Regulation of hepatic cell mobilization in experimental myocardial ischemia

Myocardial ischemia induces cardiomyocyte injury and death, resulting in impairment of cardiac function. The adult cardiomyocytes possess a limited capacity of protection in myocardial ischemia, and nonmyocytic cells can be activated to support myocardial protection. We recently demonstrated that hepatic cells were able to upregulate genes encoding secreted proteins and were mobilized to the circulatory system, potentially contributing to myocardial protection against ischemic injury. In this investigation, we tested the potential mechanisms by which hepatic cells were mobilized in experimental myocardial ischemia. Following the induction of myocardial ischemia, hepatic cells, including hepatocytes and biliary epithelial cells, were mobilized to the circulatory system with a peak population 1.9 ± 0.4% at day 5. The cytokine IL-6 was upregulated in the ischemic myocardium as well as the serum. IL-6 promoted leukocyte retention in the liver as demonstrated by an increase in liver-retained leukocytes in myocardial ischemia in wild type mice, reduced leukocytes in IL-6 ^-/- mice, and restoration of leukocyte retention in response to IL-6 administration to IL-6 ^-/- mice. Liver-retained leukocytes exhibited upregulation of MMP-2, which in turn mediated hepatic cell mobilization by degrading extracellular matrix. These observations suggest that IL-6-stimulated leukocytes mediate the mobilization of hepatic cells via releasing MMP-2 in myocardial ischemia.