Overproduction of cyclo-oxygenase-2 (COX-2) is involved in the resistance to apoptosis in vascular smooth muscle cells from diabetic patients: a link between inflammation and apoptosis.
OBJECTIVE
Inflammation is a common feature in cardiovascular diseases, including diabetes mellitus. In addition to the well-known inflammatory role of cyclo-oxygenase-2 (COX-2), this protein has also been implicated in apoptosis resistance in tumour cells. Vascular smooth muscle cells (VSMC) from diabetic patients are also resistant to apoptosis because of an increased abundance of B cell lymphoma 2 protein (BCL2). In this work, we investigated whether overproduction of COX-2 was involved in the resistance to apoptosis in VSMC from diabetic patients.


METHODS
VSMC were obtained from internal mammary arteries from patients who had undergone coronary artery bypass graft surgery. Apoptosis was measured by DNA fragmentation, BCL2 degradation and cytochrome c release.


RESULTS
Apoptosis induced by C-reactive protein in cells from non-diabetic patients was mediated by COX-2. VSMC from diabetic patients showed higher basal levels of COX-2 compared with those from non-diabetic patients. Transfection of VSMC from non-diabetic patients with a plasmid containing COX-2 (also known as PTGS2) increased basal production of COX-2 and BCL2 and mimicked the resistance to apoptosis that occurs in diabetic patients. We also found a significant correlation (R = 0.846, p = 0.016) between COX-2 and BCL2 production in arterial rings from diabetic patients measured by confocal microscopy. However, inhibition of COX-2 production by small interfering RNA proved unable to reverse BCL2 production in diabetic VSMC.


CONCLUSIONS
These results suggest a link between inflammation (COX-2) and apoptosis resistance (BCL2) in the arteries of diabetic patients. This relationship is not causative and the common production of these two proteins may be co-regulated by shared regulatory elements in diabetes.
Redondo
S
S
Department of Pharmacology, Universidad Complutense, Madrid, Spain. santiredondo@hotmail.com
Ruiz
E
E
Gordillo-Moscoso
A
A
Navarro-Dorado
J
J
Ramajo
M
M
Rodríguez
E
E
Reguillo
F
F
Carnero
M
M
Casado
M
M
Tejerina
T
T
D017209:Apoptosis / Q000187:drug effects / Q000235:genetics*; D015153:Blotting, Western; D002097:C-Reactive Protein / Q000494:pharmacology; D002478:Cells, Cultured; D051546:Cyclooxygenase 2 / Q000235:genetics / Q000378:metabolism*; D053938:DNA Fragmentation / Q000187:drug effects; D003920:Diabetes Mellitus / Q000276:immunology* / Q000473:pathology*; D005455:Fluorescent Antibody Technique; D006801:Humans; D009131:Muscle, Smooth, Vascular / Q000166:cytology*; D032389:Myocytes, Smooth Muscle / Q000166:cytology* / Q000378:metabolism*; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000235:genetics / Q000378:metabolism; D034741:RNA, Small Interfering
D019253:Proto-Oncogene Proteins c-bcl-2; D034741:RNA, Small Interfering; D002097:C-Reactive Protein; D051546:Cyclooxygenase 2; C496540:PTGS2 protein, human