Abstract 453: Transgenic Overexpression of Alanine-glyoxylate Aminotransferase 2 in Mice Lowers Asymmetric Dimethylarginine and Improves Vasomotor Function

2016 ◽  
Vol 36 (suppl_1) ◽  
Author(s):  
Natalia Jarzebska ◽  
Roman N Rodionov ◽  
Dmitri Burdin ◽  
Silke Brilloff ◽  
Vladimir T Todorov ◽  
...  
Keyword(s):  
Plasma Levels ◽  
Asymmetric Dimethylarginine ◽  
Vasomotor Function ◽  
Arterial Blood ◽  
Plasma Adma ◽  
Increased Risk ◽  
Glyoxylate Aminotransferase ◽  
Oxide Synthase

Background: Elevation of the endogenous inhibitor of nitric oxide synthase asymmetric dimethylarginine (ADMA) has been shown to be associated with increased risk of cardiovascular diseases. There are two major pathways of ADMA catabolism: hydrolysis to citrulline by dimethylarginine dimethylaminohydrolases (DDAH) and transamination by alanine-glyoxylate aminotransferase 2 (AGXT2) with formation of asymmetric dimethylguanidino valeric acid (ADGV). The second pathway is poorly characterized. The goal of the current study was to test the hypothesis that transgenic overexpression of AGXT2 leads to lowering of systemic levels of ADMA and improvement of vasomotor function. Methods and Results: We generated transgenic mice (TG) with ubiquitous overexpression of AGXT2 under control of the chicken beta actin (CAG) promoter. qPCR and Western Blot were used to confirm the ubiquitous expression of the transgene. There were no developmental or phenotypic changes in the TG animals. Biochemical data were generated using HPLC-MS/MS. ADMA plasma levels were decreased by 15% (p<0.05) in the TG mice, whereas ADGV plasma levels were 6 times higher in comparison with wild-types littermates (p<0.001). Lung and heart of TG animals exhibited 2 times lower tissue ADMA content in comparison with controls (p<0.05). TG mice demonstrated improved endothelium-dependent vasodilation (in response to acetylcholine) in aortic rings. The endothelium-independent relaxation (in response to sodium nitroprusside) was unchanged. There was no difference in mean arterial blood pressure measured by telemetry between the wild type and AGXT2 TG mice. In further experiments, we crossed the AGXT2 TG mice with DDAH1 KO mice and showed that upregulation of AGXT2 protects DDAH1 KO mice from elevation of plasma ADMA levels. Conclusion: In the current study we demonstrated that upregulation of AGXT2 leads to lowering of ADMA levels and improvement of endothelium-dependent relaxation in vivo. AGXT2 thereby may be a potential drug target for long-term reduction of systemic ADMA levels in cardiovascular pathologies. This is especially important, because all the efforts to develop pharmacological ADMA-lowering interventions by means of upregulation of DDAH have not been successful so far.

scholarly journals Overexpression of Alanine-glyoxylate aminotransferase 2 Protects from Asymmetric Dimethylarginine-induced Endothelial Dysfunction and Aortic Remodeling

2021 ◽  
Author(s):  
Roman N. Rodionov ◽  
Natalia Jarzebska ◽  
Dmitrii Burdin ◽  
Vladimir Todorov ◽  
Jens Martens-Lobenhoffer ◽  
...  
Keyword(s):  
Endothelial Dysfunction ◽  
Plasma Levels ◽  
Asymmetric Dimethylarginine ◽  
Plasma Concentrations ◽  
Cardiovascular Effects ◽  
Vascular Damage ◽  
Plasma Adma ◽  
Increased Risk ◽  
Glyoxylate Aminotransferase ◽  
Aortic Remodeling

