Vascular Consequences of Endothelial Nitric Oxide Synthase Uncoupling for the Activity and Expression of the Soluble Guanylyl Cyclase and the cGMP-Dependent Protein Kinase

Abstract

Abstract-Endothelial dysfunction in the setting of cardiovascular risk factors, such as hypercholesterolemia, hypertension, diabetes mellitus, chronic smoking, as well as in the setting of heart failure, has been shown to be at least partly dependent on the production of reactive oxygen species (ROS), such as the superoxide radical, and the subsequent decrease in vascular bioavailability of nitric oxide (NO). Superoxide-producing enzymes involved in increased oxidative stress within vascular tissue include the NAD(P)H oxidase, the xanthine oxidase, and mitochondrial superoxideproducing enzymes. Superoxide produced by the NADPH oxidase may react with NO released by endothelial nitric oxide synthase (eNOS), thereby generating peroxynitrite. Peroxynitrite in turn has been shown to uncouple eNOS, thereby switching an antiatherosclerotic NO-producing enzyme to an enzyme that may initiate or even accelerate the atherosclerotic process by producing superoxide. Increased oxidative stress in the vasculature, however, is not restricted to the endothelium and has also been demonstrated to occur within the smooth muscle cell layer in the setting of hypercholesterolemia, diabetes mellitus, hypertension, congestive heart failure, and nitrate tolerance. Increased superoxide production by the endothelial and/or smooth muscle cells has important consequences with respect to signaling by the soluble guanylyl cyclase (sGC) and the cGMP-dependent protein kinase I (cGK-I), the activity and expression of which has been shown to be regulated in a redox-sensitive fashion. The present review summarizes current concepts concerning eNOS uncoupling and also focuses on the consequences for downstream signaling with respect to activity and expression of the sGC and cGK-I in various diseases. Key Words: endothelium Ⅲ vasodilation Ⅲ nitric oxide Ⅲ endothelial NO-synthase Ⅲ oxidative stress T raditionally, the role of the endothelium was thought primarily to be that of a selective barrier to the diffusion of macromolecules from the vessel lumen to the interstitial space. During the past 20 years, numerous additional roles for the endothelium have been defined such as regulation of vascular tone, modulation of inflammation, promotion, and inhibition of vascular growth and modulation of platelet aggregation and coagulation. Endothelial dysfunction is a characteristic feature of patients with coronary atherosclerosis and more recent studies indicate that it may predict long-term atherosclerotic disease progression as well as cardiovascular event rate. 1 Although the mechanisms underlying endothelial dysfunction may be multifactorial, there is a growing body of evidence that increased production of reactive oxygen species (ROS) may contribute considerably to this phenomenon. ROS production has been demonstrated to occur in the endothelial cell layer, but also within the media and adventitia, all of which may impair nitric oxide (NO) signaling within vascular tissue to endotheliumdependent, but also endothelium-independent, vasodilators. More recent...

Endothelial dysfunction in diabetic erectile dysfunction

“…Oxidation of the zinc thiolate cluster of eNOS and the cofactor BH 4 , and the decreased availability of the NOS substrate L-arginine, have been proposed to lead to monomerization of eNOS, increased production of ROS, and reduced NO production by the enzyme. 28,51 Bovine aortic endothelial cells exposed to elevated glucose and diabetic mouse heart and aorta have disrupted zinc-thiolate cluster on eNOS, reduced levels of BH 4 , and increased eNOS monomers. 28,52 eNOS phosphorylation also affects the degree of eNOS coupling.…”

“…Potential vascular sources of ROS include NAD(P)H oxidase, uncoupled eNOS, mitochondrial electron transport, xanthine oxidoreductase and cyclooxygenase. 51 Substantial experimental and clinical evidence exists for the involvement of ROS in the development of endothelial dysfunction in the diabetic penis. Penile tissue from diabetic men with ED and streptozotocin-induced diabetic rats contains lower levels of nitrate and nitrite, 56 higher levels of superoxide, 57 and higher levels of malondialdehyde, 56,58,59 a product of lipid peroxidation, compared to penile tissue from nondiabetic ED patients and nondiabetic animals.…”

“…It has been postulated that superoxide produced by NAD(P)H oxidase triggers eNOS uncoupling. 51 Recent in vivo data document that eNOS is an important superoxide source in vivo, contributing to endothelial dysfunction in diabetic animals and diabetic patients. 74 Increased formation of peroxynitrite, disruption of eNOS dimers, and reduced endothelium-dependent vasodilation has been demonstrated in the arteries of high-fat fed diabetic mice, 77 and in hearts of streptozotocin-treated LDLR knockout mice.…”

Endothelial arginase: A new target in atherosclerosis

“…In addition, increase in endogenous eNOS inhibitor asymmetric dimethylarginine (ADMA), deficiency in co-factor tetrahydrobiopterin (BH 4 ), and deficiency in the substrate L-arginine have been proposed to cause so-called "uncoupling of eNOS" in atherosclerosis, a situation in which eNOS produces free radical superoxide anion instead of NO [17,19]. This mechanism may further contribute to inactivation of bioactive NO in atherosclerosis mediated by oxidative stress mediated by other enzymes such as NADPHoxidase [19].…”

Expression of NO synthases and redox enzymes in umbilical arteries from newborns born small, appropriate, and large for gestational age

“…Free radicals, reactive oxygen species (ROS), and reactive nitrogen species are highly reactive molecules (12)(13)(14). ROS produced by the nicotinamide adenine dinucleotide phosphate (NADPH) oxidases promote the development of endothelial dysfunction and atherosclerosis.…”