title: Tissue kallikrein-modified human endothelial progenitor cell implantation improves cardiac function via enhanced activation of akt and increased angiogenesis.
abstract: Endothelial progenitor cells (EPCs) have been shown to enhance angiogenesis not only by incorporating into the vasculature but also by secreting cytokines, thereby serving as an ideal vehicle for gene transfer. As tissue kallikrein (TK) has pleiotropic effects in inhibiting apoptosis and oxidative stress, and promoting angiogenesis, we evaluated the salutary potential of kallikrein-modified human EPCs (hEPCs; Ad.hTK-hEPCs) after acute myocardial infarction (MI). We genetically modified hEPCs with a TK gene and evaluated cell survival, engraftment, revascularization, and functional improvement in a nude mouse left anterior descending ligation model. hEPCs were manipulated to overexpress the TK gene. In vitro, the antiapoptotic and paracrine effects were assessed under oxidative stress. TK protects hEPCs from oxidative stress-induced apoptosis via inhibition of activation of caspase-3 and -9, induction of Akt phosphorylation, and secretion of vascular endothelial growth factor. In vivo, the Ad.hTK-hEPCs were transplanted after MI via intracardiac injection. The surviving cells were tracked after transplantation using near-infrared optical imaging. Left ventricular (LV) function was evaluated by transthoracic echocardiography. Capillary density was quantified using immunohistochemical staining. Engrafted Ad.hTK-hEPCs exhibited advanced protection against ischemia by increasing LV ejection fraction. Compared with Ad.Null-hEPCs, transplantation with Ad.hTK-hEPCs significantly decreased cardiomyocyte apoptosis in association with increased retention of transplanted EPCs in the myocardium. Capillary density and arteriolar density in the infarct border zone was significantly higher in Ad.hTK-hEPC-transplanted mice than in Ad.Null-hEPC-treated mice. Transplanted hEPCs were clearly incorporated into CD31(+) capillaries. These results indicate that implantation of kallikrein-modified EPCs in the heart provides advanced benefits in protection against ischemia-induced MI by enhanced angiogenesis and reducing apoptosis.
authors.affiliation: Department of Cardiology, Zhongda Hospital, Medical School of Southeast University, Nanjing 210009, China. yaoyuyunj@hotmail.com
authors.forename: Yuyu
authors.initials: Y
authors.lastname: Yao
authors.forename: Zulong
authors.initials: Z
authors.lastname: Sheng
authors.forename: YeFei
authors.initials: Y
authors.lastname: Li
authors.forename: Cong
authors.initials: C
authors.lastname: Fu
authors.forename: Genshan
authors.initials: G
authors.lastname: Ma
authors.forename: Naifeng
authors.initials: N
authors.lastname: Liu
authors.forename: Julie
authors.initials: J
authors.lastname: Chao
authors.forename: Lee
authors.initials: L
authors.lastname: Chao
mesh_terms: D000256:Adenoviridae; D000818:Animals; D017209:Apoptosis / Q000187:drug effects / Q000502:physiology; D001794:Blood Pressure / Q000502:physiology; D042783:Endothelial Cells / Q000166:cytology / Q000187:drug effects / Q000201:enzymology* / Q000637:transplantation*; D005312:Fetal Blood / Q000166:cytology; D005455:Fluorescent Antibody Technique; D005818:Genetic Engineering; D015316:Genetic Therapy; D006801:Humans; D006861:Hydrogen Peroxide / Q000494:pharmacology; D008297:Male; D051379:Mice; D008819:Mice, Nude; D009203:Myocardial Infarction / Q000378:metabolism / Q000473:pathology / Q000601:surgery*; D018919:Neovascularization, Physiologic / Q000502:physiology; D061848:Optical Imaging; D018384:Oxidative Stress / Q000187:drug effects / Q000502:physiology; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism*; D011897:Random Allocation; D033581:Stem Cell Transplantation / Q000379:methods*; D013234:Stem Cells / Q000166:cytology / Q000187:drug effects / Q000201:enzymology* / Q000378:metabolism; D020840:Tissue Kallikreins / Q000235:genetics / Q000378:metabolism*; D015854:Up-Regulation; D042461:Vascular Endothelial Growth Factor A / Q000096:biosynthesis
chemical_list: D042461:Vascular Endothelial Growth Factor A; C467480:vascular endothelial growth factor A, mouse; D006861:Hydrogen Peroxide; D051057:Proto-Oncogene Proteins c-akt; D020840:Tissue Kallikreins