Abstract Objective: Elevated plasma concentrations of asymmetric dimethylarginine (ADMA) are associated with an increased risk of mortality and adverse cardiovascular outcomes. ADMA can be metabolized by dimethylarginine dimethylaminohydrolases (DDAHs) and by alanine-glyoxylate aminotransferase 2 (AGXT2). Deletion of DDAH1 in mice leads to elevation of ADMA in plasma and blood pressure, while overexpression of human DDAH1 is associated with a lower plasma ADMA concentration and protective cardiovascular effects. The possible role of alternative metabolism of ADMA by AGXT2 remains to be elucidated. The goal of the current study was to test the hypothesis that transgenic overexpression of AGXT2 leads to lowering of plasma levels of ADMA and protection from vascular damage in the setting of DDAH1 deficiency.Approach and Results: We generated transgenic mice (TG) with ubiquitous overexpression of AGXT2. qPCR and Western Blot confirmed the expression of the transgene. Systemic ADMA levels were decreased by 15% in TG mice. In comparison with wild type animals plasma levels of asymmetric dimethylguanidino valeric acid (ADGV), the AGXT2 associated metabolite of ADMA, were six times higher. We crossed AGXT2 TG mice with DDAH1 knockout mice and observed that upregulation of AGXT2 lowers plasma ADMA and pulse pressure and protects the mice from endothelial dysfunction and adverse aortic remodeling.Conclusions: Upregulation of AGXT2 led to lowering of ADMA levels and protection from ADMA-induced vascular damage in the setting of DDAH1 deficiency. This is especially important, because all the efforts to develop pharmacological ADMA-lowering interventions by means of upregulation of DDAHs have been unsuccessful.

Abstract 373: Transgenic Overexpression of Alanine-glyoxylate Aminotransferase 2 Lowers Tissue Levels of Asymmetric Dimethylarginine and Improves Endothelial Function in Mouse Aortas

2015 ◽  
Vol 35 (suppl_1) ◽  
Author(s):  
Roman N Rodionov ◽  
Dmitrii V Burdin ◽  
Vladimir Todorov ◽  
Silke Brilloff ◽  
Natalia Jarzebska ◽  
...  
Keyword(s):  
Vascular Function ◽  
Asymmetric Dimethylarginine ◽  
Physiological Role ◽  
Normal Weight ◽  
Maximal Response ◽  
Direct Role ◽  
Developmental Abnormalities ◽  
Vasomotor Function ◽  
Glyoxylate Aminotransferase

Introduction: Asymmetric dimethylarginine (ADMA) is an endogenous inhibitor of nitric oxide synthase, which has been proposed to play a direct role in the pathogenesis of cardiovascular disease. There are two enzymatic pathways for degradation of ADMA: hydrolysis to citrulline by dimethylarginine dimethylaminohydrolase (DDAH) and transamination by alanine-glyoxylate aminotransferase 2 (AGXT2) with formation of asymmetric dimethylguanidino valeric acid (ADGV). The first pathway is well characterized, whereas the physiological role of AGXT2 is still poorly understood. The goal of our study was to test the hypothesis that transgenic overexpression of AGXT2 would lead to lowering of systemic levels of ADMA and improved vasomotor function. Methods and results: We generated transgenic mice (TG) with ubiquitous overexpression of AGXT2 under control of the chicken beta actin (CAG) promoter. Ubiquitous overexpression of the transgene was confirmed by qPCR and Western Blot. TG animals had normal weight and no observed developmental abnormalities. Biochemical data were generated using HPLC-MS/MS. ADMA plasma levels in AGXT2 TG animals were decreased by 15% (p<0.05), whereas ADGV levels were 6 times higher in TG animals in comparison with wild-types (p<0.001). Lung and heart of TG animals exhibited 2 times lower tissue ADMA content in comparison with controls (p<0.05). Isolated aortic rings were used to estimate endothelium-dependent and -independent relaxation in response to acetylcholine (Ach) and sodium nitroprusside (SNP), respectively. Aortas from AGXT2 TG mice demonstrated an increase in maximal response to ACh (p<0.05). There was a similar relaxation in response to SNP in both groups. Conclusions: Our findings show that upregulation of AGXT2 results in lower ADMA levels and improved endothelial-dependent relaxation in vivo. AGXT2 thereby may be a therapeutic target for long-term reduction of systemic ADMA levels and improvement of vascular function in vivo. This is especially important, because all the efforts to develop ADMA-lowering interventions by means of upregulation of DDAH have not been successful so far. Our data suggest that AGXT2 might be a promising drug target for cardiovascular pathologies associated with elevated ADMA levels.

scholarly journals Association of Urinary and Plasma Levels of Trimethylamine N-Oxide (TMAO) with Foods

