Title: Abstract 5800: Angiopoietin-2 Induced Left Ventricular Hypertrophy is Reduced by AAV-mediated Angiopoietin-1 Overexpression
Abstract: Angiopoietin-2 (Ang-2), a co-factor in postnatal angiogenesis interacting at the endothelial Tie-2 receptor, is a potential target for therapeutic angiogenesis. Though antagonistic functions of Ang-2 and Angiopoietin-1 (Ang-1) have been described, the impact of long lasting Ang-2 expression on cardiac function has not been characterized. Here we analysed the impact of chronic Ang-2 overexpression and interaction with Ang-1 on myocardial morphology and function using a AAV2.9-vector overexpressing Ang-1 (rAAV-Ang-1). Methods: For this purpose conditional Ang-2 overexpressing mice (Tet-off transgenic mice, under control of Tie2-promoter = Ang2-tg) were established and analyzed by echocardiography, non-invasive heart rate (HR), mean arterial pressure (MAP) and invasive catheterization. Results: Ang2-tg mice displayed a significant cardiac dilation from 12 wks to 24 wks of age (LV-EDD: Ang2-tg: 0,47±0,02cm, control: 0,39±0,01cm, n=18). Application of doxycycline (Dox) or transfection of rAAV-Ang-1 (Ang2-tg+rAAV-Ang1) reversed the phenotype almost entirely (Ang2-tg+Dox: 0,43±0,01cm, Ang2-tg+rAAV-Ang1: 0,40±0,02cm, control 0,40±0,01cm), while absence of treatment resulted in progressive cardiac dilation (Ang2-tg: 0,55±0,04cm). Furthermore Ang2-tg mice revealed increased heart weight (hw) normalized to body weight (bw) (hw/bw) mg/g. (Ang2-tg: 8,0±1,5, control: 5,2±1,2). Hypertrophy was not observed in Dox or rAAV-Ang1 treated animals. In addition increased HR and reduced MAP shown in Ang2-tg-mice (HR: 615±43bpm, MAP: 84±3mmHg) normalized in Dox-treated (HR: 542±69bpm, MAP:102±9mmHg) or rAAV-Ang1 transfected animals (HR: 506±62bpm, MAP:94±4mmHg) to control level (HR: 545±36bpm, MAP:95±2mmHg). Invasive data confirmed these findings. Summary: Our results indicate that prolonged Ang-2 overexpression induces progressive LV-dilation and myocardial dysfunction. The cardiac morphology at 12 wks is reversible, if Ang-2 overexpression is shut off, or antagonised by or Ang-1 upregulation. It is tempting to speculate that Ang-2 affects the vascular system profoundly, forcing reactive dilation and cardiac dysfunction.
Publication Year: 2009
Publication Date: 2009-11-03
Language: en
Type: article
Indexed In: ['crossref']
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