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

• Published in: Diabetes (New York, N.Y.) Vol. 53; no. 9; pp. 2383 - 2391
• Main Authors: MARFELLA, Raffaele, ESPOSITO, Katherine, BARBOSO, Guglielmo, BALDI, Feliciano, ROSSI, Francesco, D'AMICO, Michele, GIUGLIANO, Dario, NAPPO, Francesco, SINISCALCHI, Mario, SASSO, Ferdinando Carlo, PORTOGHESE, Michele, DI MARINO, Maria Pia, BALDI, Alfonso, CUZZOCREA, Salvatore, DI FILIPPO, Clara
• Format: Journal Article
• Language: English
• Published: Alexandria, VA American Diabetes Association 01-09-2004
• Subjects: Acute Disease; Angina pectoris; Angina, Unstable - complications; Angina, Unstable - physiopathology; Angina, Unstable - surgery; Angiogenesis; Angiogenin; Biological and medical sciences; Biopsy; Cardiology. Vascular system; Collateral Circulation - physiology; Coronary Artery Bypass; Coronary heart disease; Coronary vessels; Diabetes; Diabetes Mellitus, Type 2 - complications; Diabetes Mellitus, Type 2 - physiopathology; Diabetes. Impaired glucose tolerance; Diagnosis; Emergency medical care; Endocrine pancreas. Apud cells (diseases); Endocrinopathies; Female; Gene expression; Heart; Heart failure; Heart surgery; Humans; Hypoxia; Hypoxia-Inducible Factor 1, alpha Subunit; Ischemia; Male; Medical imaging; Medical sciences; Middle Aged; Nitric oxide; Nitric Oxide Synthase - genetics; Nitric Oxide Synthase Type II; Patients; Proteins; RNA, Messenger - analysis; Superoxides - metabolism; Transcription Factors - genetics; Type 2 diabetes; Tyrosine - analogs & derivatives; Tyrosine - metabolism; Vascular endothelial growth factor; Vascular Endothelial Growth Factor A - genetics; Ventricular Function; United States; Type 2 diabetes; Endocrinopathy; Human; Cardiovascular disease; Coronary heart disease
• ISSN: 0012-1797; 1939-327X
• DOI: 10.2337/diabetes.53.9.2383

Expression of Angiogenic Factors During Acute Coronary Syndromes in Human Type 2 Diabetes
Raffaele Marfella 1 2 ,
Katherine Esposito 1 2 ,
Francesco Nappo 1 ,
Mario Siniscalchi 1 ,
Ferdinando Carlo Sasso 1 ,
Michele Portoghese 3 ,
Maria Pia Di Marino 4 ,
Alfonso Baldi 4 ,
Salvatore Cuzzocrea 5 ,
Clara Di Filippo 2 6 ,
Guglielmo Barboso 6 ,
Feliciano Baldi 4 ,
Francesco Rossi 2 6 ,
Michele D’Amico 2 6 and
Dario Giugliano 1 2
1 Department of Geriatrics and Metabolic Diseases, Section of Pathology, Second University of Naples, Naples, Italy
2 Centro di Eccellenza Cardiovascolare, Section of Pathology, Second University of Naples, Naples, Italy
3 Cardiovascular Surgery Unit, Hospital Sassari, Sassari, Italy
4 Department of Biochemistry, Section of Pathology, Second University of Naples, Naples, Italy
5 Department of Pharmacology, University of Messina, Messina, Italy
6 Department 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 (O 2 − ) 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 O 2 − ( P < 0.001). Diabetes is associated with increased myocardial tissue levels of iNOS, O 2 − , 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
Accepted May 26, 2004.
Received March 13, 2004.
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