Munir Boodhwani1, Neel R. Sodha1, Shu-Hua Xu1, Shigetoshi Mieno1, Jun Feng1, Marc Ruel2, Frank W. Sellke1; 1Beth Israel Deaconess Medical Center, Boston, MA; 2Cardiac Surgery, University of Ottawa Heart Institute, Ottawa, ON, Canada
Objective: Growth factor and cell-based angiogenesis are attractive therapeutic options for diabetic patients with end-stage coronary disease. Reduced collateral vessel formation observed in diabetes is associated with increased expression of anti-angiogenic proteins, angiostatin and endostatin. We sought to determine the effects of insulin treatment on the diabetic angiogenic response in a clinically relevant large animal model of chronic myocardial ischemia.Methods: Yucatan miniswine, treated with alloxan, (pancreatic β-cell specific toxin, 150 mg/kg) were divided into two groups. In the DM group (n = 8), blood glucose (BG) levels were kept >250 mg/dL, and in the IDM group (n = 6), intramuscular insulin was administered daily to keep BG < 150 mg/dL. A third group of age-matched swine served as non-diabetic controls (ND; n = 8). Eight weeks later, all animals underwent circumflex ameroid constrictor placement to induce chronic ischemia. Myocardial perfusion was assessed at 3 and 7 weeks after ameroid placement using isotope-labeled microspheres. Microvascular function, capillary density, and expression of anti-angiogenic mediators were evaluated.
Results: Diabetic animals exhibited significant impairments in endothelium-dependent microvessel relaxation to adenosine diphosphate (ADP; Fig 1A) and substance P, which were reversed in insulin treated animals. Collateral dependent perfusion in the ischemic circumflex territory, which was profoundly reduced in diabetic animals (-0.18 ± 0.02 vs. 0.27 ± 0.06 ml/min/g; p < 0.001), improved significantly with insulin treatment (0.12 ± 0.05, p < 0.01; Fig 1B). Myocardial expression of anti-angiogenic proteins, angiostatin and endostatin, showing a 4.4 and 3.2 fold increase in diabetic animals respectively (both p < 0.05 vs. ND), was markedly reduced in insulin treated animals (1.8 and 2.3 fold vs. ND, p < 0.05 vs. DM, fig 1C)
Conclusion: Insulin treatment reversed diabetic coronary endothelial dysfunction and significantly improved the angiogenic response. These pro-angiogenic effects may be mediated through down regulation of anti-angiogenic proteins. Insulin therapy appears to be a promising modality to enhance the angiogenic response in diabetes.
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