CLINICAL RESEARCH: DIABETES AND CARDIOVASCULAR DISEASE
Increased Vascular Endothelial Growth Factor Expression But Impaired Vascular Endothelial Growth Factor Receptor Signaling in the Myocardium of Type 2 Diabetic Patients With Chronic Coronary Heart Disease
Ferdinando Carlo Sasso, MD, PhD*, ,*,
Daniele Torella, MD, ,
Ornella Carbonara, MD*,,
Georgina M. Ellison, PhD||,
Michele Torella, MD ,,
Michelangelo Scardone, MD,,
Claudio Marra, MD,,
Rodolfo Nasti, MD*,,
Raffaele Marfella, MD, PhD*,,
Domenico Cozzolino, MD*,,
Ciro Indolfi, MD,,
Maurizio Cotrufo, MD,,
Roberto Torella, MD*, and
Teresa Salvatore, MD*,
* Department of Geriatrics and Metabolic Disease, Second University of Naples, Naples, Italy
Department of Cardio-Thoracic and Respiratory Sciences, Second University of Naples, Naples, Italy
Excellence Centre for Cardiovascular Disease, Second University of Naples, Naples, Italy
Division of Cardiology, Magna Graecia University, Catanzaro, Italy
|| The Research Institute for Sport & Exercise Sciences, Liverpool John Moores University, Liverpool, United Kingdom
Manuscript received December 9, 2004;
revised manuscript received January 15, 2005,
accepted March 31, 2005.
* Reprint requests and correspondence: Dr. Ferdinando Carlo Sasso, Department of Geriatrics and Metabolic Disease, Institute of Internal Medicine, Second University of Naples, Via F. Petrarca, 64, 80122 Naples, Italy (Email: ferdinando.sasso{at}unina2.it).
OBJECTIVES: The aim of the present study was to evaluate the expression and the activity of vascular endothelial growth factor (VEGF) in the hearts of diabetic patients with chronic coronary heart disease (CHD).
BACKGROUND: Diabetes is characterized by a decreased collateral vessel formation in response to coronary ischemic events, although the role of VEGF in human diabetic macroangiopathy has not been fully investigated.
METHODS: Biopsies of left ventricular (LV) myocardium were obtained from 10 patients with type 2 diabetes and 10 non-diabetic patients with chronic CHD, all undergoing surgical coronary revascularization. Right ventricle myocardial samples taken from normal hearts were used as control specimens. Vascular endothelial growth factor and VEGF-receptors (flt-1 and flk-1) were evaluated by Western blot, reverse transcriptase-polymerase chain reaction (RT-PCR) and real-time RT-PCR. Akt and endothelial nitric oxide synthase (eNOS) protein expression and their phosphorylated forms were also evaluated by Western blot.
RESULTS: Vascular endothelial growth factor, flt-1, and flk-1 messenger ribonucleic acid (mRNA) and protein expressions were increased in non-diabetic patients with CHD compared with control subjects. Remarkably, in diabetic patients, VEGF mRNA and protein levels were significantly higher, whereas flt-1, flk-1 mRNA, and protein were lower when compared with non-diabetic patients. Interestingly, phospho-flk-1 was reduced in diabetic patients compared with non-diabetic patients. As a consequence, Akt phosphorylation, eNOS protein and its phosphorylated form were significantly higher in the samples from non-diabetic patients compared with diabetic patients.
CONCLUSIONS: Chronic CHD in diabetic patients is characterized by an increased VEGF myocardial expression and a decreased expression of its receptors along with a down-regulation of its signal transduction. The latter could be partially responsible for the reduced neoangiogenesis in diabetic patients with ischemic cardiomyopathy.
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Abbreviations and Acronyms
| | CHD = coronary heart disease | | CVD = cardiovascular disease | | EC = endothelial cell | | eNOS = endothelial nitric oxide synthase | | flt-1/VEGF-R1 = fms-like tyrosine kinase 1/VEGF-receptor 1 | | flk-1/VEGF-R2 = fetal liver kinase 1/VEGF-receptor 2 | | LV = left ventricle/ventricular | | MI = myocardial infarction | | mRNA = messenger ribonucleic acid | | OD = optical density | | PI3K = phosphatidylinositol-3 kinase | | RT-PCR = reverse transcriptase-polymerase chain reaction | | RV = right ventricle/ventricular | | Ser-1177 = phospho-eNOS | | VEGF = vascular endothelial growth factor |
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