Expression of angiogenic factors during acute coronary syndromes in human type 2 diabetes.
Inadequate angiogenic response to ischemia in diabetic myocardium could result in poor collateral formation. Because hypoxia-inducible factor (HIF)-1alpha 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-1alpha 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-1alpha 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.
Marfella
Raffaele
R
Department of Geriatrics and Metabolic Diseases, Section of Pathology, Second University of Naples, Naples, Italy. raffaele.marfella@unina2.it
Esposito
Katherine
K
Nappo
Francesco
F
Siniscalchi
Mario
M
Sasso
Ferdinando Carlo
FC
Portoghese
Michele
M
Di Marino
Maria Pia
MP
Baldi
Alfonso
A
Cuzzocrea
Salvatore
S
Di Filippo
Clara
C
Barboso
Guglielmo
G
Baldi
Feliciano
F
Rossi
Francesco
F
D'Amico
Michele
M
Giugliano
Dario
D
D000208:Acute Disease; D000789:Angina, Unstable / Q000150:complications / Q000503:physiopathology* / Q000601:surgery; D003097:Collateral Circulation / Q000502:physiology; D001026:Coronary Artery Bypass; D003924:Diabetes Mellitus, Type 2 / Q000150:complications / Q000503:physiopathology*; D005260:Female; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D008297:Male; D008875:Middle Aged; D019001:Nitric Oxide Synthase / Q000235:genetics; D052247:Nitric Oxide Synthase Type II; D012333:RNA, Messenger / Q000032:analysis; D013481:Superoxides / Q000378:metabolism; D014157:Transcription Factors / Q000235:genetics*; D014443:Tyrosine / Q000031:analogs & derivatives* / Q000378:metabolism; D042461:Vascular Endothelial Growth Factor A / Q000235:genetics*; D016276:Ventricular Function
C497442:HIF1A protein, human; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D012333:RNA, Messenger; D014157:Transcription Factors; D042461:Vascular Endothelial Growth Factor A; D013481:Superoxides; C002744:3-nitrotyrosine; D014443:Tyrosine; C496319:NOS2 protein, human; D019001:Nitric Oxide Synthase; D052247:Nitric Oxide Synthase Type II