title: Epac-Rap1-activated mesenchymal stem cells improve cardiac function in rat model of myocardial infarction.
abstract: BACKGROUND
  Rap1, a member of Ras superfamily of small GTP-binding proteins, is involved in cardiovascular biology in numerous ways. It is an evolutionary conserved regulator of adhesion, polarity, differentiation and growth.
  
  
  OBJECTIVE
  Our aim was to analyze Rap1-activated rat bone marrow mesenchymal stem cells (MSCs) for their potential role in adhesion and cardiac differentiation.
  
  
  METHODS
  Myocardial infarction (MI) was produced in Sprague Dawley (SD) rats through occlusion of the left anterior descending coronary artery. MSCs were treated with 8-pCPT-2'-O-Me-cAMP (CPT) to activate Rap1. Normal (untreated) and CPT-treated MSCs were transplanted through intramyocardial injection in respective groups. Cardiac function was assessed by echocardiography at 2 and 4 weeks after cell transplantation. Histological analysis was performed to observe changes at tissue level.
  
  
  RESULTS
  Homing of CPT-treated MSCs was significantly (***P<.001) higher as compared to normal MSCs in the infarcted hearts. This may be due to increase in the gene expression of some of the cell adhesion molecules as evident by qRT-PCR analysis. Significant (***P<.001) improvement in the restoration of heart function in terms of left ventricular diastolic and systolic internal diameters (LVIDd, LVIDs), % ejection fraction, % fraction shortening and end-systolic and end-diastolic volumes were observed in CPT-treated MSCs as compared to the MI model. Histological analyses showed significant (***P<.001) reduction in scar formation in the CPT-treated group. Differentiation of treated MSCs into functional cardiomyocytes was evident through immunohistochemical staining. LV wall thickness was also preserved significantly (***P<.001). Blood vessel formation was more pronounced in CPT-treated group although both cell therapy groups showed significant increase as compared to MI model.
  
  
  CONCLUSIONS
  Our findings showed that pharmacological activation of Epac-Rap1 improves cardiac function through better survival, adhesion and differentiation of transplanted cells. Transplantation of these MSCs in the infarct area restored functional myocardium.
authors.affiliation: Dr. Panjwani Center for Molecular Medicine and Drug Research, International Center for Chemical and Biological Sciences, University of Karachi, Karachi, Pakistan.
authors.forename: Irfan
authors.initials: I
authors.lastname: Khan
authors.affiliation: Dr. Panjwani Center for Molecular Medicine and Drug Research, International Center for Chemical and Biological Sciences, University of Karachi, Karachi, Pakistan.
authors.forename: Anwar
authors.initials: A
authors.lastname: Ali
authors.affiliation: Dr. Panjwani Center for Molecular Medicine and Drug Research, International Center for Chemical and Biological Sciences, University of Karachi, Karachi, Pakistan.
authors.forename: Muhammad Aleem
authors.initials: MA
authors.lastname: Akhter
authors.affiliation: Dr. Panjwani Center for Molecular Medicine and Drug Research, International Center for Chemical and Biological Sciences, University of Karachi, Karachi, Pakistan.
authors.forename: Nadia
authors.initials: N
authors.lastname: Naeem
authors.affiliation: Dr. Panjwani Center for Molecular Medicine and Drug Research, International Center for Chemical and Biological Sciences, University of Karachi, Karachi, Pakistan.|Center for Cardiovascular & Pulmonary Research, The Research Institute at Nationwide Children's Hospital, Columbus, OH, USA.|Department of Pediatrics, The Ohio State University, Columbus, OH, USA.
authors.forename: Maqsood Ahmed
authors.initials: MA
authors.lastname: Chotani
authors.affiliation: Dr. Panjwani Center for Molecular Medicine and Drug Research, International Center for Chemical and Biological Sciences, University of Karachi, Karachi, Pakistan.
authors.forename: Hana'a
authors.initials: H
authors.lastname: Iqbal
authors.affiliation: Dr. Panjwani Center for Molecular Medicine and Drug Research, International Center for Chemical and Biological Sciences, University of Karachi, Karachi, Pakistan.
authors.forename: Nurul
authors.initials: N
authors.lastname: Kabir
authors.affiliation: Department of Pediatrics and Child Health, The Aga Khan University, Karachi, Pakistan.
authors.forename: Mehnaz
authors.initials: M
authors.lastname: Atiq
authors.affiliation: Dr. Panjwani Center for Molecular Medicine and Drug Research, International Center for Chemical and Biological Sciences, University of Karachi, Karachi, Pakistan.
authors.forename: Asmat
authors.initials: A
authors.lastname: Salim
mesh_terms: D000818:Animals; D002448:Cell Adhesion; D002454:Cell Differentiation; D002478:Cells, Cultured; D000242:Cyclic AMP / Q000031:analogs & derivatives* / Q000494:pharmacology; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D004452:Echocardiography; D004789:Enzyme Activation; D020536:Enzyme Activators / Q000494:pharmacology*; D005838:Genotype; D020662:Guanine Nucleotide Exchange Factors / Q000378:metabolism*; D008297:Male; D045164:Mesenchymal Stem Cell Transplantation; D059630:Mesenchymal Stem Cells / Q000187:drug effects* / Q000201:enzymology; D009203:Myocardial Infarction / Q000201:enzymology / Q000473:pathology / Q000503:physiopathology / Q000601:surgery*; D009206:Myocardium / Q000201:enzymology* / Q000473:pathology; D010641:Phenotype; D017207:Rats, Sprague-Dawley; D020127:Recovery of Function; D012038:Regeneration; D013997:Time Factors; D016277:Ventricular Function, Left; D020827:rap1 GTP-Binding Proteins / Q000378:metabolism*
chemical_list: C473217:8-(4-chloro-phenylthio)-2'-O-methyladenosine-3'-5'-cyclic monophosphate; D020536:Enzyme Activators; D020662:Guanine Nucleotide Exchange Factors; C526973:Rapgef3 protein, rat; D000242:Cyclic AMP; D020827:rap1 GTP-Binding Proteins
keywords: Cardiomyogenesis; Cell therapy; Differentiation; Homing; Myocardial infarction; Rap1 GTPase; Transplantation