Abstract 471: Acute Myocardial Infarction Augments Neointimal Hyperplasia at Sites of Angioplasty, not by Increasing Mobilization of Bone Marrow-Derived Cells, But by Stimulating Signaling via TNF-α, TNFR1 and IL-6
Background: Cardiac levels of several inflammatory cytokines and their plasma levels are elevated following acute myocardial infarction (AMI). These inflammatory responses possibly may stimulate recruitment of bone marrow (BM)-derived cells into peripheral circulation and contribute the neointima (NI) at remote site of angioplasty. Given that both a medial smooth muscle cell lineage and a BM-derived cell lineage are now thought to contribute to NI formation, the primary aims of the present study were to determine whether AMI augments NI hyperplasia at sites of angioplasty, and whether BM-derived cells contribute to that process.
Methods and Results: We simultaneously generated models of AMI and femoral artery injury in the same mice, some of which had received BM transplantation from GFP mice. We found that AMI augments NI hyperplasia at sites of femoral artery injury by about 35% (p<0.05) (n=8 in each AMI+arterial injury group and arterial injury alone group), but that while BM-derived cells contributed to NI hyperplasia, they did not contribute to the AMI-related augmentation (n=5 in each group). Expression of interleukin (IL)-6 mRNA showed preferential rise in the NI of mice subjected to both AMI and arterial injury compared with those of mice subjected to arterial injury alone (about 500-fold vs. 70-fold, as compared with the sham-arterial injury group, respectively). In addition, we observed increased synthesis of tumor necrosis factor (TNF)-α within infarcted hearts and TNF-α receptor type 1 (TNFR1) within injured arteries. Therefore, we hypothesized that in the setting of AMI, it is likely that TNF-α released from the infarcted heart binds to newly upregulated-TNFR1 on the surface of cells at remote sites of arterial injury, leading to IL-6 production and stimulation of NI hyperplasia. To prove a cause-effect relationship between expression of TNF-α in heart and IL-6 in arteries, we demonstrated that blockade of TNF-α synthesis by pentoxifylline inhibited the AMI-induced increases in plasma TNF-α and attenuated NI formation after arterial injury.
Conclusions: Conditions following AMI could exacerbate post-angioplasty restenosis, not by increasing mobilization of BM-derived cells, but by stimulating signaling via TNF-α, TNFR1 and IL-6.