Abstract Body: Background: Cardiac fibrosis can be reduced by limiting fibroblast-to-myofibroblast differentiation and proliferation. Our previous study shows that glypican 3 (GPC3)-metabolically reprogrammed diabetic mesenchymal stromal cells enhanced cardiac reparative activities following post-myocardial infarction (MI). However, the direct role of GPC3 in cardiac fibrosis remains unknown.

Methods: We first analyzed GPC3 protein and mRNA levels in heart samples from patients with heart failure and mouse MI heart. The mechanisms and functional significance of GPC3 in cardiac fibrosis were further investigated with both in vitro and in vivo models using AAV9 with a periostin promoter specifically targets GPC3 in myofibroblasts.

Results: Human cardiac biopsies from patients with HF showed significant increases in GPC3 expression compared with nonfailing control hearts. GPC3 expression was significantly increased in mouse hearts at 7, 14, and 28 days after MI. Furthermore, cardiac fibroblasts treated with TGF-b1 resulted in a significant elevation in GPC3 expression. Knockdown of GPC3 in TGF-b1 treated cardiac fibroblasts suppressed myofibroblast differentiation. AAV9-periostin promoter mediated knockdown of GPC3 post-MI, which improved left ventricular function and reduced cardiac remodeling post-MI in mice.

Conclusion: Overall, these data suggest that inhibiting GPC3 in cardiac fibroblasts may be a promising therapeutic approach to limiting cardiac fibrosis.