22 Mar The anti-infarct effect of Endonuclease III in a model of myocardial rat ischemia reperfusion
Myocardial infarction (MI) or acute myocardial infarction (AMI), commonly known as a heart attack, occurs when blood flow stops to a part of the heart causing damage to the heart muscle. It results from a biphasic ischemia/reperfusion (I/R) injury to the heart. Despite considerable effort, therapeutic interventions to disrupt this injury pattern are not optimal and often not on time. Loss of contractile myocardium following acute myocardial infarction continues to be a serious medical problem.
Animal studies (rat ischemia reperfusion) indicate that the preservation of myocardium could still be accomplished through interventions that block specific processes. In particular, mitochondria have recently emerged as central players in the ischemia/reperfusion injury process. After a MI, the reintroduction of oxygen to mitochondria that have experienced a prolonged period of hypoxia can generate a burst of reactive oxygen species, which can damage mitochondrial DNA (mtDNA). These liberated mtDNA can cause harm the myocardial cells and can be one of the reasons for injury.
Recent reports indicate that elevating DNA glycosylase/AP lyase repair enzyme activity offers marked cytoprotection in cultured cells and a variety of injury models. Researchers from the University of Alabama in the USA created and measured the effect of a fusion protein (EndoIII) containing Endonuclease III, a DNA glycosylase/AP lyase, which was engineered to allow its rapid uptake into the matrix of mitochondria, on infarct size in a rat model of myocardial ischemia/reperfusion.
In a preliminary report, this protein had reduced infarct size in a mouse model of coronary occlusion/reperfusion. For the present work, this protein was tested in rat hearts to determine whether systemic administration could protect the heart from infarction resulting from myocardial ischemia/reperfusion and to provide novel information concerning its mechanism of action.
The magnitude of EndoIII’s protection was comparable to that seen with the platelet aggregation inhibitor cangrelor, the standard of care for treatment of acute myocardial, and could further reduce infarct size in rats treated with a maximally protective dose of cangrelor. The combination reduced infarct size to 15.1 ± 0.9 % which was significantly smaller than that seen with either cangrelor or EndoIII alone. However, both those molecules were shown to use differing cellular mechanisms to act.
Indeed, according to the new findings, EndoIII protects the heart from spreading necrosis by preventing the release of proinflammatory fragments of mtDNA into the heart tissue. The researchers validated the hypothesis that mtDNA were causing inflammation in heart tissue. Infarct size doubled when the coronary vasculature was filled with mtDNA fragments during the period of global ischemia.
Additive protection was possible by adding deoxyribonuclease I (DNase I), which degrades any DNA fragments escaping into the extracellular space. While EndoIII can maintain mitochondrial integrity in many of the ischemic cardiomyocytes, DNase I can further prevent mtDNA release from those cells that EndoIII could not save from propagating further necrosis.
According to the scientists, EndoIII and DNase are the first agents that can both be given at reperfusion and add to the protection of current available treatments, and thus should be effective in today’s patient with acute myocardial infarction.
Syncrosome, a scientific preclinical CRO based in France, also uses mouse models for Myocardial Ischemia for efficacy testing. They monitor Coronary artery ligation, reperfusion, blood pressure, heart rate, planimetry, histology and morphological and functional biomarkers. By combining all these parameters, they can most reliably test for appropriate reaction.
Key words: preclinical CRO, preclinical study, animal model, animal research, myocardial, ischemia, infarction, reperfusion, heart, porcine model, mouse model, inflammation, inflammatory, proinflammatory, isoform, myocardial, acute, rat model