Pyridines; Regeneration; Wnt Signaling Pathway