Mechanisms and therapeutic modulation of myocardial infarct healing

Abstract

This thesis aimed to increase the basic mechanistic understanding of myocardial infarct healing and to develop novel approaches to prevent heart failure following myocardial infarction (MI). Different approaches have been tested to reduce myocardial injury in the acute phase of MI, leading to reduced myocardial infarct size and improved cardiac function. Exenatide, a GLP-1 receptor agonist, reduces infarct size by 40% in a pig model of acute MI, thereby boosting the potential of metabolic interventions in the treatment of acute MI. These experiments may have clinical implications on short notice, since Exenatide is currently on the market as a glucose lowering treatment for type 2 diabetes, and has been proven to be safe in patients. Also secretions of MSCs reduce myocardial infarct size in our pig model. These findings support the paracrine hypothesis of stem cell therapy, according to which some of the therapeutic benefits of stem cells are to be attributed to their secretions rather than by the cells themselves. For the first time to our knowledge, we have demonstrated cardioprotective properties of human MSC secretions. The MSC secretions were generated using a clinically compliant protocol, which may imply that cardioprotection by MSC secretions in patients is realistic in the near future. Interestingly, treatment with MSC secretions also reduced infarct size following permanent coronary artery ligation. The mechanisms behind this observation are not understood at the moment, and remain a subject of investigation. Potential mechanisms include reduced apoptosis, increased myocardial perfusion or myocardial regeneration. Cardiac remodeling, leading to chamber dilatation, functional impairment and eventually heart failure, is another target for intervention following MI. This thesis extends the existing mechanistic knowledge of the involvement of the innate immune system in the cardiac remodeling process, of TLR4 and NF-?B p50 in specific. TLR4, a proximal signaling receptor within the innate immune system, is also activated following MI and elicits an inflammatory response and ECM degradation, enhancing the remodeling process. Mice with defective TLR4, suffer less remodeling compared with wild-type mice and cardiac function is partly preserved in these mice. The results of these experiments, may imply that TLR4 inhibition may be a way to counteract cardiac remodeling. The role of NF-?B in cardiac remodeling is well established. The role of the different subunits however, is relatively unexplored. Our experiments reveal that cardiac remodeling is enhanced in NF-?B p50 knock-out mice due to increased inflammation and matrix turnover. These results are in line with studies that identified p50 as an inhibitory subunit, providing a negative feedback mechanism. We therefore discourage the development of compounds to target NF-?B p50 for the treatment of cardiac remodeling following MI. Finally, we found that selective COX-2 inhibition enhances cardiac remodeling after MI. Since COX-2 inhibitors are among the most frequently prescribed pharmaceutics for patients with chronic inflammatory disease, this is an important observation, which warrants the use of COX-2 inhibitors in patients that suffered MI in the past.