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Proc Natl Acad Sci U S A. 2017 Feb 14;114(7):1649-1654. doi: 10.1073/pnas.1621346114. Epub 2017 Jan 31.

Blockade to pathological remodeling of infarcted heart tissue using a porcupine antagonist.

Author information

1
Department of Pediatrics, University of Texas Southwestern Medical Center, Dallas, TX 75390.
2
Department of Molecular Biology, University of Texas Southwestern Medical Center, Dallas, TX 75390.
3
Hamon Center for Regenerative Science and Medicine, University of Texas Southwestern Medical Center, Dallas, TX 75390.
4
Department of Cell Biology, University of Texas Southwestern Medical Center, Dallas, TX 75390.
5
Department of Biomedical Sciences, Texas A&M University College of Dentistry, Dallas, TX 75246.
6
Advanced Imaging Research Center, University of Texas Southwestern Medical Center, Dallas, TX 75390.
7
Department of Biochemistry, University of Texas Southwestern Medical Center, Dallas, TX 75390.
8
Department of Chemical and Biological Engineering, University of Wisconsin Madison, Madison, WI 53706.
9
Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, TX 75390.
10
Department of Molecular Biology, University of Texas Southwestern Medical Center, Dallas, TX 75390; Eric.Olson@utsouthwestern.edu lawrence.lum@utsouthwestern.edu.
11
Hamon Center for Regenerative Science and Medicine, University of Texas Southwestern Medical Center, Dallas, TX 75390; Eric.Olson@utsouthwestern.edu lawrence.lum@utsouthwestern.edu.

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.

KEYWORDS:

Wnt; adult tissue homeostasis; extracellular matrix; heart regeneration; protein lipidation

PMID:
28143939
PMCID:
PMC5320972
DOI:
10.1073/pnas.1621346114
[Indexed for MEDLINE]
Free PMC Article

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