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Shigetoshi Mieno
Basel Ramlawi
Marc Ruel
Frank W. Sellke
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J Thorac Cardiovasc Surg 2007;134:1453-1460
© 2007 The American Association for Thoracic Surgery

Cardiopulmonary Support and Physiology

Insulin treatment enhances the myocardial angiogenic response in diabetes

Munir Boodhwani, MD, MMSca,2, Neel R. Sodha, MDb, Shigetoshi Mieno, MD, PhDb, Basel Ramlawi, MD, MMScb, Shu-Hua Xu, PhDb, Jun Feng, MD, PhDb, Richard T. Clements, PhDb, Marc Ruel, MD, MPHa,3, Frank W. Sellke, MDb,1,*

a Division of Cardiac Surgery, University of Ottawa Heart Institute, Ottawa, Ontario, Canada
b Division of Cardiothoracic Surgery, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Mass.

Read at the Eighty-seventh Annual Meeting of The American Association for Thoracic Surgery, Washington, DC, May 5-9, 2007.

Received for publication May 8, 2007; revisions received July 24, 2007; accepted for publication August 2, 2007.

* Address for reprints: Frank W. Sellke, Beth Israel Deaconess Medical Center, 110 Francis St, LMOB 2A, Boston, MA 02215. (Email: fsellke{at}caregroup.harvard.edu).

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 ß-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.

Abbreviations and Acronyms ADP = adenosine 5’-diphosphate; Ang-1 = angiopoiten-1; DM = diabetes group; dP/dt = first derivative of left ventricular pressure; IDM = insulin-treated diabetes group; ND = no diabetes control group; VEGF = vascular endothelial growth factor


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J. Thorac. Cardiovasc. Surg. 2007 134: 1460. [Extract] [Full Text] [PDF]





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