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.

Interventions in WNT Signaling to Induce Cardiomyocyte Proliferation: Crosstalk with Other Pathways

“…Histologically, fewer apoptotic CMs were detected and the number of myofibroblasts in the border zone was reduced (Bastakoty and Young, 2016). A similar reduction in infarct size with a concomitant improvement in cardiac function was reported in mice treated systemically with the Porcupine inhibitor WNT-974 from weeks 1 to 10 after MI induction (Moon et al, 2017). The authors conclude, however, that an antifibrotic effect involving collagen-VI was responsible for the beneficial effect on infarct healing of WNT-974.…”

Therapeutic approaches for cardiac regeneration and repair

“…Multiple signalling pathways, such as the renin-angiotensin-aldosterone system and the TGFβ and WNT signalling pathways, contribute to this fibrotic process after injury 20 . Targeting these pathways and inhibiting the progressive phase of fibrosis has been shown to improve cardiac function by attenuating cardiac remodelling 20,151–153 (FIG. 4).…”

Identification of Key Genes and Pathways in First Acute Myocardial Infarction Based on Gene Expression Profiling by Bioinformatics Analysis

“…Wnt-5a, a subtype of Wnt protein, is exclusively expressed in cardiomyocytes. It can promote the release of IL-1, IL-6 and IL-8 from mononuclear cells, suggesting a pro-inflammatory effect of Wnt signaling [24,25]. Previous study reported that the activity of Wnt signaling pathway plays an important role in cardiac tissue repair process after MI [26].…”