Endothelial nitric oxide (NO) and its pathophysiologic regulation

Abstract

Nitric oxide (NO) is a gaseous lipophilic free radical generated by three distinct isoforms of nitric oxide synthases (NOS), type 1 or neuronal (nNOS), type 2 or inducible (iNOS) and type 3 or endothelial NOS (eNOS). Expression of eNOS is altered in many types of cardiovascular disease, such as atherosclerosis, diabetes and hypertension. The ubiquitous chaperone heat shock protein 90 (hsp90) associates with NOS and is important for its proper folding and function. Current studies point toward a therapeutic potential by modulating hsp90-NOS association in various vascular diseases. Here we review the transcriptional regulation of endothelial NOS and factors affecting eNOS activity and function, as well as the important vascular pathologies associated with altered NOS function, focusing on the regulatory role of hsp90 and other factors in NO-associated pathogenesis of these diseases. Keywords nitric oxide; hsp90; cardiovascular disease Transcriptional and post-transcriptional regulation of eNOS in endothelial cellsEndothelial cells have a constitutive expression of eNOS and like other constitutively expressed proteins, the eNOS promoter lacks the typical TATA box. Instead, it has other multiple cisregulatory DNA sequences like SP-1, GATA, activator protein-1, activator protein-2, nuclear factor-1, sheer stress response elements and sterol-regulatory elements (Marsden et al., 1993). The presence of these consensus sites is consistent with evidence showing that levels of eNOS transcripts are elevated by sheer stress (Davis et al., 2001;Woodman et al., 2005), exercise (Sessa et al., 1994;Yang et al., 2002) and hypoxia (Le Cras et al., 1996). Regulation of eNOS transcription by estrogens is still a matter of debate (Arnal et al., 1996;Kleinert et al., 1998), however, estradiol relaxes rat aortic segments via endothelium-dependent andindependent mechanisms involving the NO-cGMP signaling system (Abou-Mohamed et al., 2003). Both lipopolysaccharide (Arriero et al., 2000) and tumor necrosis factor-α (Yoshizumi et al., 1993) decrease eNOS gene expression by reducing the stability of eNOS mRNAs. Basal human eNOS transcription is controlled by two regulatory regions, the positive regulatory Address correspondence to: Dr. John D. Catravas Vascular Biology Center Medical College of Georgia Augusta, GA 30912-2500 USA e-mail: jcatrava@mcg.edu tel: +1-706-721-6338 fax: +1-706-721-9799. Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final citable form. Please note that during the production process errorsmaybe discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. Searles, 2006). Moreover, these regions also contain differentially methylated nucleotides that restrict eNOS transcription largely in vascular endothel...

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“…Modulation of eNOS expression and activity affects the outcome of inflammatory vascular diseases (36). Despite the clear contribution of immune responses to these pathologies, the effect of IL-17 on eNOS expression has been poorly characterized.…”

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“…The B2R is selectively activated by bradykinin (BK) or kallidin (KD), which can be further processed by plasma carboxypeptidase N or membrane carboxypeptidase M to generate des-Arg 9 -BK or des-Arg 10 -KD, which no longer activate the B2R, but instead are specific B1R agonists (16 -18). Stimulation of the B2R or B1R differentially activates eNOS or iNOS, respectively (19).…”

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