Expression of Angiogenic Factors During Acute Coronary Syndromes in Human Type 2 Diabetes

  1. Raffaele Marfella12,
  2. Katherine Esposito12,
  3. Francesco Nappo1,
  4. Mario Siniscalchi1,
  5. Ferdinando Carlo Sasso1,
  6. Michele Portoghese3,
  7. Maria Pia Di Marino4,
  8. Alfonso Baldi4,
  9. Salvatore Cuzzocrea5,
  10. Clara Di Filippo26,
  11. Guglielmo Barboso6,
  12. Feliciano Baldi4,
  13. Francesco Rossi26,
  14. Michele D’Amico26 and
  15. Dario Giugliano12
  1. 1Department of Geriatrics and Metabolic Diseases, Section of Pathology, Second University of Naples, Naples, Italy
  2. 2Centro di Eccellenza Cardiovascolare, Section of Pathology, Second University of Naples, Naples, Italy
  3. 3Cardiovascular Surgery Unit, Hospital Sassari, Sassari, Italy
  4. 4Department of Biochemistry, Section of Pathology, Second University of Naples, Naples, Italy
  5. 5Department of Pharmacology, University of Messina, Messina, Italy
  6. 6Department of Experimental Medicine, Section of Pathology, Second University of Naples, Naples, Italy
  1. Address correspondence and reprint requests to Dott. Raffaele Marfella, Via Emilio Scaglione 141, 80145 Napoli, Italy. E-mail: raffaele.marfella{at}


Inadequate angiogenic response to ischemia in diabetic myocardium could result in poor collateral formation. Because hypoxia-inducible factor (HIF)-1α is a transcriptional activator of vascular endothelial growth factor (VEGF) and is critical for initiating angiogenic responses to hypoxia, we investigated the expression of HIF-1α and VEGF in specimens of human heart tissue to elucidate the molecular responses to myocardial ischemia in diabetic patients during unstable angina. Moreover, accumulation of a marker of protein nitration nitrotyrosine, as well as the superoxide anion (O2) levels and inducible nitric oxide synthase (iNOS), were evaluated. Ventricular biopsy specimens from 15 type 2 diabetic and 14 nondiabetic patients presenting with unstable angina (ischemic group) and from 20 patients (11 type 2 diabetic and 9 nondiabetic patients) who underwent coronary bypass surgery without angina within the preceding 10 days (control group) were collected during coronary bypass surgery. Nondiabetic patients had higher HIF-1α and VEGF expressions compared with diabetic patients (P < 0.001). As compared with nondiabetic specimens, diabetic specimens showed higher levels of both iNOS mRNA and protein levels (P < 0.001) associated with the highest tissue levels of nitrotyrosine and O2 (P < 0.001). Diabetes is associated with increased myocardial tissue levels of iNOS, O2, and nitrotyrosine and reduced expression of myocardial angiogenesis factors during ischemia.


    • Accepted May 26, 2004.
    • Received March 13, 2004.
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