Cthrc1 deficiency aggravates wound healing and promotes cardiac rupture after myocardial infarction via non-canonical WNT5A signaling pathway.

Abstract

Cardiac fibroblasts are crucial for scar formation and cardiac repair after myocardial infarction (MI). Collagen triple helix repeat containing 1 (CTHRC1), an extracellular matrix protein, is involved in the pathogenesis of vascular remodeling, bone formation, and tumor progression. However, the role and underlying mechanism of CTHRC1 in post-MI wound repair are not fully clear. Bioinformatics analysis demonstrated CTHRC1 up-regulation in cardiac fibroblasts after ischemic cardiac injury. Serum levels of CTHRC1 were increased in MI mice and CTHRC1 expression was up-regulated in cardiac fibroblasts after MI. In vitro results showed that the induction of CTHRC1 expression in cardiac fibroblasts was mediated by canonical TGFβ1-Smad2/3 signaling axis. Moreover, CTHRC1 improved wound healing and boosted cardiac fibroblast activation in vitro. Cthrc1 deficiency aggravated cardiac function and reduced collagen deposition as well as increased mortality attributable to cardiac rupture after MI. Consistent with above phenotypes, reduced the levels of myocardial CD31, α-smooth muscle actin, collagen I, and collagen III was observed, whereas myocardial expression of matrix metalloproteinase 2 and matrix metalloproteinase 9 were increased in Cthrc1 knockout mice post-MI. Above effects could be partly reversed by rCTHRC1 protein or rWNT5A protein. Our study indicates that cardiac fibroblast-derived, canonical TGFβ1-Smad2/3-dependent CTHRC1 could improve wound repair and prevent cardiac rupture after MI via selectively activating non-canonical WNT5A-PCP signaling pathway.

• Authors: Di Wang, Yaping Zhang, Tianbao Ye, Runlei Zhang, Lili Zhang, Dongmei Shi, Taixi Li, Guofang Xia, Kaifan Niu, Zhe Zhao, Yu Chen, Weijun Pan, Liang Liu, Xian Jin, Chengxing Shen
• Journal: International journal of biological sciences (Int J Biol Sci) Vol. 19 Issue 4 Pg. 1299-1315 ( 2023) ISSN: 1449-2288 [Electronic] Australia
• PMID: 36923925 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © The author(s).

Chemical References

• Collagen
• Extracellular Matrix Proteins
• Matrix Metalloproteinase 2
• Cthrc1 protein, mouse

Topics

• Animals
• Mice
• Collagen (metabolism)
• Extracellular Matrix Proteins (genetics, metabolism)
• Fibroblasts (metabolism)
• Heart Rupture (metabolism, pathology)
• Matrix Metalloproteinase 2 (genetics, metabolism)
• Mice, Knockout
• Myocardial Infarction (metabolism)
• Wnt Signaling Pathway
• Wound Healing (genetics)