(Circulation. 2001;103:2760.)
© 2001 American Heart Association, Inc.
Current Perspective |
Therapeutic Potential of Nitric Oxide Synthase Gene Manipulation
From the Division of Cardiovascular Research, Department of Medicine, Harvard Medical School and Brigham and Women’s Hospital, Boston, Mass (V.J.D.), and Cardion AG, Erkrath, Germany (H.E.v.d.L.).
Correspondence to Victor J. Dzau, Division of Cardiovascular Research, Department of Medicine, Harvard Medical School and Brigham and Women’s Hospital, 75 Francis St, Boston, MA 02115. E-mail vdzau@partners.org
Key Words: gene therapy • nitric oxide synthase
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Introduction |
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Nitric oxide (NO) plays an important role in many fields of medicine, including immunology, neuroscience, and cardiovascular medicine. NO functions both as a signaling molecule in endothelial and nerve cells and as a killer molecule for activated immune cells. Its ubiquitous distribution in the body and its multiple roles have influenced our understanding of how cells communicate and function.1 Cloning and characterization of the different isoforms of NO synthase (NOS) paved the way for a better understanding of the regulation of NO pathways and for the development of therapeutic gene transfer.2 3 Three isoforms of NOS have been described: constitutive-type isoforms like neuronal NOS (NOS I) and endothelial cell NOS (eNOS; NOS III), and the inducible type of the enzyme (inducible NOS [iNOS; NOS II]). The constitutive isoforms are calcium-dependent and regulated (eg, by shear stress); the inducible isoform can be rapidly induced by cytokines to produce high amounts of NO.2 With the recent availability of efficient transduction systems for in vivo gene transfer, as well as other methods of gene manipulation, the time is ripe to consider NOS gene therapy.4 This article will focus on potentially feasible approaches of the manipulation of the NOS gene(s) using DNA expression vectors or antisense oligonucleotides designed to enhance or modify NOS activity for clinical therapeutic benefit.
NO mediates vasorelaxation, inhibits vascular smooth muscle
cell (VSMC) migration and proliferation, attenuates platelet
activation and adhesion, and reduces vascular
inflammation.1 In patients
with cardiovascular risk factors such as hypertension,
hypercholesterolemia, smoking, or diabetes,
endothelium-dependent relaxation is
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