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Matrix metalloproteinase‐2 co‐localizes with titin in cardiac myocytes and contributes to its proteolysis in ischemia‐reperfusion injury
Author(s) -
Ali Mohammad AbdelMotaal,
Cho Woo Jung,
Granzier Henk,
Schulz Richard
Publication year - 2009
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.23.1_supplement.812.11
Subject(s) - titin , sarcomere , myocyte , ischemia , obscurin , reperfusion injury , chemistry , microbiology and biotechnology , matrix metalloproteinase , cardiac function curve , proteolysis , medicine , biology , biochemistry , heart failure , enzyme
Titin, the largest known protein in mammalian cells, plays a central role as a molecular spring of the cardiomyocyte and thus is an important determinant of cardiac function. Although loss of titin in ischemic hearts has been reported, the mechanism of this is unclear. Matrix metalloproteinase‐2 (MMP‐2) is a protease ubiquitously expressed in cardiomyocytes. We have shown that MMP‐2 is localized to the cardiac sarcomere and proteolyzes specific myofilament proteins in ischemia‐reperfusion (I‐R) injury. Hypothesis Titin is an intracellular substrate for MMP‐2 and its degradation during I‐R contributes to cardiac dysfunction. Results Immunohistochemistry showed the clear co‐localization of MMP‐2 and titin using an antibody to the Z disc region. In vitro incubation of purified titin with MMP‐2 led to titin degradation which was prevented by inhibiting MMP‐2. Isolated working rat hearts were subjected to I‐R injury (25 min global, no‐flow ischemia followed by 60 min aerobic reperfusion) with or without ONO4817 (MMP‐2/9 inhibitor). Titin in heart samples was analyzed by gel electrophoresis (1% agarose‐SDS) and immunohistochemistry. I‐R caused a loss of titin in the heart. ONO4817 prevented I‐R‐induced titin degradation and improved the recovery of mechanical function. Conclusion MMP‐2 localizes to titin at the Z disc region of the cardiac sarcomere and contributes to titin degradation in I/R injury.