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Pellino-1 Gene Therapy Promotes Angiogenesis, Cell Survivability and Improves Myocardial Function Following Infarction by Activating PI-3kinase and MAPkinase 2 Signaling
*Vladimir Coca-Soliz1,2, *Leonidas Tapias1, *Vaithinathan Selvaraju2, *Mahesh Thirunavukkarasu2, David W McFadden2, J. Alexander Palesty1, *Nilanjana Maulik3
1Saint Mary's Hospital, Waterbury, CT;2University of Connecticut Health Center, Farmington, CT;3Saint Mary's Hospital, University of Connecticut Health Center, CT
1. Objective
This study evaluates the effect of Pellino1 (Peli1) overexpression on angiogenesis and myocardial function by intramyocardial administration of adenovirus encoding peli1 (Ad.Peli1) following myocardial infarction (MI) in mice.
2. Design
randomized control trial
3. Setting
Basic science
4. Patients (or Other Participants)
CD-1/ICR mice
5. Interventions (if any)
Following left anterior descending coronary artery ligation or sham surgery Ad.LacZ (1x10-9 IFU) or Ad.Peli1 (1x10-9 IFU) was injected at 4 border zone sites to either Ad.LacZS/Ad.LaczMI or Ad.Peli1S/Ad.Peli1MI group respectively
6. Main Outcome Measure (s)
Left ventricular heart tissue was collected 24 hours post MI for Western blot analysis and 30 days later for immunohistochemistry after echocardiographic analysis.
7. Results
Ad.Peli1 gene therapy after MI increased capillary density [2342±122 vs. 1776±54 counts/mm2 (n=6);p<0.05] as compared to the Ad.LacZMI group. Immunohistochemical analysis for fibrosis with picrosirius red staining exhibited a decrease in collagen deposition in Ad.Peli1MI group [16±1.05 vs. 29±2.05% (n=8); p<0.0001] as compared to Ad.LacZMI group. Echocardiographic analysis revealed increased ejection fraction [48±0.75 vs. 33±0.98% (n=10-11);p<0.05] and fractional shortening [24±0.0.49 vs. 16±0.51% (n=10-11) p<0.05] along with decreased LVIDs [3.74±0.14 vs. 5.21±0.19(mm) (n=10-11); p<0.05] in the Ad.Peli1MI as compared to the Ad.LacZMI group. Western blot analysis 24 h after MI revealed Ad.Peli1 gene therapy increased phosphorylation of Akt (3.4 fold), eNOS (1.9 fold) and MK2 (1.7 fold) compared to Ad.LacZ treatment. Inhibition of Peli1 showed decreased NFkB activity by Gel-shift analysis 8 h after MI
8. Conclusions
Taken together, these data shows the potential of Peli1 gene therapy in inducing angiogenesis and reducing ventricular remodeling in infarcted myocardium
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