Myocardial ischemia-reperfusion (I/R) injury is a significant clinical problem that contributes to loss of myocardial tissue after restoration of blood flow. The acute phase results in an infarct and the chronic phase involves remodeling, hypertrophy, and eventually heart failure. Recently, we have shown that the inhibition of TF or thrombin reduces infarct size in a rabbit model of myocardial I/R injury (Figures 7a and 7b). Furthermore, we determined that the TF-thrombin pathway contributed to the inflammatory response during myocardial I/R injury by increasing chemokine expression and the recruitment of neutrophils.
Figures 7a and 7b: Cardiac I/R injury induces infarction and remodeling
The fibrin degradation product E1 was found to enhance neutrophil recruitment by linking the CDIIc/CD18 receptor on neutrophils to VE-cadherin on the endothelium (Figure 8). Our recent studies have focused on the role of PAR-1 and PAR-2 in mycocardial I/R injury. Interestingly, PAR-2 -/- mice have a decreased infarct size in an I/R injury model suggesting that PAR-2 activation contributes to inflammation and infarct size. In contrast, a deficiency in PAR-1 does not affect infarct size but reduces long-term remodeling with less hypertrophy. These results suggest that both PAR-1 and PAR-2 may represent new targets to reduce damage to the cardiac tissue after a heart attack.
Figure 8: Coagulant and Non-Coagulant Roles of TF in Cardiac I/R Injury