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Human Vascular Smooth Muscle Cells From Diabetic Patients Are Resistant to Induced Apoptosis Due to High Bcl-2 Expression

¹ Department of Pharmacology, School of Medicine, Universidad Complutense, Madrid, Spain
² Cardiac Surgery Service, Hospital Clínico San Carlos, Madrid, Spain
³ Department of Pharmacology and Therapeutics, School of Medicine, Universidad Autónoma de Madrid, Madrid, Spain
⁴ Department of Anesthesiology, Pharmacology and Therapeutics, The University of British Columbia, Vancouver, British Columbia, Canada

Address correspondence and reprint requests to Teresa Tejerina, Department of Pharmacology, School of Medicine, Universidad Complutense, 28040 Madrid, Spain. E-mail: teje{at}med.ucm.es

Abbreviations: CRP, C-reactive protein; ERK1/2, extracellular signal–related kinases 1 and 2; IMA, internal mammary artery; TBS-T, Tris-buffered saline with Tween; VSMC, vascular smooth muscle cell

An emerging body of evidence suggests that vascular remodeling in diabetic patients involves a perturbation of the balance between cell proliferation and cell death. Our aim was to study whether arteries and vascular smooth muscle cells (VSMCs) isolated from diabetic patients exhibit resistance to apoptosis induced by several stimuli. Internal mammary arteries (IMAs) were obtained from patients who had undergone coronary artery bypass graft surgery. Arteries from diabetic patients showed increasing levels of Bcl-2 expression in the media layer, measured by immunofluorescence and by Western blotting. Human IMA VSMCs from diabetic patients showed resistance to apoptosis, measured as DNA fragmentation and caspase-3 activation, induced by C-reactive protein (CRP) and other stimuli, such as hydrogen peroxide and 7ß-hydroxycholesterol. The diabetic cells also exhibited overexpression of Bcl-2. Knockdown of Bcl-2 expression with Bcl-2 siRNA in cells from diabetic patients reversed the resistance to induced apoptosis. Consistent with the above, we found that pretreatment of nondiabetic VSMCs with high glucose abolished the degradation of Bcl-2 induced by CRP. Moreover, cell proliferation was increased in diabetic compared with nondiabetic cells. This differential effect was potentiated by glucose. We conclude that the data provide strong evidence that arterial remodeling in diabetic patients results from a combination of decreased apoptosis and increased proliferation.

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