Abstract-Oxidized low-density lipoproteins increase arginase activity and reciprocally decrease endothelial NO in human aortic endothelial cells. Here, we demonstrate that vascular endothelial arginase activity is increased in atherogenicprone apolipoprotein E-null (ApoE Ϫ/Ϫ ) and wild-type mice fed a high cholesterol diet. In ApoE Ϫ/Ϫ mice, selective arginase II inhibition or deletion of the arginase II gene (Arg II Ϫ/Ϫ mice) prevents high-cholesterol diet-dependent decreases in vascular NO production, decreases endothelial reactive oxygen species production, restores endothelial function, and prevents oxidized low-density lipoprotein-dependent increases in vascular stiffness. Furthermore, arginase inhibition significantly decreases plaque burden. These data indicate that arginase II plays a critical role in the pathophysiology of cholesterol-mediated endothelial dysfunction and represents a novel target for therapy in atherosclerosis. (Circ Res. 2008;102:923-932.) Key Words: vascular stiffness Ⅲ eNOS uncoupling Ⅲ pulse wave velocity Ⅲ nitric oxide Ⅲ L-arginine I n atherosclerosis, 1 oxidized low-density lipoprotein (OxLDL) is known to impair endothelial NO production by mechanisms that involve altered endothelial NO synthase (eNOS) expression, increased reactive oxygen species (ROS) production, 2 and alterations in proteins that regulate eNOS function (eg, caveolin and heat shock protein-90). 3 The concept has emerged that arginase, which shares the substrate L-arginine with NO synthase (NOS), reciprocally regulates NOS activity by competing for arginine and can inhibit NO-dependent processes by depleting the substrate pool for NO biosynthesis. This is dependent on L-arginine concentrations in microdomains in which NOS isoforms and/or arginase are located. 4 Reciprocal regulation of NOS by arginase has been demonstrated in cells/organs in which NO is an important signaling molecule including the endothelium, 5 cardiac myocyte, 6 penis, 7,8 airway, 9 skin, 10 and inflammatory cells. 11 Upregulation of arginase activity contributes to vasoregulatory dysfunction in systemic [12][13][14] and pulmonary hypertension, 15,16 aging, 5,17,18 diabetes, 19 and erectile dysfunction 20 and to bronchodilatory dysfunction in asthma. 21 In cultured endothelial cells, we have demonstrated that OxLDL-dependent activation and upregulation of arginase impairs NO production and endothelial function. 22 This novel mechanism may be pivotal in the pathogenesis of atherosclerosis. 23 We have demonstrated that OxLDL facilitates arginase II (ArgII) release from the endothelial microtubular structure, 22 and the resulting increased arginase activity contributes to impaired endothelial cell NO production. Finally, L-arginine depletion secondary to arginase activation and upregulation may result in eNOS uncoupling, 24,25 with increased endothelial ROS production and nitroso-redox imbalance.Our objectives were to determine: (1) whether OxLDLdependent activation of arginase causes impaired vascular NO production, increased ROS production,...
Rationale: Although an age-related decrease in NO bioavailability contributes to vascular stiffness, the underlying molecular mechanisms remain incompletely understood. We hypothesize that NO constrains the activity of the matrix crosslinking enzyme tissue transglutaminase (TG2) via S-nitrosylation in young vessels, a process that is reversed in aging. Objective: We sought to determine whether endothelium-dependent NO regulates TG2 activity by S-nitrosylation and whether this contributes to age-related vascular stiffness. Methods and Results: We first demonstrate that NO suppresses activity and increases S-nitrosylation of TG2 in cellular models. Next, we show that nitric oxide synthase (NOS) inhibition leads to increased surface and extracellular matrix-associated TG2. We then demonstrate that endothelium-derived bioactive NO primarily mediates its effects through TG2, using TG2 ؊/؊ mice chronically treated with the NOS inhibitor L-N Gnitroarginine methyl ester (L-NAME). We confirm that TG2 activity is modulated by endothelium-derived bioactive NO in young rat aorta. In aging rat aorta, although TG2 expression remains unaltered, its activity increases and S-nitrosylation decreases. Furthermore, TG2 inhibition decreases vascular stiffness in aging rats. Finally, TG2 activity and matrix crosslinks are augmented with age in human aorta, whereas abundance remains unchanged. Conclusions: Decreased S-nitrosylation of TG2 and increased TG activity lead to enhanced matrix crosslinking and contribute to vascular stiffening in aging. TG2 appears to be the member of the transglutaminase family primarily contributing to this phenotype. Inhibition of TG2 could thus represent a therapeutic target for age-associated vascular stiffness and isolated systolic hypertension. (Circ Res. 2010;107:117-125.)Key Words: tissue transglutaminase Ⅲ S-nitrosylation Ⅲ S-nitrosation Ⅲ aging Ⅲ vascular stiffness A ging is associated with alterations in the properties of all elements of the vascular wall including endothelium, vascular smooth muscle, and matrix. 1 These changes result in increased vascular stiffness and isolated systolic hypertension. In addition, increased vascular stiffness promotes atherosclerosis at various sites in the vascular tree, such as the carotid artery. 2,3 Both dynamic changes (alterations in endothelial function and effects on vascular smooth muscle contractility), as well as structural alterations (eg, fracturing of elastin, increased collagen content, and accumulation of advanced glycation end products) have been described in aging. Vessel structure can additionally be regulated by alterations in matrix crosslinking. 1 Transglutaminases (TGs) are enzymes that catalyze a transamidation reaction, leading to the crosslinking of proteins through the formation of the stable N--(␥-glutamyl)lysine isopeptide bonds. 4,5 At least 3 of the 9 members of the TG superfamily are expressed in vascular systems. Tissue transglutaminase (TG2) in particular is ubiquitously expressed in vasculature, including in endothelial ce...
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.
hi@scite.ai
10624 S. Eastern Ave., Ste. A-614
Henderson, NV 89052, USA
Copyright © 2024 scite LLC. All rights reserved.
Made with 💙 for researchers
Part of the Research Solutions Family.