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Increased MMP8 and 12 activation correlates with elevated endostatin and angiostatin and impaired coronary collateral growth in the metabolic syndrome

We have previously shown that repetitive ischemia (RI) stimulated coronary collateral growth (CCG) in healthy (SD) but not metabolic syndrome (JCR) rats, and that matrix metalloproteinases (MMPs) play a critical role in the regulation of CCG by extracellular matrix (ECM) degradation. We hypothesized that MMPs may also negatively regulate CCG via the release of anti‐angiogenic peptides, endostatin and angiostatin, generated during ECM degradation. To generate RI, an occluder was implanted over the LAD, and rats underwent the RI protocol (8 40 sec occlusions; every 20 min, every 8 hrs for 0, 3, 6, or 9 days). CCG was measured in the ischemic, collateral‐dependent and the normal zones by microspheres, MMP8 and 12 expression and activation by Western blot, and endostatin and angiostatin levels by ELISA on days 0, 3, 6 and 9 of RI. Endostatin and angiostatin were highly increased in JCR but not in the SD rats on days 6 and 9 of RI. Increased endostatin and angiostatin levels correlated with a significant increase in MMP8 and 12 activation in JCR on days 6 and 9 of RI, which were not observed in the SD rats. We conclude that compromised CCG in the metabolic syndrome may be partially due to increased MMP8 and 12 activation and consequent increased generation of anti‐angiogenic peptides, which may preclude collateral vessel expansion. Support: RO1 HL093052