title: Hyperglycemia suppresses cardiac stem cell homing to peri-infarcted             myocardium via regulation of ERK1/2 and p38 MAPK activities.
abstract: Hyperglycemia in the acute phase of myocardial infarction (MI) is a marker of worse prognosis in both diabetic and non-diabetic patients; however, the role of hyperglycemia in the homing of cardiac stem cells (CSCs) to damaged myocardium post-MI and the possible mechanisms involved are not well understood. In this study, an MI model was induced in normoglycemic and hyperglycemic rats by left coronary artery ligation. Immunofluorescence was used to examine the migration of CSCs in vivo by injecting BrdU-labeled CSCs into the atrium-ventricle groove (AV-groove). Immunohistochemistry, western blot analysis and ELISA were carried out to detect the expression of stem cell factor (SCF) protein and RT-PCR was conducted for the expression of SCF mRNA. Phosphorylation of ERK1/2 and p38 MAPK was detected by western blot analysis. Afterwards, cardiac function was evaluated by hemodynamic measurement. On Day 5 post-MI, the accumulation of CSCs significantly increased in the peri-infarcted myocardium in normoglycemic rats, which led to an improvement in cardiac function 3 weeks after MI. However, the accumulation of CSCs markedly decreased in hyperglycemic rats, followed by the decline of cardiac function. SCF expression, followed with phosphorylation of ERK1/2 and p38 MAPK, were also significantly downregulated in the peri-infarcted myocardium in hyperglycemic rats compared to normoglycemic rats. Moreover, SCF expression and the migration of CSCs were blocked by either the MEK-specific inhibitor PD98059 or the p38 MAPK-selective inhibitor SB203580. The experiments in vitro confirmed that hyperglycemia decreased SCF expression via reduction in ERK1/2 and p38 MAPK activities and further inhibited the migration of CSCs. The results suggest that hyperglycemia suppresses CSC migration towards the ischemic area post-MI. This is possibly due to decreased myocardial SCF expression via reduction of ERK1/2 and p38 MAPK activities in hyperglycemic rats.
authors.affiliation: Institute of Pathology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, P.R. China.
authors.forename: Tonghui
authors.initials: T
authors.lastname: She
authors.forename: Xiaoyan
authors.initials: X
authors.lastname: Wang
authors.forename: Yaping
authors.initials: Y
authors.lastname: Gan
authors.forename: Dong
authors.initials: D
authors.lastname: Kuang
authors.forename: Junqiu
authors.initials: J
authors.lastname: Yue
authors.forename: Juan
authors.initials: J
authors.lastname: Ni
authors.forename: Xia
authors.initials: X
authors.lastname: Zhao
authors.forename: Guoping
authors.initials: G
authors.lastname: Wang
mesh_terms: D000818:Animals; D002465:Cell Movement; D002478:Cells, Cultured; D003921:Diabetes Mellitus, Experimental / Q000150:complications / Q000201:enzymology / Q000503:physiopathology; D048049:Extracellular Signal-Regulated MAP Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D005419:Flavonoids / Q000494:pharmacology; D015870:Gene Expression / Q000187:drug effects; D006943:Hyperglycemia / Q000150:complications* / Q000201:enzymology / Q000503:physiopathology; D007093:Imidazoles / Q000494:pharmacology; D020935:MAP Kinase Signaling System; D008297:Male; D009203:Myocardial Infarction / Q000150:complications* / Q000201:enzymology / Q000503:physiopathology; D009206:Myocardium / Q000201:enzymology / Q000473:pathology; D032383:Myocytes, Cardiac / Q000201:enzymology; D010766:Phosphorylation; D011499:Protein Processing, Post-Translational; D011725:Pyridines / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D019089:Stem Cell Factor / Q000235:genetics / Q000378:metabolism; D013234:Stem Cells / Q000201:enzymology / Q000502:physiology*; D017725:Ventricular Pressure; D048051:p38 Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism*
chemical_list: D005419:Flavonoids; D007093:Imidazoles; D011725:Pyridines; D019089:Stem Cell Factor; D048049:Extracellular Signal-Regulated MAP Kinases; D048051:p38 Mitogen-Activated Protein Kinases; C093642:SB 203580; C093973:2-(2-amino-3-methoxyphenyl)-4H-1-benzopyran-4-one