title: Blockade to pathological remodeling of infarcted heart tissue using a porcupine antagonist.
abstract: 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,COL6A1, has been shown to decrease aberrant remodeling and fibrosis in infarcted heart tissue. We demonstrate that WNT-974 can improve the recovery of heart function after left anterior descending coronary artery ligation by mitigating adverse remodeling of infarcted tissue. Injured heart tissue exposed to WNT-974 exhibits decreased scarring and reduced Col6 production. Our findings support the development of Porcn inhibitors as antifibrotic agents that could be exploited to promote heart repair following injury.
authors.affiliation: Department of Pediatrics, University of Texas Southwestern Medical Center, Dallas, TX 75390.
authors.forename: Jesung
authors.initials: J
authors.lastname: Moon
authors.affiliation: Department of Molecular Biology, University of Texas Southwestern Medical Center, Dallas, TX 75390.|Hamon Center for Regenerative Science and Medicine, University of Texas Southwestern Medical Center, Dallas, TX 75390.
authors.forename: Huanyu
authors.initials: H
authors.lastname: Zhou
authors.affiliation: Hamon Center for Regenerative Science and Medicine, University of Texas Southwestern Medical Center, Dallas, TX 75390.|Department of Cell Biology, University of Texas Southwestern Medical Center, Dallas, TX 75390.
authors.forename: Li-Shu
authors.initials: LS
authors.lastname: Zhang
authors.affiliation: Department of Molecular Biology, University of Texas Southwestern Medical Center, Dallas, TX 75390.|Hamon Center for Regenerative Science and Medicine, University of Texas Southwestern Medical Center, Dallas, TX 75390.
authors.forename: Wei
authors.initials: W
authors.lastname: Tan
authors.affiliation: Department of Biomedical Sciences, Texas A&M University College of Dentistry, Dallas, TX 75246.
authors.forename: Ying
authors.initials: Y
authors.lastname: Liu
authors.affiliation: Advanced Imaging Research Center, University of Texas Southwestern Medical Center, Dallas, TX 75390.
authors.forename: Shanrong
authors.initials: S
authors.lastname: Zhang
authors.affiliation: Department of Biochemistry, University of Texas Southwestern Medical Center, Dallas, TX 75390.
authors.forename: Lorraine K
authors.initials: LK
authors.lastname: Morlock
authors.affiliation: Department of Chemical and Biological Engineering, University of Wisconsin Madison, Madison, WI 53706.
authors.forename: Xiaoping
authors.initials: X
authors.lastname: Bao
authors.affiliation: Department of Chemical and Biological Engineering, University of Wisconsin Madison, Madison, WI 53706.
authors.forename: Sean P
authors.initials: SP
authors.lastname: Palecek
authors.affiliation: Department of Biomedical Sciences, Texas A&M University College of Dentistry, Dallas, TX 75246.
authors.forename: Jian Q
authors.initials: JQ
authors.lastname: Feng
authors.affiliation: Department of Biochemistry, University of Texas Southwestern Medical Center, Dallas, TX 75390.
authors.forename: Noelle S
authors.initials: NS
authors.lastname: Williams
authors.affiliation: Department of Pediatrics, University of Texas Southwestern Medical Center, Dallas, TX 75390.|Department of Molecular Biology, University of Texas Southwestern Medical Center, Dallas, TX 75390.|Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, TX 75390.
authors.forename: James F
authors.initials: JF
authors.lastname: Amatruda
authors.affiliation: Department of Molecular Biology, University of Texas Southwestern Medical Center, Dallas, TX 75390; Eric.Olson@utsouthwestern.edu lawrence.lum@utsouthwestern.edu.|Hamon Center for Regenerative Science and Medicine, University of Texas Southwestern Medical Center, Dallas, TX 75390.
authors.forename: Eric N
authors.initials: EN
authors.lastname: Olson
authors.affiliation: Department of Molecular Biology, University of Texas Southwestern Medical Center, Dallas, TX 75390.|Hamon Center for Regenerative Science and Medicine, University of Texas Southwestern Medical Center, Dallas, TX 75390.
authors.forename: Rhonda
authors.initials: R
authors.lastname: Bassel-Duby
authors.affiliation: Hamon Center for Regenerative Science and Medicine, University of Texas Southwestern Medical Center, Dallas, TX 75390; Eric.Olson@utsouthwestern.edu lawrence.lum@utsouthwestern.edu.|Department of Cell Biology, University of Texas Southwestern Medical Center, Dallas, TX 75390.
authors.forename: Lawrence
authors.initials: L
authors.lastname: Lum
mesh_terms: D000217:Acyltransferases / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D000818:Animals; D064752:Atrial Remodeling / Q000187:drug effects* / Q000235:genetics; D002478:Cells, Cultured; D024142:Collagen Type VI / Q000235:genetics / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000737:chemistry / Q000494:pharmacology*; D015870:Gene Expression / Q000187:drug effects; D057809:HEK293 Cells; D006801:Humans; D008565:Membrane Proteins / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D008810:Mice, Inbred C57BL; D015394:Molecular Structure; D009203:Myocardial Infarction / Q000235:genetics / Q000503:physiopathology / Q000517:prevention & control*; D011719:Pyrazines / Q000737:chemistry / Q000494:pharmacology; D011725:Pyridines / Q000737:chemistry / Q000494:pharmacology; D012038:Regeneration / Q000187:drug effects / Q000235:genetics; D060449:Wnt Signaling Pathway / Q000187:drug effects / Q000235:genetics
chemical_list: D024142:Collagen Type VI; D004791:Enzyme Inhibitors; D008565:Membrane Proteins; D011719:Pyrazines; D011725:Pyridines; D000217:Acyltransferases; C491187:Porcn protein, mouse; C586458:LGK974
keywords: Wnt; adult tissue homeostasis; extracellular matrix; heart regeneration; protein lipidation