Insulin treatment enhances the myocardial angiogenic response in diabetes.
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. The aim of this study was to determine the effects of insulin treatment on the diabetic angiogenic response to chronic myocardial ischemia.


METHODS
Yucatan miniswine were treated with alloxan (pancreatic beta-cell specific toxin, 150 mg/kg) and divided into two groups. In the diabetic group (DM, n = 8), blood glucose levels were kept greater than 250 mg/dL, and in the insulin-treated group (IDM, n = 6), intramuscular insulin was administered daily to keep blood glucose less than 150 mg/dL. A third group of age-matched swine served as nondiabetic controls (ND; n = 8). Eight weeks later, all animals underwent circumflex artery ameroid constrictor placement to induce chronic ischemia. Myocardial perfusion was assessed at 3 and 7 weeks after ameroid placement using microspheres. Microvascular function, capillary density, and myocardial expression of anti-angiogenic mediators were evaluated.


RESULTS
Diabetic animals exhibited significant impairments in endothelium-dependent microvessel relaxation to adenosine diphosphate 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 +0.23 +/- 0.07 mL . min(-1) . g(-1); P < .001), improved significantly with insulin treatment (0.12 +/- 0.05 mL . min(-1) . g(-1); P < .01). Myocardial expression of anti-angiogenic proteins, angiostatin and endostatin, showing a 4.3- and 3.6-fold increase in diabetic animals respectively (both P < .01 vs ND), was markedly reduced in insulin-treated animals (2.3- and 1.8-fold vs ND; both P < .01).


CONCLUSIONS
Insulin treatment successfully reversed diabetic coronary endothelial dysfunction and significantly improved the endogenous angiogenic response. These pro-angiogenic effects may be mediated through downregulation of anti-angiogenic mediators. Insulin therapy appears to be a promising modality to enhance the angiogenic response in diabetic patients.
Boodhwani
Munir
M
Division of Cardiac Surgery, University of Ottawa Heart Institute, Ottawa, Ontario, Canada.
Sodha
Neel R
NR
Mieno
Shigetoshi
S
Ramlawi
Basel
B
Xu
Shu-Hua
SH
Feng
Jun
J
Clements
Richard T
RT
Ruel
Marc
M
Sellke
Frank W
FW
D020533:Angiogenesis Inhibitors; D000818:Animals; D002908:Chronic Disease; D003097:Collateral Circulation / Q000187:drug effects; D003326:Coronary Circulation / Q000187:drug effects; D003331:Coronary Vessels / Q000187:drug effects*; D003925:Diabetic Angiopathies / Q000150:complications / Q000188:drug therapy*; D004195:Disease Models, Animal; D004730:Endothelium, Vascular / Q000187:drug effects; D007004:Hypoglycemic Agents / Q000494:pharmacology* / Q000627:therapeutic use; D066298:In Vitro Techniques; D007328:Insulin / Q000494:pharmacology* / Q000627:therapeutic use; D008297:Male; D008833:Microcirculation / Q000187:drug effects; D017202:Myocardial Ischemia / Q000209:etiology / Q000503:physiopathology; D018919:Neovascularization, Physiologic / Q000187:drug effects*; D013552:Swine
D020533:Angiogenesis Inhibitors; D007004:Hypoglycemic Agents; D007328:Insulin