Nutrients ◽  
2021 ◽  
Vol 13 (5) ◽  
pp. 1426
Author(s):  
Mauro Lombardo ◽  
Giovanni Aulisa ◽  
Daniele Marcon ◽  
Gianluca Rizzo ◽  
Maria Grazia Tarsisano ◽  
...  
Keyword(s):  
Gut Microbiota ◽  
Fish Consumption ◽  
Plasma Levels ◽  
Cooking Methods ◽  
Saltwater Fish ◽  
Increased Risk ◽  
Mediator Role ◽  
Fish And Shellfish ◽  
The Relationship

Introduction: Trimethylamine N-oxide (TMAO) may play a key mediator role in the relationship between the diet, gut microbiota and cardiovascular diseases, particularly in people with kidney failure. The aim of this review is to evaluate which foods have a greater influence on blood or urinary trimethylamine N-oxide (TMAO) levels. Methods: 391 language articles were screened, and 27 were analysed and summarized for this review, using the keywords “TMAO” AND “egg” OR “meat” OR “fish” OR “dairy” OR “vegetables” OR “fruit” OR “food” in December 2020. Results: A strong correlation between TMAO and fish consumption, mainly saltwater fish and shellfish, but not freshwater fish, has been demonstrated. Associations of the consumption of eggs, dairy and meat with TMAO are less clear and may depend on other factors such as microbiota or cooking methods. Plant-based foods do not seem to influence TMAO but have been less investigated. Discussion: Consumption of saltwater fish, dark meat fish and shellfish seems to be associated with an increase in urine or plasma TMAO values. Further studies are needed to understand the relationship between increased risk of cardiovascular disease and plasma levels of TMAO due to fish consumption. Interventions coupled with long-term dietary patterns targeting the gut microbiota seem promising.

scholarly journals Increased tissue factor expression on circulating monocytes in chronic HIV infection: relationship to in vivo coagulation and immune activation

Blood ◽  
2010 ◽  
Vol 115 (2) ◽  
pp. 161-167 ◽  
Author(s):  
Nicholas T. Funderburg ◽  
Elizabeth Mayne ◽  
Scott F. Sieg ◽  
Robert Asaad ◽  
Wei Jiang ◽  
...  
Keyword(s):  
Hiv Infection ◽  
Tissue Factor ◽  
Immune Activation ◽  
Interleukin 6 ◽  
Plasma Levels ◽  
Thrombus Formation ◽  
Hiv Replication ◽  
Increased Risk

Abstract HIV infection is associated with an increased risk of thrombosis; and as antiretroviral therapy has increased the lifespan of HIV-infected patients, their risk for cardiovascular events is expected to increase. A large clinical study found recently that all-cause mortality for HIV+ patients was related to plasma levels of interleukin-6 and to D-dimer products of fibrinolysis. We provide evidence that this elevated risk for coagulation may be related to increased proportions of monocytes expressing cell surface tissue factor (TF, thromboplastin) in persons with HIV infection. Monocyte TF expression could be induced in vitro by lipopolysaccharide and flagellin, but not by interleukin-6. Monocyte expression of TF was correlated with HIV levels in plasma, with indices of immune activation, and with plasma levels of soluble CD14, a marker of in vivo lipopolysaccharide exposure. TF levels also correlated with plasma levels of D-dimers, reflective of in vivo clot formation and fibrinolysis. Thus, drivers of immune activation in HIV disease, such as HIV replication, and potentially, microbial translocation, may activate clotting cascades and contribute to thrombus formation and cardiovascular morbidities in HIV infection.

Proton Pump Inhibitors and Dabigatran Therapy: Impact on Gastric Bleeding and Dabigatran Plasma Levels

2019 ◽  
Vol 45 (08) ◽  
pp. 846-850 ◽  
Author(s):  
Tomáš Bolek ◽  
Matej Samoš ◽  
Ingrid Škorňová ◽  
Peter Galajda ◽  
Ján Staško ◽  
...  
Keyword(s):  
Proton Pump Inhibitors ◽  
Proton Pump ◽  
Plasma Levels ◽  
Thrombin Inhibitor ◽  
Gi Bleeding ◽  
Gastric Bleeding ◽  
Increased Risk ◽  
The Impact ◽  
Dabigatran Therapy

AbstractDabigatran etexilate, a direct thrombin inhibitor, is now frequently used for long-term pharmacological prevention of stroke or systemic embolism in patients with atrial fibrillation. However, such long-term dabigatran therapy (DT) significantly increases the risk of upper gastrointestinal (GI) bleeding. This increased risk of gastric bleeds might be reduced with gastroprotective agents, such as proton pump inhibitors (PPIs). PPIs coadministrated with dabigatran reduce the risk of upper GI bleeding in patients on long-term oral DT. Nevertheless, there is heated discussion regarding interactions between PPI and dabigatran that lead to decreases in dabigatran plasma levels. This article reviews up to date data about the risk of gastric bleeding on dabigatran, the impact of PPI on the reduction of gastric bleeding, and the interaction between PPI and dabigatran leading to decreased dabigatran plasma levels.

