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Mar 06, 2014
 |  BC Innovations  |  Tools & Techniques

Taking TIMP3 to heart

A U.S. team has found a way to harness the cardioprotective activity of tissue inhibitor of metalloproteinases 3 while avoiding its off-target effects by embedding it in a hydrogel for direct injection into the heart.1 Although preclinical data show that local delivery of the molecule could help prevent heart failure after myocardial infarction in patients with ventricular dilation, it may have a detrimental effect in other patients, making patient selection critical.

After myocardial infarction (MI), left ventricular wall damage is partly caused by overactive matrix metalloproteinase (MMP) enzymes that break down extracellular matrix in the ischemic tissue.

Under normal conditions, tissue inhibitors of metalloproteinases (TIMPs) control MMP activity and help regulate the breakdown of matrix proteins. After MI, however, there is an increase in MMP plasma levels without a matching change in levels of TIMPs, creating an imbalance in MMP regulation.

The unchecked proteolysis causes thinning of the left ventricle wall, dilation and eventual loss of structural support-termed left ventricular remodeling-which leads to heart failure.

Previous clinical studies have tested various MMP inhibitors.2 However, according to Merry Lindsey, problems in achieving proper doses and side effects of systemic administration of MMP inhibitors have prevented clinical use.

Lindsey is director of The University of Mississippi Medical Center's Jackson Center for Heart Research, a professor of physiology and biophysics at the University of Mississippi Medical Center and director of the San Antonio Cardiovascular Proteomics Center at The University of Texas Health Science Center at San Antonio.

Tissue inhibitor of metalloproteinases 3 (TIMP3) was pegged as a key player in the heart in 2009 when knockout studies in mice showed that eliminating Timp3 causes adverse ventricular remodeling and...

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