Vascular-targeting anti-oxidant therapy in a model of hypertension and stroke

Greig, J.A., Shirley, R., Graham, D. , Denby, L., Dominiczak, A.F. , Work, L.M. and Baker, A. (2010) Vascular-targeting anti-oxidant therapy in a model of hypertension and stroke. Journal of Cardiovascular Pharmacology, 56(6), pp. 642-650. (doi:10.1097/FJC.0b013e3181f8f19f)

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Publisher's URL: http://dx.doi.org/10.1097/FJC.0b013e3181f8f19f

Abstract

Oxidative stress is implicated in the pathogenesis of hypertension and stroke. Superoxide (SO) is produced by NAD(P)H oxidase in the vasculature and reduces nitric oxide (NO) bioavailability, which leads to increased blood pressure. The objective of this study was to determine whether targeting an anti-oxidant peptide to the vasculature would increase the anti-oxidant effect and reduce systolic blood pressure (SBP) in a model of genetic hypertension, the stroke-prone spontaneously hypertensive rat (SHRSP). Vascular-targeting peptides CRPPR and CSGMARTKC were identified by phage display in mice. These peptides retain their selectivity across species and target the aorta (CRPPR) and cardiac vasculature (CSGMARTKC) in the SHRSP. These vascular-targeting peptides were linked to the anti-oxidant peptide gp91ds, which selectively inhibits assembly of NAD(P)H oxidase, thereby reducing SO production. SBP was determined for one week prior to treatment, followed by three weeks of study duration before sacrifice. SBP in the control animals increased from 178.1 +/- 4.1 mmHg to 201.6 +/- 9.0 mmHg. The SBP of the animals treated with gp91ds alone, HIV-tat-gp91ds and CSGMARTKC-gp91ds increased from 177.8 +/- 3.5 mmHg, 179.8 +/- 4.7 mmHg and 177.9 +/- 5.2 mmHg, respectively, to 201.6 +/- 10.8 mmHg, 200.3 +/- 11.7 mmHg and 205.7 +/- 10.9 mmHg, respectively. This increase in SBP was significantly attenuated in animals receiving CRPPR-gp91ds (maximum SBP 187.5 mmHg +/- 5.2, * p < 0.001 vs. other treatment groups and control group). Additionally, animals treated with CRPPR-gp91ds, CSGMARTKC-gp91ds and gp91ds alone showed significantly improved nitric oxide (NO) bioavailability determined by large vessel myography. Therefore, targeting an anti-oxidant to the aortic vasculature in vivo using peptides can significantly improve NO bioavailability and attenuate the time-dependent and progressive increase in SBP in the SHRSP. This study has demonstrated the importance and potential benefit of targeting a biologically active peptide in the context of a pre-clinical model of endothelial dysfunction and hypertension.

Item Type:Articles
Status:Published
Refereed:Yes
Glasgow Author(s) Enlighten ID:Shirley, Dr Rachel and Baker, Professor Andrew and Graham, Dr Delyth and Denby, Dr Laura and Dominiczak, Professor Anna and Greig, Ms Jenny and Work, Dr Lorraine
Authors: Greig, J.A., Shirley, R., Graham, D., Denby, L., Dominiczak, A.F., Work, L.M., and Baker, A.
Subjects:R Medicine > RC Internal medicine
College/School:College of Medical Veterinary and Life Sciences > Institute of Cardiovascular and Medical Sciences
Journal Name:Journal of Cardiovascular Pharmacology
Publisher:Lippincott Williams & Wilkins
ISSN:0160-2446
ISSN (Online):1533-4023

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