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- De Muinck, Ebo D., et al.
(författare)
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Protection against myocardial ischemia-reperfusion injury by the angiogenic masterswitch protein PR 39 gene therapy : the roles of HIF1 alpha stabilization and FGFR1 signaling
- 2007
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Ingår i: Antioxidants and Redox Signaling. - : Mary Ann Liebert. - 1523-0864 .- 1557-7716. ; 9:4, s. 437-445
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Tidskriftsartikel (refereegranskat)abstract
- PR-39, a proline-arginine-rich angiogenic response peptide, has been implicated in myocardial ischemic reperfusion injury. The present study examined the cardioprotective abilities of PR39 gene therapy. Male C5713146 mice were randomized to intramyocardial injecton of 10(9) p.f.u. adenovirus encoding PR39 (PR39), FGFR1 dominant negative signaling construct (FGFR1-dn), empty vector (EV), or PR39 adenovirus plus 4 mu g of plasmid endcoding a HIF1 alpha dominant negative construct (PR39 + HIF1 alpha-dn). Seven days later, hearts were subjected to 20 min of ischemia (1) and 2 h. reperfusion (R) ex vivo and aortic and coronary flow, left ventricular developed pressure (LVDP), and LVdp/dt were measured. Myocardial infarct (MI) size and cardiomyocyte apoptosis were measured by TTC staining and TUNEL, respectively. PR39 expression was robust up to 14 days after gene transfer and was absent after EV and FGFR1-dn. Hemodynamics showed no differences at baseline, and heart rate remained unchanged in all groups throughout the experiment. After I-R, hemodynamics remained unchanged in PR39 hearts, but deteriorated significantly in the other groups, except for aortic flow, which remained significantly higher in FGFR1-dn than in EV and PR39 + HIF1 alpha-dn (p less than 0.05), although it was lower than in PR39 (p less than 0.05). MI was 8.7 +/- 0.9 % in PR39, 23.8 +/- 1.1 % in FGFR1-dn, 29.9 +/- 2.2% in EV, and 30.8 +/- 2.7 % in PR39 + HIF1 alpha-dn (PR39 vs. other groups: p less than 0.05; FGFR1-dn vs. EV and PR39 + HIF1 alpha-dn: p less than 0.05). In PR39, HIF-1 alpha protein was higher than in FGFR1-dn and EV. Importantly, cotransfection of HlF1 alpha-dn with PR39 completely abolished cardioprotection by PR39. Cardioprotection by PR39 is likely conveyed by protective metabolic and survival responses through HIF1-alpha stabilization and not by angiogenesis, because baseline coronary How was the same in all groups. Abrogation of FGFR1 signaling conveyed an intermediate degree of cardioprotection.
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| 2. |
- Zhuang, Zhen W., et al.
(författare)
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Arteriogenesis: Noninvasive quantification with multi-detector row CT angiography and three-dimensional volume rendering in rodents
- 2006
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Ingår i: Radiology. - : Radiological Society of North America (RSNA). - 0033-8419 .- 1527-1315. ; 240:3, s. 698-707
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Tidskriftsartikel (refereegranskat)abstract
- PURPOSE:To evaluate two-dimensional (2D) multi-detector row computed tomographic (CT) angiography and three-dimensional (3D) volume rendering for depiction of patterns of arterial growth and quantification of blood vessel density and volume.MATERIALS AND METHODS:The institutional animal care and use committee approved this study. The right femoral artery and its branches were ligated and excised in 16 inbred Lewis rats; animals were randomly assigned to receive 70 microL Dulbecco's modified Eagle's medium (DMEM) or 1.5 x 10(7) bone marrow-derived mononuclear cells (BMC) from isogenic donor rats in 70 microL DMEM. At 2 weeks, CT angiography was performed with injection of 0.45 mL barium sulfate suspension at 0.7 mL/min, followed by silver staining. Number of blood vessels, area, mean area, volume, and blood vessel size distribution derived from digitally subtracted 2D CT angiographic sections were quantified; 3D images were reconstructed. Two-way analysis of variance and paired and unpaired Student t tests were performed.RESULTS:CT angiography showed two patterns of arterial growth: collateral arterial formation and branching arteriogenesis. Two-way analysis of variance indicated that differences within subjects (ischemic vs nonischemic legs) and between subjects (BMC vs DMEM treatment) were significant for total blood vessel area, total blood vessel volume, and mean of blood vessel area (P < .001). In the BMC group, there were significantly more arteries (mean, 241.6 +/- 77.0 [standard deviation] vs 196.4 +/- 75.2, P = .028), but mean cross-sectional area of these arteries was smaller in ischemic versus nonischemic legs (5.4 mm(2) +/- 1.2 vs 6.8 mm(2) +/- 1.3, P = .006). Total arterial area and volume did not differ significantly between ischemic and nonischemic legs.CONCLUSION:BMC injection had a substantial effect on arteriogenesis, with normalization of total arterial area and volume in the BMC group; this effect was successfully depicted.
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