The Paracrine Effect Of Phenytoin On The Post-Infarct Healing Process And Gene Expression Profiles After Experimental Myocardial Infarction

Background:Tissue repair after myocardial infarction(MI) is the determinant factor of ventricular remodeling.Accelerated healing process and increased extracellular matrix deposition in the infardt area could effectively conteract increased intra-ventricular pressure,which may further restrain the enlargement of left ventricular cavity,improve ventricular function,or even prevent ventricular aneurysm formation and free wall rupture.Phenytoin is widely used anti-epileptic drug,with well-known side effect of gingival hyperplasia,which is thought to be an effect involving increased collagen deposition by paracrine effect throught up-regulation of growth factors and related receptors.Recent studies showed that phenytoin(PHT) mediated paracrine effect can accelerate dermal wound healing.We previously conformed that PHT could accelerate tissue repair after MI,and the possible mechanism may due to PHT mediated paracrine effect through activation of macrophage.But the exact mechanisms of the role of PHT in tissue repair after MI is unclear.Objective:To investigate the role and mechanism of PHT mediated paracrine effect in the tissue repair and ventricular remodeling,we dynamically evaluated the histopathological changes gene expression profiles in infarcted left ventricles.Method:Experimental myocardial infarction was induced by permanent ligation of male Wistar rats,6-8 weeks old.Survival animals were randomly divided into Sham group(chest was opened,without ligation of suture,n=10),control group(MI group, n=26) and Phenytoin group(PHT group,n=18).PHT was dissolved in drinking water (100mg/kg per day).On the 3^rd,7^th and 14^th days after operation,some animals were sacrificed and the hearts were prepared for histologcal analysis including collagen analysis.Collagen volume fraction(CVF),collagen deposition and maturation was determined by picrosirius-red stained heart tissue sections,under circularly polarized light.Arterioles density and capillary density in infarcted region were evaluated by anti-α-SMA and anti-vWF immunofluorescent staining,respectively.Affymetrix GeneChip^? Rat Expression Set 230 system was used to determine the changes of gene expression profiles in the infarcted region.Result:(1) The index that ratio of ventricle and body weight(V/BW),ratio of left ventricle and body weight(LV/BW) and the length of tibia were not significantly different between each group.(2) Compared with MI group,arteriole density and capillary density in infarct zone at 3^rd,7^th day and 14^th day had increased in PHT group (3) In MI group,there were 1165 genes changed between 3^rd and 7^th day after MI, while there were only 81 genes changed between 3^rd and 7^th day;Cell cycle,T cell receptor signaling pathway,MAPK signaling pathway and ECM-receptor interaction were involved in the changes of gene expression.Conclusion:Phenytoin mediated paracrine effect can accelerate collagen deposition. collagen maturation,and promote neovascularization,cardiac repair,and resulted a significant changes in gene expression profiles in the infarcted area.