Secreted Frizzled Related Protein 4 Reduces Fibrosis Scar Size and Ameliorates Cardiac Function After Ischemic Injury

Abstract

Expression of the Wnt modulator secreted frizzled related protein 4 (Sfrp4) is upregulated after heart ischemic injury. We show that intramuscular administration of recombinant Sfrp4 to rat heart ischemic injury and recanalization models prevents further deterioration of cardiac function after the ischemic injury. The effect of Sfrp4 persisted for at least 20 weeks when Sfrp4 was administered in a slow release system (Sfrp4-polyhedra) to both acute and subacute ischemic models. The histology of the dissected heart showed that the cardiac wall was thicker and the area of acellular scarring was smaller in Sfrp4-treated hearts than in controls. Increased amounts of both the inactive serine 9-phosphorylated form of glycogen synthase kinase (GSK)-3β and the active form of β-catenin were observed by immunohistology 3 days after lateral anterior descendant ligation in control, but not in Sfrp4-treated hearts. All together, we show that administration of Sfrp4 interferes with canonical Wnt signaling that could mediate the formation of acellular scar and consequently contributes to the prevention of aggravation of cardiac function.

Wnt4/β−Catenin Signaling in Medullary Kidney Myofibroblasts

“…This observation provides definitive evidence that canonical Wnt signaling is important in myofibroblast transition, consistent with the ability of canonical pathway inhibitors dickkopf-1, dickkopf-2, or secreted frizzled-related protein-4 to ameliorate fibrosis in various tissue types. 17,43,[58][59][60] These results are also consistent with an important role for b-catenin signaling in the development of fibrosis in other organs. [43][44][45][46][47][48][49][50][51] As a consequence, efforts to develop antifibrotic therapies should not target a single Wnt ligand but rather should block either multiple Wnt ligands or alternatively inhibit downstream effectors of the entire pathway.…”

Wnt Signaling in Cardiac Disease

“…It must be noted that these are protein levels whereas the previously mentioned study used mRNA as a measure of sFRP2 expression. Finally, sFRP4 gene expression peaked early following MI too (3-5 days), but remained increased for 3 weeks and returned to baseline at 28 days (156).…”

“…Recombinant sFRP4 administration was shown to be beneficial following permanent MI as well as in the reperfused myocardium in rats (156). sFRP4 was able to increase cardiac wall thickness and to reduce scar size and was accompanied by prevention of impaired cardiac function.…”

View from the heart: cardiac fibroblasts in development, scarring and regeneration

“…In general, strategies involving the use of Wnt antagonists throughout myocardial remodelling after infarct exert beneficial effects on myocardial function due to the modulation of fibroblast activity and reduction of scarring (Barandon et al, 2003(Barandon et al, , 2005He et al, 2010;Laeremans et al, 2011;Matsushima et al, 2010;Saraswati et al, 2010). Paradoxically, however, removal of the (Furtado et al, 2014a).…”