Time course of vascular arginase expression and activity in spontaneously hypertensive rats

Demougeot, Céline; Prigent‐Tessier, Anne; Bagnost, Teddy; André, Carl; Guillaume, Yves Claude; Bouhaddi, Malika; Marie, Christine; Berthelot, Alain

doi:10.1016/j.lfs.2006.12.003

Cited by 52 publications

(43 citation statements)

References 26 publications

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“…In contrast, nor-NOHA had no effect on ACh-induced relaxation in control rats. These findings indicate that increased arginase contributes to endothelial dysfunction, probably by limiting the L-arginine availability for NOS, as previously observed in animal models of cardiovascular diseases (19)(20)(21)(22)24). It is noteworthy that beyond its effect on vascular NO production, decreased L-arginine availability secondary to arginase up-regulation might theoretically contribute to the eNOS uncoupling recently identified in vessels of AIA rats (12).…”

Section: Discussionsupporting

confidence: 80%

“…Arginase uses L-arginine (the substrate of NOS) as substrate and can thereby limit the availability of L-arginine for NO synthesis. Consistent with this theory are the studies demonstrating that arginase inhibition enhanced NOmediated vasodilatory function under pathologic conditions such as aging, hypertension, diabetes, and atherosclerosis (19)(20)(21)(22)(23)(24). Therefore, inhibition of vascular arginase activity might represent a new pharmacologic strategy for increasing availability of arginine for NO synthesis in conditions associated with endothelial dysfunction.…”

Section: Discussionmentioning

confidence: 79%

“…Because NOS and arginase use L-arginine as a common substrate, arginase may down-regulate NO biosynthesis by competing with NOS for L-arginine degradation. Consistent with this hypothesis, increased vascular arginase activity was reported to contribute to decreased endotheliumdependent NO production in pathologic conditions such as hypertension (19,20), atherosclerosis (21), diabetes (22), and erectile dysfunction (23), or in aging (24). Moreover, even though the regulating factors of arginase expression/activity remain largely unknown, it was demonstrated that various proinflammatory cytokines can act as inducers of arginase expression in cultured endothelial cells (18,25,26).…”

mentioning

confidence: 78%

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Endothelial dysfunction in rat adjuvant‐induced arthritis: Up‐regulation of the vascular arginase pathway

Prati¹,

Berthelot²,

Wendling³

et al. 2011

Arthritis & Rheumatism

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Objective. To investigate whether arginase pathway abnormalities occur in vessels from rats with adjuvant-induced arthritis (AIA), and to determine whether the up-regulation of arginase, which reciprocally regulates nitric oxide synthase (NOS) by competing for the same substrate, L-arginine, contributes to endothelial dysfunction in AIA.Methods. We performed vascular reactivity experiments on thoracic aortic rings from AIA rats and control rats, and we investigated the response of rings to norepinephrine (NE), sodium nitroprusside (SNP), and acetylcholine (ACh). ACh-induced relaxation was evaluated in the presence (or not in the presence) of the NOS inhibitor N G -nitro-L-arginine methyl ester (L-NAME), the arginase inhibitor N -hydroxy-nor-Larginine (nor-NOHA), or both. Aortic arginase activity was measured using a spectrophotometric method, and the expression of arginase and endothelial NOS (eNOS) was evaluated by Western blotting.Results. ACh-induced vasodilation was significantly impaired in AIA rats, while the responses to NE and to SNP did not differ from those in control rats. L-NAME reduced ACh-induced vasodilation to a lesser extent in AIA rats than in control rats. Incubation of aortic rings with nor-NOHA enhanced the vascular response to ACh in AIA rats and reversed the effects of L-NAME. Compared with control rats, AIA rats exhibited increased vascular expression of arginase II (by 22%) (P < 0.05) as well as increased arginase activity (by 49%) (P < 0.05), whereas eNOS expression was unchanged. Finally, arginase activity and expression correlated positively with arthritis severity.Conclusion. Our results are consistent with the notion that arginase up-regulation plays a role in AIAassociated endothelial dysfunction. They suggest that arginase might be an attractive new target for treating endothelial dysfunction in arthritis.

