title: Critical role of angiopoietins/Tie-2 in hyperglycemic exacerbation of myocardial infarction and impaired angiogenesis.
abstract: Angiopoietin-1 (Ang-1) and angiopoietin-2 (Ang-2) are the two ligands of the Tie-2 receptor, a receptor tyrosine kinase that is expressed on the endothelium. A balanced angiopoietin/Tie-2 system is critical for the maintenance of vascular integrity. We investigated the potential role of a disrupted angiopoietin/Tie-2 system on hyperglycemic exacerbation of myocardial infarction and impaired angiogenesis. Using streptozotocin (STZ) mice subjected to myocardial ischemia, we examined the effects of shifting the Ang-2-to-Ang-1 ratio on myocardial infarction size, apoptosis, bone marrow (BM) cell-endothelial progenitor cell (EPC) differentiation, and angiogenesis. In control mice, myocardial ischemia increased expression of both Ang-2 and Tie-2. In STZ mice, Ang-2 expression was elevated, whereas Tie-2 expression was reduced, and neither was significantly altered by ischemia. Myocardial infarct size and apoptosis were increased in STZ compared with control mice. Using in vivo administration of an adenovirus containing Ang-1 or Ang-2, we found that shifting the Ang-2-to-Ang-1 ratio to favor Ang-1 reduced myocardial apoptosis and infarct size in STZ mice, while shifting the Ang-2-to-Ang-1 ratio to favor Ang-2 resulted in a significant increase in myocardial infarct size and apoptosis in control mice. Myocardial ischemia-stimulated BM cell-EPC differentiation was inhibited and myocardial angiogenesis was reduced in STZ mice. Systemic administration of Ad-Ang-1 restored BM cell-EPC differentiation and increased myocardial VEGF expression and angiogenesis in STZ mice. Our data demonstrate that disturbed angiopoietin/Tie-2 signaling contributes to the hyperglycemic exacerbation of myocardial infarction and impaired angiogenesis. Restoration of the Ang-2-to-Ang-1 ratio may be a novel therapeutic strategy for the treatment of diabetic myocardial ischemic diseases.
authors.affiliation: Division of Neonatology, Department of Pediatrics, Vanderbilt University Medical Center, Nashville, Tennessee, USA.
authors.forename: Qin-Hui
authors.initials: QH
authors.lastname: Tuo
authors.forename: Heng
authors.initials: H
authors.lastname: Zeng
authors.forename: Amanda
authors.initials: A
authors.lastname: Stinnett
authors.forename: Heidi
authors.initials: H
authors.lastname: Yu
authors.forename: Judy L
authors.initials: JL
authors.lastname: Aschner
authors.forename: Daun-Fang
authors.initials: DF
authors.lastname: Liao
authors.forename: Jian-Xiong
authors.initials: JX
authors.lastname: Chen
mesh_terms: D000256:Adenoviridae / Q000235:genetics; D042683:Angiopoietin-1 / Q000235:genetics / Q000378:metabolism*; D042702:Angiopoietin-2 / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D017209:Apoptosis; D001854:Bone Marrow Cells / Q000378:metabolism; D002454:Cell Differentiation; D048909:Diabetes Complications / Q000209:etiology* / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D003921:Diabetes Mellitus, Experimental / Q000150:complications / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D004195:Disease Models, Animal; D042783:Endothelial Cells / Q000378:metabolism; D005822:Genetic Vectors; D006943:Hyperglycemia / Q000150:complications / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology; D051379:Mice; D008810:Mice, Inbred C57BL; D009203:Myocardial Infarction / Q000209:etiology* / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D017202:Myocardial Ischemia / Q000150:complications* / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D009206:Myocardium / Q000378:metabolism / Q000473:pathology; D018919:Neovascularization, Physiologic; D042787:Receptor, TIE-2 / Q000378:metabolism*; D015398:Signal Transduction; D013234:Stem Cells / Q000378:metabolism; D013997:Time Factors; D014161:Transduction, Genetic; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism
chemical_list: D042683:Angiopoietin-1; D042702:Angiopoietin-2; C467628:Angpt1 protein, mouse; D042461:Vascular Endothelial Growth Factor A; C467480:vascular endothelial growth factor A, mouse; D042787:Receptor, TIE-2