{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,12,18]],"date-time":"2025-12-18T19:49:00Z","timestamp":1766087340224,"version":"3.41.2"},"reference-count":32,"publisher":"Wiley","issue":"6","license":[{"start":{"date-parts":[[2018,11,14]],"date-time":"2018-11-14T00:00:00Z","timestamp":1542153600000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["bpspubs.onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Pharmacology Res &amp; Perspec"],"published-print":{"date-parts":[[2018,12]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:p>Tissue Inhibitor of Metalloproteinase 3 (<jats:styled-content style=\"fixed-case\">TIMP<\/jats:styled-content>3) is a secreted protein that has a great utility to inhibit elevated metalloproteinase (<jats:styled-content style=\"fixed-case\">MMP<\/jats:styled-content>) activity in injured tissues including infarcted cardiac tissue, inflamed vessels, and joint cartilages. An imbalance between <jats:styled-content style=\"fixed-case\">TIMP<\/jats:styled-content>3 and active <jats:styled-content style=\"fixed-case\">MMP<\/jats:styled-content> levels in the local tissue area may cause worsening of disease progression. To counter balance elevated <jats:styled-content style=\"fixed-case\">MMP<\/jats:styled-content> levels, exogenous administration of <jats:styled-content style=\"fixed-case\">TIMP<\/jats:styled-content>3 appeared to be beneficial in preclinical studies. However, the current form of <jats:styled-content style=\"fixed-case\">WT<\/jats:styled-content>\u2010<jats:styled-content style=\"fixed-case\">TIMP<\/jats:styled-content>3 molecule has a limitation to be a therapeutic candidate due to low production yield, short plasma half\u2010life, injection site retention, and difficulty in delivery, etc. We have engineered <jats:styled-content style=\"fixed-case\">TIMP<\/jats:styled-content>3 molecules by adding extra glycosylation sites or fusing with albumin, Fc, and antibody to improve pharmacokinetic properties. In general, the C\u2010terminal fusion of <jats:styled-content style=\"fixed-case\">TIMP<\/jats:styled-content>3 improved expression and production in mammalian cells and extended half\u2010lives dramatically 5\u201020 folds. Of note, a site\u2010specific glycosylation at K22S\/F34N resulted in a higher level of expression and better cardiac function compared to other fusion proteins in the context of left ventricle ejection fraction (<jats:styled-content style=\"fixed-case\">LVEF<\/jats:styled-content>) changes in a rat myocardial infarction model. It appeared that cardiac efficacy depends on a high <jats:styled-content style=\"fixed-case\">ECM<\/jats:styled-content> binding affinity, in which K22S\/F34N and N\u2010<jats:styled-content style=\"fixed-case\">TIMP<\/jats:styled-content>3 showed a higher binding to the <jats:styled-content style=\"fixed-case\">ECM<\/jats:styled-content> compared to other engineered molecules. In conclusion, we found that the <jats:styled-content style=\"fixed-case\">ECM<\/jats:styled-content> binding and sustained residence of injected <jats:styled-content style=\"fixed-case\">TIMP<\/jats:styled-content>3 molecules are important for cardiac tissue localization and inhibition of adverse remodeling activity.<\/jats:p>","DOI":"10.1002\/prp2.442","type":"journal-article","created":{"date-parts":[[2018,11,14]],"date-time":"2018-11-14T10:25:01Z","timestamp":1542191101000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":18,"title":["Utility of Glycosylated TIMP3 molecules: Inhibition of MMPs and TACE to improve cardiac function in rat myocardial infarct model"],"prefix":"10.1002","volume":"6","author":[{"given":"Vishnu","family":"Chintalgattu","sequence":"first","affiliation":[{"name":"Cardiometabolic Disorders &amp; Therapeutic Discovery Amgen Discovery Research South San Francisco California"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Joanne","family":"Greenberg","sequence":"additional","affiliation":[{"name":"Cardiometabolic Disorders &amp; 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