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1.
Int J Cardiol ; 301: 207-214, 2020 Feb 15.
Artigo em Inglês | MEDLINE | ID: mdl-31785959

RESUMO

Endothelial dysfunction represents an early change in the vascular wall in areas prone to atherosclerotic plaque formation and is present in association with several risk factors for cardiovascular disease. The underlying mechanisms behind endothelial dysfunction are multifactorial and complex. Arginase has emerged as a key player in the regulation of endothelial integrity by the ability of reciprocally inhibits nitric oxide formation and promoting oxidative stress. A chain of evidence suggest that arginase is implicated in the pathogenesis underlying endothelial dysfunction induced by several cardiovascular risk factors and established cardiovascular disease including diabetes, hypercholesteremia, ischemia/reperfusion, atherosclerosis, obesity, ageing and hypertension. Recent data has unveiled a key role of arginase as one of the key mechanisms underlying endothelial dysfunction in diabetes and may serve as a potential therapeutic target in previously overlooked compartments including red blood cells. The current review is devoted to discuss arginase as a key mediator in endothelial dysfunction and the potential for therapeutic possibilities to target this enzyme in various diseases, especially type 2 diabetes, atherosclerosis and ischemia/reperfusion with focus on translational and clinical aspects. Moreover, approaches of how and in which patient group(s) arginase may be targeted in future clinical trials are discussed.

2.
Front Pharmacol ; 10: 861, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31427970

RESUMO

Red blood cells (RBCs) from patients with type 2 diabetes mellitus (T2DM) induce endothelial dysfunction and impair cardiac function following ischemia via increase in RBC arginase and oxidative stress. Here, we aimed to elucidate whether the effect of RBC-mediated cardiac impairment following ischemia and endothelial dysfunction in T2DM is dependent on glycemic control. Patients with T2DM at poor glycemic control (T2DM PGC) and at improvement in glycemic control (T2DM IGC) and healthy subjects were recruited. Isolated RBCs from subjects were incubated with aortic rings from healthy wild-type rats with subsequent evaluation of endothelium-dependent relaxation (EDR) using wire myograph. Moreover, RBCs were administered to isolated wild-type rat hearts with subsequent evaluation of left ventricular developed pressure (LVDP) during reperfusion using Langendorff setup. In separate experiments, RBCs were preincubated with an arginase inhibitor before perfusion. Blood glucose and glycated hemoglobin were 33 and 26%, respectively, lower in T2DM IGC compared with those in T2DM PGC. RBCs from T2DM PGC and T2DM IGC impaired EDR to a similar magnitude compared with RBCs from healthy subjects. LVDP was significantly impaired in hearts given RBCs from T2DM PGC as compared with those from healthy subjects. The impairment of LVDP induced by T2DM PGC was attenuated by RBCs from T2DM IGC. Arginase inhibition improved LVDP to a similar extent between T2DM PGC and IGC groups. These observations indicate that glycemic control abrogate the impairment in postischemic recovery but not endothelial dysfunction induced by RBCs from T2DM. Moreover, inhibition of RBC arginase improves cardiac function irrespective of glycemic control.

3.
Rejuvenation Res ; 22(5): 385-389, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-30526321

RESUMO

Reduced bioavailability of nitric oxide (NO) is accompanied by endothelial dysfunction, which precedes clinical signs of atherosclerosis. The metalloenzyme arginase reciprocally inhibits the formation of NO and available data demonstrate that arginase contributes to reduced bioavailability of NO and increases the formation of reactive oxygen species. Emerging evidence suggests that arginase thereby plays a key role in the pathophysiology of age-associated vascular complications in animal models. However, the role of arginase in elderly human subjects in vivo with regard to macrovascular endothelial function is unclear. We hypothesized that arginase inhibition improves endothelial function in an age-dependent manner in elderly healthy subjects. Twenty-one subjects ranging from 48 to 75 years of age were included for evaluation of endothelial function using forearm venous occlusion plethysmography. Endothelium-dependent vasodilatation (EDV) and endothelium-independent vasodilatation (EIDV) were evaluated before and after 2-hour intra-arterial infusion of the arginase inhibitor Nω-hydroxy-nor-L-arginine (nor-NOHA). Baseline EDV, but not EIDV, was inversely correlated with age (p < 0.05, R = -0.48 and p = 0.62, R = -0.14, respectively). The magnitude of the improvement in EDV induced by arginase inhibition was significantly correlated with age (p < 0.05, R = 0.56), whereas EIDV was not (p = 0.25, R = 0.26). Arginase inhibition improves endothelial function in an age-dependent manner in elderly healthy subjects. The results suggest that arginase is a key factor contributing to endothelial dysfunction and may serve as a future pharmacological target for improving endothelial function in elderly subjects.

