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Cadherin‐3 and Catenin‐α2 are novel MMP‐12 substrates
Author(s) -
Chalise Upendra,
Lindsey Merry L.
Publication year - 2020
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.2020.34.s1.02384
Subject(s) - hippo signaling pathway , cadherin , matrix metalloproteinase , extracellular matrix , yap1 , ve cadherin , catenin , wnt signaling pathway , ventricular remodeling , signal transduction , microbiology and biotechnology , chemistry , medicine , cancer research , myocardial infarction , biology , transcription factor , gene , biochemistry , cell
Adverse cardiac remodeling after myocardial infarction (MI) is a major cause of heart failure. Degradation of the existing extracellular matrix (ECM) and subsequent formation of a new ECM scar are prominent components of cardiac remodeling. Matrix metalloproteinases (MMPs) increase after MI to dictate the degradation component. MMP‐12 inhibition after MI worsens dilation of the left ventricle by increasing its wall thinning, suggesting a possible protective role for MMP‐12 in MI remodeling. We hypothesized that identifying MMP‐12 substrates could provide mechanistic insight into MI roles. We used the Mouse Heart Attack Research Tool 1.0 (mHART 1.0) database and performed regression analysis to identify ECM genes that correlated with MMP‐12 expression. Of the 83 ECM genes compared to MMP‐12, 41 showed significant regressions (all p<0.05). This indicates a strong relationship between ECM breakdown after MI and MMP‐12. Synaptotagmin‐1, Contactin‐1, MMP‐10, MMP‐13, and Catenin‐α2 were the top 5 genes with significant positive correlation (Pearson coefficient r>0.99 and p<0.0001 for all). By Enrichr analysis for transcription factor pathway exploration, Yap1 signaling had a top combined score of 9.37 and p‐value 0.0033, indicating the upregulation of HIPPO signaling as the most enriched pathway. Catenin‐α2(Ctnna2), Cadherin‐1 (Cdh1), and Cadherin‐3 (Cdh3) were the three genes linked to Yap1‐ Hippo signaling. By substrate cleavage assay using 0.1 μg MMP‐12 enzyme to 0.5 μg substrate, Cdh3 and Ctnna2 but not Cdh1 were identified as novel MMP‐12 substrates. Cdh3 and Ctnna2 showed robust cleavage at 15 min, and Ctnna2 was completely processed by 3h. Our combined results reveal that MMP‐12 actions in MI remodeling could be attributed in part to Cdh3 and Ctnna2 proteolytic processing. Support or Funding Information We acknowledge funding from the National Institutes of Health under Award Numbers HL075360, HL129823, and HL137319, and the Biomedical Laboratory Research and Development Service of the Veterans Affairs Office of Research and Development under Award Numbers 5I01BX000505.