Titin is a target of matrix metalloproteinase-2: Implications in myocardial ischemia/reperfusion injury

Mohammad A.M. Ali, Woo Jung Cho, Bryan Hudson, Zamaneh Kassiri, Henk Granzier, Richard Schulz

Research output: Contribution to journalArticlepeer-review

148 Scopus citations


Background: Titin is the largest mammalian (≈3000 to 4000 kDa) and myofilament protein that acts as a molecular spring in the cardiac sarcomere and determines systolic and diastolic function. Loss of titin in ischemic hearts has been reported, but the mechanism of titin degradation is not well understood. Matrix metalloproteinase-2 (MMP-2) is localized to the cardiac sarcomere and, on activation in ischemia/reperfusion injury, proteolyzes specific myofilament proteins. Here we determine whether titin is an intracellular substrate for MMP-2 and if its degradation during ischemia/reperfusion contributes to cardiac contractile dysfunction. Methods and Results: Immunohistochemistry and confocal microscopy in rat and human hearts showed discrete colocalization between MMP-2 and titin in the Z-disk region of titin and that MMP-2 is localized mainly to titin near the Z disk of the cardiac sarcomere. Both purified titin and titin in skinned cardiomyocytes were proteolyzed when incubated with MMP-2 in a concentration-dependent manner, and this was prevented by MMP inhibitors. Isolated rat hearts subjected to ischemia/reperfusion injury showed cleavage of titin in ventricular extracts by gel electrophoresis, which was confirmed by reduced titin immunostaining in tissue sections. Inhibition of MMP activity with ONO-4817 prevented ischemia/reperfusion-induced titin degradation and improved the recovery of myocardial contractile function. Titin degradation was also reduced in hearts from MMP-2 knockout mice subjected to ischemia/reperfusion in vivo compared with wild-type controls. Conclusion: MMP-2 localizes to titin at the Z-disk region of the cardiac sarcomere and contributes to titin degradation in myocardial ischemia/reperfusion injury.

Original languageEnglish (US)
Pages (from-to)2039-2047
Number of pages9
Issue number20
StatePublished - Nov 16 2010


  • contractile dysfunction
  • ischemia
  • matrix metalloproteinase-2
  • sarcomere
  • titin

ASJC Scopus subject areas

  • Cardiology and Cardiovascular Medicine
  • Physiology (medical)


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