Expression of Angiogenic Factors During Acute Coronary Syndromes in Human Type 2 Diabetes
- Raffaele Marfella12,
- Katherine Esposito12,
- Francesco Nappo1,
- Mario Siniscalchi1,
- Ferdinando Carlo Sasso1,
- Michele Portoghese3,
- Maria Pia Di Marino4,
- Alfonso Baldi4,
- Salvatore Cuzzocrea5,
- Clara Di Filippo26,
- Guglielmo Barboso6,
- Feliciano Baldi4,
- Francesco Rossi26,
- Michele D’Amico26 and
- Dario Giugliano12
- 1Department of Geriatrics and Metabolic Diseases, Section of Pathology, Second University of Naples, Naples, Italy
- 2Centro di Eccellenza Cardiovascolare, Section of Pathology, Second University of Naples, Naples, Italy
- 3Cardiovascular Surgery Unit, Hospital Sassari, Sassari, Italy
- 4Department of Biochemistry, Section of Pathology, Second University of Naples, Naples, Italy
- 5Department of Pharmacology, University of Messina, Messina, Italy
- 6Department of Experimental Medicine, Section of Pathology, Second University of Naples, Naples, Italy
- Address correspondence and reprint requests to Dott. Raffaele Marfella, Via Emilio Scaglione 141, 80145 Napoli, Italy. E-mail: raffaele.marfella{at}unina2.it
Abstract
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.
- HIF, hypoxia-inducible factor
- iNOS, inducible nitric oxide synthase
- MI, myocardial infarction
- VEGF, vascular endothelial growth factor
Footnotes
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- Accepted May 26, 2004.
- Received March 13, 2004.
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