title: Angiogenic signal triggered by ischemic stress induces myocardial repair in rat during chronic infarction.
abstract: In the present study, we examined a novel method of stimulating myocardial angiogenesis through ischemic preconditioning (IP) in the form of in vivo four repetitive cycles of coronary artery occlusion each followed by reperfusion. Rats divided into 4 groups: Control+Sham surgery (CS), Control+ Left anterior descending coronary artery (LAD) occlusion (CMI), IP+ Sham surgery (IPS) and IP+LAD occlusion (IPMI). For cardiac function, rats were subjected to stress testing with dobutamine after 2, 4, 7, 14 and 21 operative days. Capillary density (CD) and arteriolar density (AD) were evaluated by immunohistochemistry. Western blot was performed to examine the expression pattern for VEGF and anti-death candidates, Bcl-2 and survivin. Blood flow and the extent of endothelial and cardiomyocyte cell death were examined. The protein/DNA array was performed to determine the status of various transcription factor related to stress signal. Left ventricular functional reserve was better preserved in IPMI compared to the CMI group. The infarct size and apoptotic cell death were reduced in IPMI group significantly. Left ventricular regional blood flow, perfused capillary density and AD increased significantly in the IPMI group. VEGF, Bcl-2 and survivin expression were increased in IPMI compared to CMI. VEGF mediated vascular permeability was controlled in the IPMI due to suppression of c-Src in the infarcted myocardium. Our study documented first time the ability of IP to induce angiogenesis in the infarcted myocardium along with the activation of several transcription factors such as Stat3, Pax-5, NF kappa B, TFIID, SP1 and reduction of VEGF mediated vascular permeability by inhibition of c-Src in IPMI group thereby reducing ischemic injury in rat MI model.
authors.affiliation: Molecular Cardiology Laboratory, University of Connecticut Medical School, Farmington, Connecticut 06030, USA.
authors.forename: Shoji
authors.initials: S
authors.lastname: Fukuda
authors.forename: Shigeaki
authors.initials: S
authors.lastname: Kaga
authors.forename: Hiroaki
authors.initials: H
authors.lastname: Sasaki
authors.forename: Lijun
authors.initials: L
authors.lastname: Zhan
authors.forename: Li
authors.initials: L
authors.lastname: Zhu
authors.forename: Hajime
authors.initials: H
authors.lastname: Otani
authors.forename: Reni
authors.initials: R
authors.lastname: Kalfin
authors.forename: Dipak K
authors.initials: DK
authors.lastname: Das
authors.forename: Nilanjana
authors.initials: N
authors.lastname: Maulik
mesh_terms: D000818:Animals; D017209:Apoptosis; D001783:Blood Flow Velocity; D015153:Blotting, Western; D002196:Capillaries / Q000473:pathology; D016923:Cell Death; D002478:Cells, Cultured; D004247:DNA / Q000737:chemistry; D004280:Dobutamine / Q000494:pharmacology; D004487:Edema; D004730:Endothelium, Vascular / Q000473:pathology; D006321:Heart / Q000502:physiology; D007150:Immunohistochemistry; D020287:In Situ Nick-End Labeling; D051034:Inhibitor of Apoptosis Proteins; D007511:Ischemia; D008297:Male; D008869:Microtubule-Associated Proteins / Q000378:metabolism; D009203:Myocardial Infarction / Q000473:pathology*; D017202:Myocardial Ischemia; D009206:Myocardium / Q000166:cytology / Q000473:pathology; D009363:Neoplasm Proteins; D009389:Neovascularization, Pathologic; D020411:Oligonucleotide Array Sequence Analysis; D010477:Perfusion; D040081:Protein Array Analysis; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D000077022:Survivin; D013997:Time Factors; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism; D014867:Water / Q000737:chemistry; D014945:Wound Healing; D019061:src-Family Kinases / Q000378:metabolism
chemical_list: C107489:BIRC5 protein, human; D051034:Inhibitor of Apoptosis Proteins; D008869:Microtubule-Associated Proteins; D009363:Neoplasm Proteins; D019253:Proto-Oncogene Proteins c-bcl-2; D000077022:Survivin; D042461:Vascular Endothelial Growth Factor A; D014867:Water; D004280:Dobutamine; D004247:DNA; D019061:src-Family Kinases