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

Abstract

Aims/hypothesis Inflammation is a common feature in cardiovascular diseases, including diabetes mellitus. In addition to the well-known inflammatory role of cyclooxygenase-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/interpretation 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.

Alterations of specific biomarkers of metabolic pathways in vascular tree from patients with Type 2 diabetes

“…Our data agree with the results recently published by Redondo et al (2011), who demonstrated that there is a link between inflammation (COX-2) and apoptosis resistance (BCL2) in the vessels of diabetic patients [28]. …”

Viscum album Exerts Anti-Inflammatory Effect by Selectively Inhibiting Cytokine-Induced Expression of Cyclooxygenase-2

“…However, it also exerts potent pro-inflammatory effects including the induction fever and pain. Overproduction of PGE2 occurs in response to pro-inflammatory stimuli and correlates with the severity of certain infectious and inflammatory conditions [46]–[49]. PGE2 exerts autocrine and paracrine actions on the target cells and can induce pro-inflammatory reactions.…”

“…Overproduction of PGE2 is observed in many of the human pathologies associated with inflammation and pro-tumoral condition [46]–[49]. PGE2 is synthesized by cyclo-oxygenases, COX-1 (expressed constitutively) and COX-2 (induced in response to inflammatory stimulus).…”

Viewing cancer pathophysiology as a lead in understanding cardiac and vascular disease mechanisms

“…Cox-2/EGFR/MAPK signal cascade acts in cancer [67] as well as being a pro-hypertrophic mechanism in the heart [68]. Following on, targeting Cox-2 may be beneficial in hypertension [69] and atheroma/vascular dysfunction [70]. e The omega-3 polyunsaturate Docosahexaenoate, DHA, downregulates Cox-2 and NF-kappa B prosurvival signaling axis in cancer [72] via the arachidonic lipoxygenase Lox [73].…”

“…In atherogenesis, prosurvival Cox-2 is involved as a mediator. Somewhat predictably, it is involved in endothelial dysfunction/resistance to apoptosis seen in diabetic vasculature for example [70]. Along with TNFalpha doi: 10.7243/2052-4358-2-6 and interleukin-6, prosurvival Cox-2 forms a therapeutic target for anti-atherogenic therapies.…”