Functional, cellular, and molecular characterization of the angiogenic response to chronic myocardial ischemia in diabetes

Munir Boodhwani, Neel R. Sodha, Shigetoshi Mieno, Shu Hua Xu, Jun Feng, Basel Ramlawi, Richard T. Clements, Frank W. Sellke

Research output: Contribution to journalArticle

75 Scopus citations

Abstract

BACKGROUND - Ischemic heart disease is the most common cause of mortality in diabetic patients. Although therapeutic angiogenesis is an attractive option for these patients, they appear to have reduced collateral formation in response to myocardial ischemia. The aims of this study were to establish a large animal model of diabetes and chronic myocardial ischemia, evaluate the effects of diabetes on the angiogenic response, and elucidate the molecular pathways involved. METHODS AND RESULTS - Diabetes was induced in male Yucatan miniswine using a pancreatic β-cell specific toxin, alloxan (150 mg/kg; n=8). Age-matched swine served as controls (n=8). Eight weeks after induction, chronic ischemia was induced by ameroid constrictor placement around the circumflex coronary artery. Myocardial perfusion and function were assessed at 3 and 7 weeks after ameroid placement using isotope-labeled microspheres. Endothelial cell density and myocardial expression of angiogenic mediators was evaluated. Diabetic animals exhibited significant endothelial dysfunction. Collateral dependent perfusion and LV function were significantly impaired in diabetic animals. Diabetic animals also demonstrated reduced endothelial cell density (173±14 versus 234±23 cells/hpf, P=0.03). Expression of VEGF, Ang-1, and Tie-2 was reduced, whereas antiangiogenic proteins, angiostatin (4.4±0.9-fold increase, P<0.001), and endostatin (2.9±0.4-fold increase, P=0.03) were significantly elevated in the diabetic myocardium. CONCLUSIONS - Diabetes results in a profound impairment in the myocardial angiogenic response to chronic ischemia. Pro- and antiangiogenic mediators identified in this study offer novel targets for the modulation of the angiogenic response in diabetes.

Original languageEnglish (US)
Pages (from-to)I31-I37
JournalCirculation
Volume116
Issue number11 SUPPL. 1
DOIs
StatePublished - Sep 2007
Externally publishedYes

Keywords

  • Angiogenesis
  • Diabetes
  • Endothelium
  • Growth factors
  • Ischemia

ASJC Scopus subject areas

  • Physiology
  • Cardiology and Cardiovascular Medicine

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