Catestatin for the treatment of myocardial ischemia

Myocardial infarction often leads to left ventricular dysfunction, cardiomyopathy and heart failure through cell injury and death. An immediate revascularization of ischemic myocardium can significantly improve global ventricular function. However, coronary artery disease in patients with ischemic cardiomyopathy often is not amendable to either percutaneous revascularization or coronary artery bypass grafting. This has promoted extensive investigation in alternative revascularization strategies, such as exogenously induced angiogenesis using a variety of growth factors. Unfortunately, it has been observed, that in a clinical trial with vascular endothelial growth factor (RAVE trial) severe side effects like edema formation impaired the beneficial effects of neovascularisation. Therefore, alternative angiogenic factors are of high interest. Because of its potent angiogenic effects, we postulate that local catestatin therapy might have beneficial effects on cardiac repair and on reduction of heart failure development. Our group recently published beneficial effects for the treatment of experimental hind limb ischemia for catestatin. The overall goal of this grant submission is a detailed study of catestatin induced therapeutic angiogenesis in the hypoxic myocardium and testing the hypothesis that intramyocardial catestatin therapy is capable of augmenting therapeutic neovascularization, leading to restoration of left ventricular remodelling and prevention of cardiac dysfunction in a mouse model of myocardial infarction. We plan to construct a gene therapeutic vector for catestatin delivery and to compare catestatin single-therapy with a combination therapy (for example catestatin plus vascular endothelial growth factor or catestatin plus basic fibroblast growth factor). If plasmid therapy fails we will test a special microcapsule formulation for peptide transfer allowing a sustained peptide release. The efficacy of this method was published recently. Moreover, the impact of catestatin on coronary endothelial cells and cardiomyocytes will be investigated intensively in-vitro using a variety of methods such as BrdU-incorporation, caspase activation, real time PCR and western blotting.

Cardiovascular disorders including coronary heart disease represent the most common cause of death in the western world. Myocardial infarction, a severe manifestation of coronary heart disease, is caused by occlusion of a coronary vessel and results in irreversible damage of the heart muscle due to myocardial cell death. Although treatment of myocardial infarction improved significantly due to the possibility of interventional treatment a particular part of patients will suffer from ischemic heart failure after myocardial infarction. Typical symptoms of heart failure include shortage of breath, reduced output or angina pectoris. The aim of this project was to investigate the role of the neuropeptide catestatin as possible novel therapeutic factor for the treatment of heart failure. Recently, we were able to show that catestatin improves function of peripheral vascular cells in-vitro (e.g.: proliferation, protection from cell death, ). Moreover, we could demonstrate in an experimental model of limb ischemia that treatment with this neuropeptide improves limb perfusion and reduces ischemia-related tissue defects due to generation of new blood vessels. For the current project catestatin mediated effects were evaluated using human coronary vascular cells. Moreover, we aimed to develop a gene therapeutic vector that guarantees stable expression of catestatin in the myocardial tissue. Our current in-vitro results show that catestatin mediates proliferation and chemotaxis of coronary endothelial and smooth muscle cells. Moreover, catestatin activates crucial signaling transduction pathways that are important for cell development and survival. Consistent with these findings we observed a reduced cell death rate of human cardiac muscle cells in-vitro. The observed effects seem to be mediated via the prominent angiogenic factor basic fibroblast growth factor. Regarding the gene therapeutic vector we were able to construct a functional catestatin-expressing-plasmid and subsequently a functional adeno-associated-virus serotype 9. The final in-vivo studies evaluating the therapeutic effect are currently in the final stage. In sum catestatin influences coronary vascular cell function and therefore might be a promising novel therapeutic factor for the treatment of ischemic heart failure.