Arginase Inhibition Improves Microvascular Endothelial Function in Patients With Type 2 Diabetes Mellitus

Kövamees, Oskar; Shemyakin, Alexey; Checa, Antonio; Wheelock, Craig E.; Lundberg, Jon O.; Östenson, Claes‐Göran; Pernow, John

doi:10.1210/jc.2016-2007

Cited by 60 publications

(39 citation statements)

References 31 publications

(35 reference statements)

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“…It is likely that supplemented Arg is consumed in the synthesis of NO, and citrulline is recreated as a byproduct of NO. Indeed, the pattern of changes in the ratio of Arg to citrulline, which reflects the relative activity of systemic NOS [32], among the three groups was similar to that observed for urinary nitrite + nitrate levels, indicating that NO production in KK‐Akita mice was probably higher than that in KK mice.…”

Section: Discussionmentioning

confidence: 74%

“…As such, the bioavailability of Arg and NO production is reduced in the diabetic state. In fact, studies of arginase inhibition in patients with diabetes or diabetic rats have shown an improvement of microvascular endothelial function [13,31,32]. Based on these results, we guessed that Asp was consumed to sustain the bioavailability of Arg in KK‐Akita mice.…”

Section: Discussionmentioning

confidence: 97%

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Aspartic acid supplementation ameliorates symptoms of diabetic kidney disease in mice

et al. 2020

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Diabetic kidney disease (DKD) is among the most common and serious complications of both type 1 and type 2 diabetes. In this study, we used KK/Ta‐Ins2Akita (KK‐Akita) mice as a model of DKD and KK/Ta (KK) mice as controls to identify novel factors related to the development/progression of DKD. Capillary electrophoresis coupled with mass spectrometry analysis revealed that circulating Asp (l‐aspartic acid) levels in diabetic KK‐Akita mice tend to be lower than those in control KK mice. Therefore, we evaluated the effect of Asp supplementation to prevent the progression of DKD in KK‐Akita mice. Mice were divided into three groups: (a) untreated KK mice (Control group), (b) untreated KK‐Akita mice (DKD group), and (c) treated (double‐volume Asp diet) KK‐Akita mice (Tx group). Kidney sections were stained with fluorescein isothiocyanate‐labeled lectins, wheat germ agglutinin (WGA), and anti‐endothelial nitric oxide synthase (eNOS) antibody for evaluation of endothelial surface layer (ESL) and NO synthesis. The mesangial area and glomerular size in the DKD group were significantly larger than those in the Control group; however, there was no significant difference in those between the DKD and Tx groups. Albuminuria, the ratio of foot process effacement, and thickness of glomerular basement membrane in the Tx group were significantly lower than those in the DKD group. Furthermore, the expression levels of glomerular WGA and microvascular eNOS in the Tx group improved significantly and approached the level in the Control group. In conclusion, the improvement of albuminuria in the Tx group may be caused by the reduction of oxidative stress in the kidneys, which may lead to the subsequent improvement of glomerular ESL.

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Section: Discussionmentioning

confidence: 74%

Section: Discussionmentioning

confidence: 97%

Aspartic acid supplementation ameliorates symptoms of diabetic kidney disease in mice

et al. 2020

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“…Serum arginase levels were evaluated in various diseases such as asthma, (23–25) type-2 diabetes mellitus, (26) cancer, (27) and atherosclerosis (28) by activity assay and the ELISA method. In a healthy population, arginase I was associated with oxidative stress, exhaled nitric oxide, and l -arginine.…”

Section: Introductionmentioning

confidence: 99%

Effects of exercise training on nitric oxide, blood pressure and antioxidant enzymes

Tsukiyama

Itö

Nagaoka

et al. 2017

J. Clin. Biochem. Nutr.

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The relationship between exercise training and nitric oxide-related parameters was examined in a cross-sectional study and an intervention study. A cross-sectional study using 184 employees was conducted to observe the association of exercise habits with serum arginase (ELISA and activity), l-arginine, l-citrulline, l-ornithine, NOx, exhaled nitric oxide, blood pressure, FEV1%, hs-CRP, HDL-cholesterol, IgE, and life style factors. An intervention study was also conducted to evaluate the changes of serum arginase I, nitric oxide-related parameters, and mRNA levels of anti-oxidant enzymes in blood monocytes before and after 1 h of aerobic exercise training per day for a month. Exercise habits were associated with increased arginase activity and a moderate alcohol drinking habit, after adjustment with several covariates. Aerobic exercise training induced a decrease in l-arginine and diastolic blood pressure and induced an increase in NO2− and urea. Moreover, mRNA expression of anti-oxidant enzymes, such as catalase and GPX1, and a life elongation enzyme, SIRT3, were significantly increased after aerobic exercise. The results that aerobic exercise training increased NO generation, reduced blood pressure, and induced anti-oxidant enzymes via SIRT3 suggest that exercise training may be an important factor for the prevention of disease by inducing intrinsic NO and anti-oxidant enzymes.

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“…Numerous preclinical investigations testing this approach have demonstrated promising results [26]. Consequently, several clinical studies have proved that inhibiting arginase with Nωhydroxy-nor-L-arginine significantly improves microcirculation and endothelial function in diabetic patients [56,57].…”

Section: Discussionmentioning

confidence: 99%

Norvaline reduces blood pressure and induces diuresis in rats with inherited stress-induced arterial hypertension

Gilinsky

Polityko

et al. 2019

Preprint

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Growing evidence suggests that increased arginase activity affects vital bioprocesses in various systems and universally mediates the pathogenesis of numerous metabolic diseases. The adverse effects of arginase are associated with a severe decline in L-arginine bioavailability, which leads to nitric oxide synthase substrate insufficiency, uncoupling, and, eventually, to superoxide anion generation and substantial reduction of nitric oxide (NO) synthesis. In cooperation, it contributes to chronic oxidative stress and endothelial dysfunction, which might lead to hypertension and atherosclerosis.Recent preclinical investigations point to arginase as a promising therapeutic target in ameliorating metabolic and vascular dysfunctions. In the present study, adult rats with inherited stress-induced arterial hypertension (ISIAH) were used as a model of hypertension. Wistar rats served as normotensive controls. Experimental animals were intraperitoneally administered for seven days with non-proteinogenic amino acid L-norvaline (30 mg/kg/day), which is a potent arginase inhibitor, or with the vehicle. Blood pressure (BP), body weight, and diuresis were monitored. The changes in blood and urine levels of creatinine, urea, and NO metabolites were analyzed.We observed a significant decline in BP and induced diuresis in ISIAH rats following the treatment. The same procedure did not affect the BP of control animals. Remarkably, the treatment had no influence upon glomerular filtration rate in two experimental groups, just like the daily excretion of creatinine and urea. Conversely, NO metabolites levels were amplified in normotonic but not in hypertensive rats following the treatment.The data indicate that L-norvaline is a potential antihypertensive agent, and deserves to be clinically investigated. Moreover, we suggest that changes in blood and urine are causally related to the effect of L-norvaline upon the BP regulation.

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Arginase Inhibition Improves Microvascular Endothelial Function in Patients With Type 2 Diabetes Mellitus

Abstract: 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.

Cited by 60 publications

References 31 publications

Aspartic acid supplementation ameliorates symptoms of diabetic kidney disease in mice

Aspartic acid supplementation ameliorates symptoms of diabetic kidney disease in mice

Effects of exercise training on nitric oxide, blood pressure and antioxidant enzymes

Norvaline reduces blood pressure and induces diuresis in rats with inherited stress-induced arterial hypertension

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