Therapeutic effect of a novel Wnt pathway inhibitor on cardiac regeneration after myocardial infarction

Clin Sci (Lond). 2017 Dec 8;131(24):2919-2932. doi: 10.1042/CS20171256. Print 2017 Dec 15.


After myocardial infarction (MI), the heart is difficult to repair because of great loss of cardiomyoctyes and lack of cardiac regeneration. Novel drug candidates that aim at reducing pathological remodeling and stimulating cardiac regeneration are highly desirable. In the present study, we identified if and how a novel porcupine inhibitor CGX1321 influenced MI and cardiac regeneration. Permanent ligation of left anterior descending (LAD) coronary artery was performed in mice to induce MI injury. Cardiac function was measured by echocardiography, infarct size was examined by TTC staining. Fibrosis was evaluated with Masson's trichrome staining and vimentin staining. As a result, CGX1321 administration blocked the secretion of Wnt proteins, and inhibited both canonical and non-canonical Wnt signaling pathways. CGX1321 improved cardiac function, reduced myocardial infarct size, and fibrosis of post-MI hearts. CGX1321 significantly increased newly formed cardiomyocytes in infarct border zone of post-MI hearts, evidenced by the increased EdU+ cardiomyocytes. Meanwhile, CGX1321 increased Ki67+ and phosphohistone H3 (PH3+) cardiomyocytes in culture, indicating enhanced cardiomyocyte proliferation. The mRNA microarray showed that CGX1321 up-regulated cell cycle regulating genes such as Ccnb1 and Ccne1 CGX1321 did not alter YAP protein phosphorylation and nuclear translocation in cardiomyocytes. In conclusion, porcupine inhibitor CGX1321 reduces MI injury by limiting fibrosis and promoting regeneration. It promotes cardiomyocyte proliferation by stimulating cell cycle regulating genes with a Hippo/YAP-independent pathway.

Keywords: CGX; Cardiac Remodeling; Cardiomyocyte Proliferation; Myocardial Infarction; Regeneration; Wnt Pathway.

MeSH terms

  • Acyltransferases / antagonists & inhibitors*
  • Acyltransferases / metabolism
  • Adaptor Proteins, Signal Transducing / metabolism
  • Animals
  • Cell Cycle Proteins / genetics
  • Cell Cycle Proteins / metabolism
  • Cell Proliferation / drug effects
  • Cells, Cultured
  • Disease Models, Animal
  • Enzyme Inhibitors / pharmacology*
  • Fibrosis
  • Ki-67 Antigen / metabolism
  • Male
  • Membrane Proteins / antagonists & inhibitors*
  • Membrane Proteins / metabolism
  • Mice, Inbred C57BL
  • Myocardial Infarction / drug therapy*
  • Myocardial Infarction / enzymology
  • Myocardial Infarction / pathology
  • Myocardial Infarction / physiopathology
  • Myocardium / enzymology*
  • Myocardium / pathology
  • Myocytes, Cardiac / drug effects*
  • Myocytes, Cardiac / enzymology
  • Myocytes, Cardiac / pathology
  • Phosphoproteins / metabolism
  • Phosphorylation
  • Rats
  • Regeneration / drug effects*
  • Time Factors
  • Up-Regulation
  • Wnt Proteins / metabolism
  • Wnt Signaling Pathway / drug effects*
  • Wnt-5a Protein / metabolism
  • YAP-Signaling Proteins


  • Adaptor Proteins, Signal Transducing
  • Cell Cycle Proteins
  • Enzyme Inhibitors
  • Ki-67 Antigen
  • Membrane Proteins
  • Phosphoproteins
  • Wnt Proteins
  • Wnt-5a Protein
  • Wnt5a protein, rat
  • Wnt5b protein, rat
  • YAP-Signaling Proteins
  • Yap1 protein, mouse
  • Acyltransferases
  • Porcn protein, mouse