Ischemia / reperfusion
Ischemia / reperfusion: Acute myocardial infarction
The standard treatment for occluded coronary arteries is rapid recanalization of the affected vessels, known as revascularization. This method is time-sensitive and the proportion of salvaged tissue decreases the longer the vascular occlusion lasts. However, the reopening of the occluded vessel also results in damage, known as reperfusion damage. This is caused by the rapid influx of oxygen-rich blood into the ischaemic heart tissue and is characterized by increased cell death, migration of inflammatory cells and reduced contractile performance in this area. This damage is partially reversible and therefore very suitable for new therapeutic strategies. Optimized pharmacological and interventional therapy has contributed significantly to improved survival of patients with myocardial ischemia, but adverse remodeling still occurs, particularly in patients with large myocardial infarction, which can lead to heart failure in one third of patients with acute myocardial infarction.
Ischemia / reperfusion: microRNAs
Therapeutic approaches
MicroRNAs (miRs) are small, ~18-22 nucleotide long, non-coding RNAs that are processed intracellularly by the RNases Drosha and Dicer. By binding to complementary sequences on their specific messenger RNAs(mRNAs), miRs can prevent translation or induce mRNA degradation and thus regulate a variety of target genes post-transcriptionally. MiRs play a central role in developmental biology, in the maintenance of tissue homeostasis and especially under pathophysiological conditions. Several studies have shown that molecular interventions with miR antisense molecules (antimiRs) can be used to specifically target dysregulated miRs in animal models of different diseases.
Review: Gene therapy for ischemic heart disease.
Inhibition of miR-92a using a locked-nucleic acid antisense (LNA)-modified antagonist showed a significant improvement in ischemia-reperfusion injury. In addition to the reduction in infarct size, this treatment showed an improvement in microcirculation and a reduction in local inflammation, all of which are central processes involved in ischemia-reperfusion injury.
Chronic ischemia
The gradual occlusion of coronary arteries can result in a reversible loss of cardiomyocyte function (hibernating myocardium). This hibernating myocardium appears to be amenable to therapeutic neovascularization, as it can be reactivated by adequate perfusion. However, in our view, therapeutic neovascularization not only requires the growth of new blood vessels, i. e. angiogenesis, but also the maturation of these newly formed vessels. Two novel factors, thymosin ß4 and MRTF-A, are able to recruit significantly more pericytes, which support the maturation of these new vessels. We were able to demonstrate the essential role of vascular maturation in the rabbit hind limb ischemia model. Whether this concept could be a therapeutic option in patients with ischemic cardiomyopathy was investigated in further studies in a pre-clinical porcine model of the hibernating myocardium.
In this model, both thymosin ß4 and MRTF-A were able to increase perfusion in the myocardium in addition to angio- and arteriogenesis. This increased perfusion was able to significantly improve global and regional myocardial function. In summary, thymosin ß4 in cooperation with MRTF-A increases both angiogenesis via CCN-1 and vascular maturation via CCN-2 and thus enables an improvement of perfusion and function in the ischemic muscles.