ABSTRACT
Activated protein C (APC) is known to be beneficial on ischemia reperfusion injury in myocardium. However, the protection mechanism of APC is not fully understood. The purpose of this study was to investigate the effects and possible mechanisms of APC on myocardial ischemic damage. Artificially ventilated anaesthetized Sprague-Dawley rats were subjected to a 30 min of left anterior descending coronary artery occlusion followed by 2 hr of reperfusion. Rats were randomly divided into four groups; Sham, I/R, APC preconditioning and postconditioning group. Myocardial infarct size, apoptosis index, the phosphorylation of ERK1/2, Bcl-2, Bax and cytochrome c genes and proteins were assessed. In APC-administrated rat hearts, regardless of the timing of administration, infarct size was consistently reduced compared to ischemia/reperfusion (I/R) rats. APC improved the expression of ERK1/2 and anti-apoptotic protein Bcl-2 which were significantly reduced in the I/R rats. APC reduced the expression of pro-apoptotic genes, Bax and cytochrome c. These findings suggest that APC produces cardioprotective effect by preserving the expression of proteins and genes involved in anti-apoptotic pathways, regardless of the timing of administration.
Subject(s)
Animals , Male , Rats , Apoptosis , Cytochromes c/genetics , Hemodynamics/physiology , Mitogen-Activated Protein Kinase 1/metabolism , Mitogen-Activated Protein Kinase 3/metabolism , Myocardial Reperfusion Injury/metabolism , Myocardium/metabolism , Phosphorylation , Protein C/therapeutic use , Proto-Oncogene Proteins c-bcl-2/metabolism , Rats, Sprague-Dawley , Signal Transduction , bcl-2-Associated X Protein/metabolismABSTRACT
A model for random molecular evolution based on recurrent mutation is proposed. Recurrent mutation replaces completely any original base in a nucleotidic site. This occurs if more than four times the number of reproductive cycles equal to the reciprocal of the mutation rate happen; no matter the population size, the number of nucleotides a genome has, or the taxa at which it belongs. The main results are: i) the expected distribution of DNA bases in a site is an isotetranomial distribution, where Adenine (A), Guanine (G), Cytosine (C) and Thymine (T) occur with probability equal to 0.25; ii) the distribution of bases in a site is independent from the distribution of bases in other sites. Several expected consequences that can be contrasted with actual data are generated. Species or operational taxonomic units (OTUs) that evolved in big populations should present distances equal to zero and similarities equal to one. OTUs evolving in small populations should present distances equal to 3/4 and similarities equal to 1/4. Thus, random molecular evolution by recurrent mutation cannot yield a tree at all. The only possible tree is that produced by random fluctuations of distances according to their variances (stochastic tree). Some consequences of the model on the expected primary structure of proteins are also analyzed. There are sufficient generations for any DNA segment evolving apart during the last four hundred million years, to reach those expected base distributions