Journal
MOLECULAR AND CELLULAR BIOCHEMISTRY
Volume 477, Issue 3, Pages 877-884Publisher
SPRINGER
DOI: 10.1007/s11010-021-04337-5
Keywords
Matrix metalloproteinase; Soluble epoxide hydrolase; Cardiovascular diseases; Extracellular matrix; Epoxyeicosatrienoic acids
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Funding
- Canadian Institutes of Health Research (CIHR) [MOP 106665]
- Alberta Innovates-Health Solutions summer studentship
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This study identified two compounds that simultaneously inhibit the activity of MMP and sEH, which could provide a promising intervention for the prevention and control of diseases, especially cardiovascular diseases.
Matrix metalloproteinase (MMP) and soluble epoxide hydrolase (sEH) have completely unrelated biological functions; however, their dysregulation produce similar effects on biological systems. Based on the similarity in the reported structural requirements for their inhibition, the current study aimed to identify a simultaneous inhibitor for MMP and sEH. Six compounds were identified as potential simultaneous MMP/sEH inhibitors and tested for their capacity to inhibit MMP and sEH. Inhibition of MMP and sEH activity using their endogenous and exogenous substrates was measured by liquid chromatography/mass spectrometry, spectrophotometry, and zymography. Two compounds, CTK8G1143 and ONO-4817, were identified to inhibit both MMP and sEH activity. CTK8G1143 and ONO-4817 inhibited the recombinant human sEH activity by an average of 67.4% and 55.2%, respectively. The IC50 values for CTK8G1143 and ONO-4817 to inhibit recombinant human sEH were 5.2 and 3.5 mu M, respectively, whereas their maximal inhibition values were 71.4% and 42.8%, respectively. Also, MMP and sEH activity of human cardiomyocytes were simultaneously inhibited by CTK8G1143 and ONO-4817. Regarding other compounds, they showed either MMP or sEH inhibitory activity but not both. In conclusion, these two simultaneous inhibitors of MMP and sEH could provide a promising intervention for the prevention and control of several diseases, especially cardiovascular diseases.
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