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

Abstract

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 and 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.

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

“…The authors conclude, however, that an antifibrotic effect involving collagen-VI was responsible for the beneficial effect on infarct healing of WNT-974. In contrast to the studies with Porcupine inhibitors mentioned above, Yang et al (2017) demonstrated not only reduced infarct size and improved function but also a significant increase in newly formed CMs in the border zone of mice treated with the Porcupine inhibitor CGX1321 for 4 weeks post-MI. The total number of 5-ethynyl-29-deoxyuridine (EdU)positive mononucleated adult CMs was found to be significantly up-regulated, which was indicative for induction of CM proliferation by the Porcupine inhibitor.…”

Endocardial Notch Signaling Promotes Cardiomyocyte Proliferation in the Regenerating Zebrafish Heart through Wnt Pathway Antagonism

“…While studies employing cultured rat cardiomyocytes and embryonic mice have demonstrated that Wnt/β-catenin signaling is a positive regulator of cardiomyocyte proliferation in the absence of insult ( Buikema et al, 2013 ; Heallen et al, 2011 ; Ozhan and Weidinger, 2015 ; Tseng et al, 2006 ; Ye et al, 2015 ), our data have uncovered an injury-dependent inhibitory role during zebrafish heart regeneration. This function is likely to be conserved in mammals as inhibition of Wnt signaling following experimental myocardial infarction in mice stimulated cardiomyocyte proliferation and improved outcomes ( Bastakoty et al, 2016 ; Yang et al, 2017 ).…”

Cardiac regeneration and remodelling of the cardiomyocyte cytoarchitecture

“…Wnt signalling is known to exert a crucial function in heart development and CM specification . Yet, the roles of this pathway on heart regeneration are still poorly understood , and current evidence appears to indicate that inhibition of this pathway promotes CM proliferation during zebrafish regeneration and in infarcted mice .…”