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Section: Discussionsupporting

confidence: 80%

Section: Discussionmentioning

confidence: 79%

mentioning

confidence: 78%

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Endothelial dysfunction in rat adjuvant‐induced arthritis: Up‐regulation of the vascular arginase pathway

Prati¹,

Berthelot²,

Wendling³

et al. 2011

Arthritis & Rheumatism

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“…There is emerging evidence for the expression of iNOS in the endothelium of aging rat aorta ( Figure 7A). 22,23,34 Inhibition of iNOS with 1400W in aortic rings led to decreased arginase activity in endothelial intact rings from old rats ( Figure 7B), accompanied by reduced arginase1-SNO (Figure 7D) and arginase1 trimer levels ( Figure 7D). This was in contrast to the inhibition of eNOS, which results in increased arginase activity in endothelial cells.…”

Section: Santhanam Et Al Inos and Arginase1 In Endothelial Dysfunctionmentioning

confidence: 98%

Inducible NO Synthase–Dependent S -Nitrosylation and Activation of Arginase1 Contribute to Age-Related Endothelial Dysfunction

Santhanam

Lim

et al. 2007

Circulation Research

167

144

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Abstract-Endothelial function is impaired in aging because of a decrease in NO bioavailability. This may be, in part, attributable to increased arginase activity, which reciprocally regulates NO synthase (NOS) by competing for the common substrate, L-arginine. However, the high K m of arginase (Ͼ1 mmol/L) compared with NOS (2 to 20 mol/L) seemingly makes direct competition for substrate unlikely. One of the mechanisms by which NO exerts its effects is by posttranslational modification through S-nitrosylation of protein cysteines. We tested the hypothesis that arginase1 activity is modulated by this mechanism, which serves to alter its substrate affinity, allowing competition with NOS for L-arginine. We demonstrate that arginase1 activity is altered by S-nitrosylation, both in vitro and ex vivo. Furthermore, using site-directed mutagenesis we demonstrate that 2 cysteine residues (C168 and C303) are able to undergo nitrosylation. S-Nitrosylation of C303 stabilizes the arginase1 trimer and reduces its K m value 6-fold. Finally, arginase1 nitrosylation is increased (and thus its K m decreased) in blood vessels from aging rats, likely contributing to impaired NO bioavailability and endothelial dysfunction. This is mediated by inducible NOS, which is expressed in the aging endothelium. These findings suggest that S-nitrosylated arginase1 can compete with NOS for L-arginine and contribute to endothelial dysfunction in the aging cardiovascular system. (Circ Res. 2007;101:692-702.)Key Words: arginase Ⅲ NO synthase Ⅲ S-nitrosylation Ⅲ aging A ging is accompanied by impaired endothelial function caused by reduced NO bioavailability. Arginase, the final enzyme of the urea cycle, uses L-arginine as a substrate 1-4 and reciprocally regulates NO synthase (NOS) by substrate depletion. [5][6][7][8] Increased arginase activity, therefore, leads to diminished production of NO. 6,[9][10][11][12] In vascular tissue, this further affects 2 important functions of NO: (1) cGMPdependent signaling and (2) modulation of protein function through S-nitrosylation. Several studies have demonstrated reciprocal regulation of arginase and NOS, where inhibition of arginase leads to increased NO activity. 7,8,13,14 Conversely, upregulation of arginase functionally inhibits NOS activity and contributes to the pathophysiology of several disease processes, 8,[15][16][17][18] including age-related vascular dysfunction. 5,6 The high K m value of human arginase for L-arginine (Ͼ1 mmol/L 19 ) is significantly higher than that of NOS (2 to 20 mol/L 20 ) and suggests that there should not be a direct competition for L-arginine. However, the role of arginase in regulating NOS activity through substrate depletion is now well detailed, as discussed above.Given the interaction between NOS and arginase signaling, we hypothesized that S-nitrosylation of arginase1 might be an important posttranslational modification mechanism that regulates its activity. The protein sequence for human arginase1 contains 3 cysteines, C45, C168, and C303, with C303 being very close...

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“…Surprisingly, the role of arginase in hypertension is poorly documented. Augmented arginase activity (AA)/expression were reported in different vascular beds in models of essential or secondary hypertension (77)(78). Recent studies reported that arginase inhibitor improved aortic endothelial function via a NO-dependent mechanism in prehypertensive or young adult SHR, and also prevented the development of hypertension (79)(80).…”

Section: Hypertension and Edmentioning

confidence: 99%

The Role Erectile Dysfunction Plays in Cardiovascular Diseases

Crestani¹,

Nunes²,

Marques³

et al. 2012

Erectile Dysfunction - Disease-Associated Mechanisms and Novel Insights Into Therapy

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Time course of vascular arginase expression and activity in spontaneously hypertensive rats

Cited by 52 publications

References 26 publications

Endothelial dysfunction in rat adjuvant‐induced arthritis: Up‐regulation of the vascular arginase pathway

Endothelial dysfunction in rat adjuvant‐induced arthritis: Up‐regulation of the vascular arginase pathway

Inducible NO Synthase–Dependent S -Nitrosylation and Activation of Arginase1 Contribute to Age-Related Endothelial Dysfunction

The Role Erectile Dysfunction Plays in Cardiovascular Diseases

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