4.
JACC Basic Transl Sci ; 3(4): 450-463, 2018 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-30175269

RESUMO

This study tested the hypothesis that red blood cell (RBC) arginase represents a potential therapeutic target in ischemia-reperfusion in type 2 diabetes. Post-ischemic cardiac recovery was impaired in hearts from db/db mice compared with wild-type hearts. RBCs from mice and patients with type 2 diabetes attenuated post-ischemic cardiac recovery of nondiabetic hearts. This impaired cardiac recovery was reversed by inhibition of RBCs arginase or nitric oxide synthase. The results suggest that RBCs from type 2 diabetics impair cardiac tolerance to ischemia-reperfusion via a pathway involving arginase activity and nitric oxide synthase-dependent oxidative stress.

5.
J Am Coll Cardiol ; 72(7): 769-780, 2018 08 14.
Artigo em Inglês | MEDLINE | ID: mdl-30092954

RESUMO

BACKGROUND: Cardiovascular complications are major clinical problems in type 2 diabetes mellitus (T2DM). The authors previously demonstrated a crucial role of red blood cells (RBCs) in control of cardiac function through arginase-dependent regulation of nitric oxide export from RBCs. There is alteration of RBC function, as well as an increase in arginase activity, in T2DM. OBJECTIVES: The authors hypothesized that RBCs from patients with T2DM induce endothelial dysfunction by up-regulation of arginase. METHODS: RBCs were isolated from patients with T2DM and age-matched healthy subjects and were incubated with rat aortas or human internal mammary arteries from nondiabetic patients for vascular reactivity and biochemical studies. RESULTS: Arginase activity and arginase I protein expression were elevated in RBCs from patients with T2DM (T2DM RBCs) through an effect induced by reactive oxygen species (ROS). Co-incubation of arterial segments with T2DM RBCs, but not RBCs from age-matched healthy subjects, significantly impaired endothelial function but not smooth muscle cell function in both healthy rat aortas and human internal mammary arteries. Endothelial dysfunction induced by T2DM RBCs was prevented by inhibition of arginase and ROS both at the RBC and vascular levels. T2DM RBCs induced increased vascular arginase I expression and activity through an ROS-dependent mechanism. CONCLUSIONS: This study demonstrates a novel mechanism behind endothelial dysfunction in T2DM that is induced by RBC arginase I and ROS. Targeting arginase I in RBCs may serve as a novel therapeutic tool for the treatment of endothelial dysfunction in T2DM.


Assuntos
Arginase/biossíntese , Diabetes Mellitus Tipo 2/sangue , Diabetes Mellitus Tipo 2/enzimologia , Endotélio Vascular/enzimologia , Eritrócitos/enzimologia , Idoso , Animais , Arginase/antagonistas & inibidores , Relação Dose-Resposta a Droga , Endotélio Vascular/efeitos dos fármacos , Inibidores Enzimáticos/farmacologia , Eritrócitos/efeitos dos fármacos , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Técnicas de Cultura de Órgãos , Ratos , Espécies Reativas de Oxigênio/metabolismo , Vasodilatação/efeitos dos fármacos , Vasodilatação/fisiologia , Vasodilatadores/farmacologia
6.
Eur J Clin Invest ; 47(1): 38-43, 2017 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-27861771

