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Nitric oxide manipulation: a therapeutic target for peripheral arterial disease?

Williams G, Shi-Wen X, Abraham D, Selvakumar S, Baker DM, Tsui JC - Cardiol Res Pract (2012)

Bottom Line: Risk factor modification and endovascular and surgical revascularisation are the main treatment options at present.However, a significant number of patients still require major amputation.There is evidence that nitric oxide (NO) and its endogenous inhibitor asymmetric dimethylarginine (ADMA) play significant roles in the pathophysiology of PAD.

View Article: PubMed Central - PubMed

Affiliation: Division of Surgery & Interventional Science, University College London, Royal Free Campus, London NW3 2QG, UK.

ABSTRACT
Peripheral Arterial Disease (PAD) is a cause of significant morbidity and mortality in the Western world. Risk factor modification and endovascular and surgical revascularisation are the main treatment options at present. However, a significant number of patients still require major amputation. There is evidence that nitric oxide (NO) and its endogenous inhibitor asymmetric dimethylarginine (ADMA) play significant roles in the pathophysiology of PAD. This paper reviews experimental work implicating the ADMA-DDAH-NO pathway in PAD, focussing on both the vascular dysfunction and effects within the ischaemic muscle, and examines the potential of manipulating this pathway as a novel adjunct therapy in PAD.

No MeSH data available.


Related in: MedlinePlus

ADMA/DDAH pathway in ischaemic muscle—preliminary data. (a) Western blot showing reduced DDAH2 expression in muscle biopsies from patients with CLI. Lanes 1–4: control, 5–8: CLI muscle. (b) ELISA showing significantly higher ADMA levels in muscle from patients with CLI (P = 0.03, Mann Whitney U test). (c) Western blot showing reduced DDAH2 expression in hypoxic myotubes (C: control, H: hypoxia). (d) Conditioned medium from hypoxic C2C12 myotubes contained elevated levels of ADMA compared to medium from myotubes cultured in normoxia. (P < 0.05, Student′s t-test). Medium from HMEC-1 cells was used as positive control.
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fig2: ADMA/DDAH pathway in ischaemic muscle—preliminary data. (a) Western blot showing reduced DDAH2 expression in muscle biopsies from patients with CLI. Lanes 1–4: control, 5–8: CLI muscle. (b) ELISA showing significantly higher ADMA levels in muscle from patients with CLI (P = 0.03, Mann Whitney U test). (c) Western blot showing reduced DDAH2 expression in hypoxic myotubes (C: control, H: hypoxia). (d) Conditioned medium from hypoxic C2C12 myotubes contained elevated levels of ADMA compared to medium from myotubes cultured in normoxia. (P < 0.05, Student′s t-test). Medium from HMEC-1 cells was used as positive control.

Mentions: In skeletal muscle from patients with CLI, we have previously found raised NOS III expression associated with both microvessels within ischaemic muscle sections as well as the muscle fibres themselves [48]. However, this was not associated with an increase in NOS activity. The involvement of endogenous inhibitors may explain this and recent preliminary data suggesting that ADMA levels in muscle homogenates from patients with CLI are raised (Figures 2(a) and 2(b)). In addition, DDAH2 protein levels are also upregulated in these ischaemic muscle biopsies.


Nitric oxide manipulation: a therapeutic target for peripheral arterial disease?

Williams G, Shi-Wen X, Abraham D, Selvakumar S, Baker DM, Tsui JC - Cardiol Res Pract (2012)

ADMA/DDAH pathway in ischaemic muscle—preliminary data. (a) Western blot showing reduced DDAH2 expression in muscle biopsies from patients with CLI. Lanes 1–4: control, 5–8: CLI muscle. (b) ELISA showing significantly higher ADMA levels in muscle from patients with CLI (P = 0.03, Mann Whitney U test). (c) Western blot showing reduced DDAH2 expression in hypoxic myotubes (C: control, H: hypoxia). (d) Conditioned medium from hypoxic C2C12 myotubes contained elevated levels of ADMA compared to medium from myotubes cultured in normoxia. (P < 0.05, Student′s t-test). Medium from HMEC-1 cells was used as positive control.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC3318888&req=5

fig2: ADMA/DDAH pathway in ischaemic muscle—preliminary data. (a) Western blot showing reduced DDAH2 expression in muscle biopsies from patients with CLI. Lanes 1–4: control, 5–8: CLI muscle. (b) ELISA showing significantly higher ADMA levels in muscle from patients with CLI (P = 0.03, Mann Whitney U test). (c) Western blot showing reduced DDAH2 expression in hypoxic myotubes (C: control, H: hypoxia). (d) Conditioned medium from hypoxic C2C12 myotubes contained elevated levels of ADMA compared to medium from myotubes cultured in normoxia. (P < 0.05, Student′s t-test). Medium from HMEC-1 cells was used as positive control.
Mentions: In skeletal muscle from patients with CLI, we have previously found raised NOS III expression associated with both microvessels within ischaemic muscle sections as well as the muscle fibres themselves [48]. However, this was not associated with an increase in NOS activity. The involvement of endogenous inhibitors may explain this and recent preliminary data suggesting that ADMA levels in muscle homogenates from patients with CLI are raised (Figures 2(a) and 2(b)). In addition, DDAH2 protein levels are also upregulated in these ischaemic muscle biopsies.

Bottom Line: Risk factor modification and endovascular and surgical revascularisation are the main treatment options at present.However, a significant number of patients still require major amputation.There is evidence that nitric oxide (NO) and its endogenous inhibitor asymmetric dimethylarginine (ADMA) play significant roles in the pathophysiology of PAD.

View Article: PubMed Central - PubMed

Affiliation: Division of Surgery & Interventional Science, University College London, Royal Free Campus, London NW3 2QG, UK.

ABSTRACT
Peripheral Arterial Disease (PAD) is a cause of significant morbidity and mortality in the Western world. Risk factor modification and endovascular and surgical revascularisation are the main treatment options at present. However, a significant number of patients still require major amputation. There is evidence that nitric oxide (NO) and its endogenous inhibitor asymmetric dimethylarginine (ADMA) play significant roles in the pathophysiology of PAD. This paper reviews experimental work implicating the ADMA-DDAH-NO pathway in PAD, focussing on both the vascular dysfunction and effects within the ischaemic muscle, and examines the potential of manipulating this pathway as a novel adjunct therapy in PAD.

No MeSH data available.


Related in: MedlinePlus