Enhancing cardiac repair : targeting I/R injury and adverse remodeling

In this thesis, we have investigated novel therapeutic targets to enhance cardiac repair and improve cardiac function after myocardial infarction. We have tried to approach this objective by targeting 3 major determinants of post-infarct adverse remodeling and subsequent heart function deterioration: infarct size, detrimental activation of circulating cells and deleterious action of danger signals. Using Toll-like receptor 2 (TLR2) as a therapeutic target, we showed that inhibition of circulating TLR2 signaling reduced infarct size and improved cardiac function in mice as well as in pigs. In addition, we identified exosomes as small particles secreted by mesenchymal stem cells to be cardioprotective. When exosomes are administered after ischemie, just prior to reperfusion, we observed a significant reduction in infarct size and enhanced cardiac performance in mice. Furthermore, we studied whether certain 'danger signals' could trigger deleterious immune responses, thereby hampering proper wound healing after myocardial infarction. First we deleted a gene encoding for the EDA-splicing variant of fibronectin, resulting in enhanced cardiac function and survival after myocardial infarction. Secondly, we also studied the effect of increased 'danger signal' burden in the heart after infarction. In the absence of haptoglobin, we observed higher oxidative stress and disturbed wound healing processes, ultimately resulting in heart failure. Together, our data show that there is large window of opportunity for adjunctive therapeutics to further improve clinical outcome after myocardial infarction.