RESUMO

BACKGROUND: Patients with heterozygous familial hypercholesterolaemia (FH) suffer from high plasma cholesterol and an environment of increased oxidative stress. We examined its potential effects on high-density lipoprotein (HDL)-associated sphingosine-1-phosphate (S1P) content (HDL-S1P) and HDL-mediated protection against oxidative stress, both with and without statin treatment. MATERIALS AND METHODS: In a case-control study, HDL was isolated from 12 FH patients with and without statin treatment and from 12 healthy controls. The HDL-S1P content and the capacity of HDL to protect cardiomyocytes against oxidative stress in vitro were measured. RESULTS: HDL-associated S1P was significantly correlated with cell protection, but not with HDL-cholesterol or apolipoprotein AI. The latter did not correlate with HDL-mediated cell protection. Neither the HDL-S1P content nor HDL protective capacity differed between nontreated FH patients and controls. The relative amounts of apolipoprotein AI and apolipoprotein M were similar between controls and FH patients. Statin treatment had no effect on any of these measures. CONCLUSIONS: The FH environment is not detrimental to HDL-S1P content or HDL-S1P-mediated cell protection. Statin treatment does not modulate HDL function in this regard.


Assuntos
Apolipoproteína A-I/metabolismo , Hiperlipoproteinemia Tipo II/metabolismo , Lipoproteínas HDL/metabolismo , Lisofosfolipídeos/metabolismo , Estresse Oxidativo , Esfingosina/análogos & derivados , Adulto , Animais , Estudos de Casos e Controles , Células Cultivadas , HDL-Colesterol/metabolismo , Cromatografia Líquida , Feminino , Heterozigoto , Humanos , Inibidores de Hidroximetilglutaril-CoA Redutases/uso terapêutico , Hiperlipoproteinemia Tipo II/tratamento farmacológico , Técnicas In Vitro , Lipoproteínas HDL/farmacologia , Masculino , Pessoa de Meia-Idade , Miócitos Cardíacos/efeitos dos fármacos , Estresse Oxidativo/efeitos dos fármacos , Ratos , Esfingosina/metabolismo , Espectrometria de Massas em Tandem , Adulto Jovem
7.
J Clin Endocrinol Metab ; 101(11): 3952-3958, 2016 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-27399350

RESUMO

OBJECTIVES: The development of microvascular complications in diabetes is a complex process in which endothelial dysfunction is important. Emerging evidence suggests that arginase is a key mediator of endothelial dysfunction in type 2 diabetes mellitus by reciprocally regulating nitric oxide bioavailability. The aim of this prospective intervention study was to test the hypothesis that arginase activity is increased and that arginase inhibition improves microvascular endothelial function in patients with type 2 diabetes and microvascular dysfunction. DESIGN: Microvascular endothelium-dependent and -independent dilatation was determined in patients with type 2 diabetes (n = 12) and healthy age-matched control subjects (n = 12) with laser Doppler flowmetry during iontophoretic application of acetylcholine and sodium nitroprusside, respectively, before and after administration of the arginase inhibitor Nω-hydroxy-nor-L-arginine (120 min). Plasma ratios of amino acids involved in arginase and nitric oxide synthase activities were determined. The laser Doppler flowmetry data were the primary outcome variable. RESULTS: Microvascular endothelium-dependent dilatation was impaired in subjects with type 2 diabetes (P < .05). After administration of Nω-hydroxy-nor-L-arginine, microvascular endothelial function improved significantly in patients with type 2 diabetes to the level observed in healthy controls. Endothelium-independent vasodilatation did not change significantly. Subjects with type 2 diabetes had higher levels of ornithine and higher ratios of ornithine/citrulline and ornithine/arginine (P < .05), suggesting increased arginase activity. CONCLUSION: Arginase inhibition improves microvascular endothelial function in patients with type 2 diabetes and microvascular dysfunction. Arginase inhibition may represent a novel therapeutic strategy to improve microvascular endothelial function in patients with type 2 diabetes.


