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Mechanisms of superoxide production in human blood vessels: relationship to endothelial dysfunction, clinical and genetic risk factors

100%

Channon K. M., Guzik T. J.

Journal of Physiology and Pharmacology

2002

tom 53

nr 4,1

Common vascular disease states including diabetes, hypertension and atherosclerosis are associated with endothelial dysfunction, characterised by reduced bioactivity of nitric oxide (NO). Loss of the vasculoprotective effects of NO contributes to disease progression, but the mechanisms underlying endothelial dysfunction remain unclear. Increased superoxide production in animal models of vascular disease contributes to reduced NO bioavailability, endothelial dysfunction and oxidative stress. In human blood vessels, the NAD(P)H oxidase system is the principal source of superoxide, and is functionally related to clinical risk factors and systemic endothelial dysfunction. Furthermore, the C242T polymorphism in the NAD(P)H oxidase p22phox subunit is associated with significantly reduced superoxide production in patients carrying the 242T allele, suggesting a role for genetic variation in modulating vascular superoxide production. In vessels from patients with diabetes mellitus, endothelial dysfunction, NAD(P)H oxidase activity and protein subunits are significantly increased compared with matched non-diabetic vessels. Furthermore, the vascular endothelium in diabetic vessels is a net source of superoxide rather than NO production, due to dysfunction of endothelial NO synthase (eNOS). This deficit is dependent on the eNOS cofactor, tetrahydrobiopterin, and is in part mediated by protein kinase C signalling. These studies suggest an important role for both the NAD(P)H oxidases and endothelial NOS in the increased vascular superoxide production and endothelial dysfunction in human vascular disease states.

Superoxide dismutase activity and expression in human venous and arterial bypass graft vessels

41%

Guzik T. J., Olszanecki R., Sadowski J., Kapelak B., Rudzinski P., Jopek A., Kawczynska A., Ryszawa N., Loster J., Jawien J., Czesnikiewicz-Guzik M., Channon K. M., Korbut R.

Journal of Physiology and Pharmacology

2005

tom 56

nr 2

Venous bypass grafts are more prone to accelerated atherosclerosis than arterial grafts, which is partly related to increased oxidative stress and diminished nitric oxide bioavailability. In veins superoxide production is dependent primarily on nox2 NAD(P)H oxidase expression, while in arteries nox4 appears to play an important role. This may in part explain differences in susceptibility to graft failure. Net levels of oxidative stress are however determined in parallel by the production as well as by degradation of free radicals (eg. by superoxide dimutases, catalases, thioredoxins etc). The differences in superoxide dismutase (SOD) expression and activity in human bypass conduit vessels remain unclear. Accordingly, we aimed to compare SOD activity and protein levels as well as its functional effects on superoxide production in segments of human internal mammary arteries (IMA) and saphenous veins (HSV) from patients undergoing bypass graft surgery (n=24). SOD activity was assessed by inhibition of pyrogallol autoxidation, Cu-Zn SOD and Mn SOD protein levels were studied by immunoblotting. Basal superoxide release was detected by lucigenin (5µM) enhanced chemiluminescence. Total SOD activity did not differ significantly between HSV and IMA. Similarly, no difference was observed in SOD activity in the presence of KCN (Mn-SOD). Human bypass conduit vessels show amounts of Cu-Zn SOD or Mn-SOD protein levels. In both HSV and IMA segments superoxide production was more than doubled in the presence of SOD inhibitor - DETC. Conclusions: These studies suggest that the differences in oxidative stress between human arteries and veins are unlikely to be caused by SOD activity. However SOD plays and important role in amelioration of oxidative stress in both types of vessels.

Ograniczanie wyników

2 Journal of Physiology and Pharmacology

2 Channon K. M.

2 Guzik T. J.

1 Czesnikiewicz-Guzik M.

1 Jawien J.

1 Jopek A.

1 Kapelak B.

1 Kawczynska A.

1 Korbut R.

1 Loster J.

1 Olszanecki R.

1 Rudzinski P.

1 Ryszawa N.

1 Sadowski J.

1 2005

1 2002

Wyniki wyszukiwania

Mechanisms of superoxide production in human blood vessels: relationship to endothelial dysfunction, clinical and genetic risk factors

Superoxide dismutase activity and expression in human venous and arterial bypass graft vessels