Angiopoietin-1 for myocardial angiogenesis: a comparison between delivery strategies.
We compare the effectiveness of direct adenoviral angiopoietin-1 (Ad-Ang-1) injection with transplantation of skeletal myoblasts (SkMs) over-expressing angiopoietin-1 (Ang-1) for angiogenic response and improvement of heart function in an experimental porcine model of myocardial infarction (MI).


METHODS
Ad-Ang-1 was used for intramyocardial injection or transduction of SkMs. Three weeks after coronary artery ligation in 32 female pigs, animals were grouped to receive multiple intramyocardial injections of DMEM without cells (group-1; n=7), or containing 3 x 10(8)Lac-z labelled SkMs transduced with Ad-Null vector carrying no gene (group-2; n=7), or 1 x 10(10) PFU Ad-Ang-1 (group-3; n=9), or 3 x 10(8)Lac-z labelled SkMs transduced with Ad-Ang-1 (group-4; n=9). The animals were immunosuppressed for 6-weeks. After euthanasia, their heart tissue was processed for histological studies.


RESULTS
Extensive survival of Lac-z positive SkMs was observed in and around the infarct 6 and 12-weeks after transplantation. Fluorescent immunostaining for vWF-VIII at 6-weeks revealed increased blood vessel density (x100) in group-4 (p<0.05) as compared with other groups. Regional blood flow (ml/g/min) in the peri-infarct area was improved in group-4 (2.7; p<0.05) as compared with group-1 (1.2+/-0.1), group-2 (1.1+/-0.4) and group-3 (1.7+/-0.1) at 6-weeks. Similarly, ejection fraction was significantly higher in group-4 (49.2+/-5.9%, p=0.03) as compared with group-1 (36.8+/-3%) at 6 weeks.


CONCLUSIONS
SkMs mediated Ang-1 delivery is associated with improved angiogenic response, regional myocardial perfusion and heart function as compared with direct Ad-Ang-1 administration.
Ye
Lei
L
National University Medical Institutes, National University of Singapore, Singapore.
Haider
Husnain Kh
HKh
Jiang
Shujia
S
Tan
Ru San
RS
Toh
Wee Chi
WC
Ge
RuoWen
R
Sim
Eugene K W
EK
D000199:Actins / Q000378:metabolism; D000256:Adenoviridae; D000704:Analysis of Variance; D042683:Angiopoietin-1 / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism* / Q000494:pharmacology*; D000818:Animals; D002470:Cell Survival / Q000187:drug effects; D003326:Coronary Circulation / Q000187:drug effects; D004195:Disease Models, Animal; D004452:Echocardiography; D005260:Female; D015870:Gene Expression; D006801:Humans; D008297:Male; D009130:Muscle, Smooth / Q000098:blood supply / Q000378:metabolism; D032448:Myoblasts, Skeletal / Q000637:transplantation*; D009203:Myocardial Infarction / Q000000981:diagnostic imaging / Q000378:metabolism* / Q000473:pathology* / Q000503:physiopathology; D018919:Neovascularization, Physiologic / Q000187:drug effects; D016133:Polymerase Chain Reaction; D012039:Regional Blood Flow / Q000187:drug effects; D013318:Stroke Volume / Q000187:drug effects; D013552:Swine; D013997:Time Factors; D016277:Ventricular Function, Left / Q000187:drug effects; D014841:von Willebrand Factor / Q000378:metabolism
D000199:Actins; D042683:Angiopoietin-1; D014841:von Willebrand Factor