Assuntos
Arginase/antagonistas & inibidores , Fármacos Cardiovasculares/uso terapêutico , Diabetes Mellitus Tipo 2/complicações , Angiopatias Diabéticas/tratamento farmacológico , Endotélio Vascular/efeitos dos fármacos , Inibidores Enzimáticos/uso terapêutico , Doenças Vasculares Periféricas/tratamento farmacológico , Acetilcolina/farmacologia , Idoso , Arginase/metabolismo , Arginina/efeitos adversos , Arginina/análogos & derivados , Arginina/uso terapêutico , Fármacos Cardiovasculares/efeitos adversos , Angiopatias Diabéticas/sangue , Angiopatias Diabéticas/metabolismo , Angiopatias Diabéticas/fisiopatologia , Endotélio Vascular/fisiopatologia , Inibidores Enzimáticos/efeitos adversos , Feminino , Humanos , Fluxometria por Laser-Doppler , Masculino , Microvasos/efeitos dos fármacos , Microvasos/fisiopatologia , Pessoa de Meia-Idade , Nitroprussiato/farmacologia , Ornitina/sangue , Doenças Vasculares Periféricas/complicações , Doenças Vasculares Periféricas/metabolismo , Doenças Vasculares Periféricas/fisiopatologia , Índice de Gravidade de Doença , Resistência Vascular/efeitos dos fármacos , Vasodilatação/efeitos dos fármacos , Vasodilatadores/farmacologia
8.
Diab Vasc Dis Res ; 13(5): 354-60, 2016 09.
Artigo em Inglês | MEDLINE | ID: mdl-27190086

RESUMO

BACKGROUND: Endothelial dysfunction contributes to the development of vascular complication in diabetes. Arginase has emerged as a key mechanism behind endothelial dysfunction by its reciprocal regulation of nitric oxide production by substrate competition. We hypothesized that increased arginase activity in patients with type 2 diabetes shifts the metabolism of l-arginine from nitric oxide synthase to arginase resulting in an increase in the plasma ratio of ornithine/citrulline, and that this ratio is associated with endothelial dysfunction. METHODS: Forearm endothelium-dependent vasodilatation and endothelium-independent vasodilatation were determined in 15 patients with type 2 diabetes and 10 healthy controls and related to amino acids reflecting arginase and nitric oxide synthase activity. RESULTS: Compared to healthy controls, patients with diabetes had impaired endothelium-dependent vasodilatation and endothelium-independent vasodilatation. The ratios of ornithine/citrulline and proline/citrulline were 60% and 95% higher, respectively, in patients with diabetes than in controls (p < 0.001). The plasma ornithine/arginine ratio was 36% higher in patients with diabetes, indicating increased arginase activity. These ratios were inversely correlated to endothelium-dependent vasodilatation and endothelium-independent vasodilatation. CONCLUSION: Patients with diabetes and macrovascular complications have increased amino acid ratios reflecting a shift in arginine metabolism due to arginase activation. These changes are inversely related to endothelial function supporting that arginase activity contributes to endothelial dysfunction.


Assuntos
Arginase/metabolismo , Arginina/metabolismo , Diabetes Mellitus Tipo 2/complicações , Angiopatias Diabéticas/etiologia , Endotélio Vascular/enzimologia , Antebraço/irrigação sanguínea , Vasodilatação , Idoso , Biomarcadores/sangue , Estudos de Casos e Controles , Citrulina/sangue , Diabetes Mellitus Tipo 2/sangue , Angiopatias Diabéticas/sangue , Angiopatias Diabéticas/enzimologia , Angiopatias Diabéticas/fisiopatologia , Endotélio Vascular/fisiopatologia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Óxido Nítrico Sintase/metabolismo , Ornitina/sangue , Regulação para Cima
9.
PLoS One ; 9(7): e103260, 2014.
Artigo em Inglês | MEDLINE | ID: mdl-25072937

RESUMO

BACKGROUND: Arginase competes with nitric oxide synthase for their common substrate L-arginine. Up-regulation of arginase in coronary artery disease (CAD) and diabetes mellitus may reduce nitric oxide bioavailability contributing to endothelial dysfunction and ischemia-reperfusion injury. Arginase inhibition reduces infarct size in animal models. Therefore the aim of the current study was to investigate if arginase inhibition protects from endothelial dysfunction induced by ischemia-reperfusion in patients with CAD with or without type 2 diabetes ( CLINICAL TRIAL REGISTRATION NUMBER: NCT02009527). METHODS: Male patients with CAD (n = 12) or CAD + type 2 diabetes (n = 12), were included in this cross-over study with blinded evaluation. Endothelium-dependent vasodilatation was assessed by flow-mediated dilatation (FMD) of the radial artery before and after 20 min ischemia-reperfusion during intra-arterial infusion of the arginase inhibitor (Nω-hydroxy-nor-L-arginine, 0.1 mg/min) or saline. RESULTS: The forearm ischemia-reperfusion was well tolerated. Endothelium-independent vasodilatation was assessed by sublingual nitroglycerin. Ischemia-reperfusion decreased FMD in patients with CAD from 12.7±5.2% to 7.9±4.0% during saline administration (P<0.05). Nω-hydroxy-nor-L-arginine administration prevented the decrease in FMD in the CAD group (10.3±4.3% at baseline vs. 11.5±3.6% at reperfusion). Ischemia-reperfusion did not significantly reduce FMD in patients with CAD + type 2 diabetes. However, FMD at reperfusion was higher following nor-NOHA than following saline administration in both groups (P<0.01). Endothelium-independent vasodilatation did not differ between the occasions. CONCLUSIONS: Inhibition of arginase protects against endothelial dysfunction caused by ischemia-reperfusion in patients with CAD. Arginase inhibition may thereby be a promising therapeutic strategy in the treatment of ischemia-reperfusion injury.


Assuntos
Arginase/antagonistas & inibidores , Doença da Artéria Coronariana/complicações , Diabetes Mellitus Tipo 2/complicações , Inibidores Enzimáticos/farmacologia , Inibidores Enzimáticos/uso terapêutico , Traumatismo por Reperfusão Miocárdica/tratamento farmacológico , Traumatismo por Reperfusão Miocárdica/etiologia , Idoso , Estudos Cross-Over , Humanos , Masculino , Pessoa de Meia-Idade , Traumatismo por Reperfusão Miocárdica/fisiopatologia , Artéria Radial/efeitos dos fármacos , Resultado do Tratamento , Vasodilatação/efeitos dos fármacos , Vasodilatadores/farmacologia , Vasodilatadores/uso terapêutico
10.
Circulation ; 126(25): 2943-50, 2012 Dec 18.
Artigo em Inglês | MEDLINE | ID: mdl-23183942

RESUMO

BACKGROUND: Endothelial dysfunction plays an important role in the early development of atherosclerosis and vascular complications in type 2 diabetes mellitus. Increased expression and activity of arginase, metabolizing the nitric oxide substrate l-arginine, may result in reduced production of nitric oxide and thereby endothelial dysfunction. We hypothesized that inhibition of arginase activity improves endothelial function in patients with coronary artery disease (CAD) and type 2 diabetes mellitus. METHODS AND RESULTS: Three groups of subjects were included: 16 patients with CAD, 16 patients with CAD and type 2 diabetes mellitus (CAD+Diabetes), and 16 age-matched healthy control subjects. Forearm endothelium-dependent and endothelium-independent vasodilatation were assessed with venous occlusion plethysmography before and during intra-arterial infusion of the arginase inhibitor N(ω)-hydroxy-nor-l-arginine (nor-NOHA; 0.1 mg/min). Nor-NOHA was also coinfused with the nitric oxide synthase inhibitor (N(G)-monomethyl L-arginine). The expression of arginase was determined in the internal mammary artery of patients undergoing bypass surgery. Nor-NOHA markedly increased endothelium-dependent vasodilatation (up to 2-fold) in patients with CAD+Diabetes and CAD (P<0.001) but not in the control group. N(G)-monomethyl L-arginine completely inhibited the increase in endothelium-dependent vasodilatation induced by nor-NOHA. Endothelium-independent vasodilatation was slightly improved by nor-NOHA in the CAD+Diabetes group. Arginase I was expressed in vascular smooth muscle cells and endothelial cells, and arginase II was expressed in endothelial cells of patients with and without diabetes mellitus. CONCLUSIONS: Arginase inhibition markedly improves endothelial function in patients with CAD and type 2 diabetes mellitus suggesting that increased arginase activity is a key factor in the development of endothelial dysfunction.


Assuntos
Arginase/antagonistas & inibidores , Doença da Artéria Coronariana/fisiopatologia , Diabetes Mellitus Tipo 2/fisiopatologia , Angiopatias Diabéticas/fisiopatologia , Endotélio Vascular/efeitos dos fármacos , Idoso , Arginase/análise , Arginina/análogos & derivados , Arginina/farmacologia , Endotélio Vascular/fisiopatologia , Antebraço/irrigação sanguínea , Humanos , Masculino , Pessoa de Meia-Idade , Óxido Nítrico/fisiologia , Vasodilatação
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