Mobile Technology to Assess Balance During Sit to Stand Manuever Among Older Adults at Risk for Falling

2018 ◽  
Vol 7 (1) ◽  
pp. 248-248
Author(s):  
Deanna Gray-Miceli ◽  
William Craelius ◽  
Kang Li
Keyword(s):  
Blood Pressure ◽  
Older Adults ◽  
Long Term Care ◽  
Measurement Unit ◽  
Term Care ◽  
Sit To Stand ◽  
Arterial Blood ◽  
Increased Risk ◽  
Loss Of Balance

Older adults over age 65 are susceptible to loss of balance for a variety of reasons including drops in blood pressure with standing (orthostatic hypotension [OH]; Gray-Miceli, Ratcliffe, Thomasson, Quigley, Li & Craelius, 2016). OH is a treatable condition, and cause of falls if detected. Nearly 50% of the 1.43 million older adults in long-term care experience falls (National Center for Injury Prevention and Control, 2017). Falls often occur among older adults in long term care during periods of transitioning, where older adults are susceptible to loss of balance and increased risk to fall. As found in our prior work, older adults with OH may not always experience classic dizziness symptoms that may accompany OH (Gray-Miceli, Ratcliffe, Liu, Wantland & Johnson, 2012; Gray). To better understand this phenomenon, our project adapted a cellphone as an inertial measurement unit attached to the person’s center of mass to determine body sway. The objective of this pilot study was to determine if a relationship was observable during the sit to stand maneuver (StS) while older adults wore a Smartphone measuring three dimensions of motion among older adults who had evidenced of symptoms or OH. A sample of four older adults from a rehabilitation facility who were 65 years of age, receiving physical therapy at the time of testing, were cognitively intact, able to perform the StS maneuver and had no active cancer, fractures or serious injuries were recruited and enrolled. Oh determinations, pulse rate and symptoms of dizziness were elicited during a 30 second StS maneuver. In Patient A and Patient B we present the Z-axis and X-axis of front acceleration and patterns of motion side by side for case comparison while highlighting clinical findings. In Patient B, a greater degree of sway at the start of the StS maneuver is noted. Patient B’s blood pressure also dropped 33 mmHg and there were symptoms of dizziness. Drops in mean arterial blood pressure were greater among those with symptomatic OH. Limitations of this pilot include noise, selection of filters and time stamping of the data. Project aims are to help clinicians prevent falls by further assessing symptoms among elders who suffer from LOB and OH.

scholarly journals Asymmetric dimethylarginine, oxidative stress, and vascular nitric oxide synthase in essential hypertension

2009 ◽  
Vol 296 (2) ◽  
pp. R195-R200 ◽  
Author(s):  
Dan Wang ◽  
Svend Strandgaard ◽  
Jens Iversen ◽  
Christopher S. Wilcox
Keyword(s):  
Oxidative Stress ◽  
Nitric Oxide ◽  
Blood Pressure ◽  
Essential Hypertension ◽  
Nitric Oxide Synthase ◽  
Plasma Levels ◽  
Asymmetric Dimethylarginine ◽  
Lipid Peroxidation Product ◽  
Individual Values ◽  
Oxide Synthase

We reported impaired endothelium-derived relaxation factor/nitric oxide (EDRF/NO) responses and constitutive nitric oxide synthase (cNOS) activity in subcutaneous vessels dissected from patients with essential hypertension ( n = 9) compared with normal controls ( n = 10). We now test the hypothesis that the patients in this study have increased circulating levels of the cNOS inhibitor, asymmetric dimethylarginine (ADMA), or the lipid peroxidation product of linoleic acid, 13-hydroxyoctadecadienoic acid (HODE), which is a marker of reactive oxygen species. Patients had significantly ( P < 0.001) elevated (means ± SD) plasma levels of ADMA (PADMA, 766 ± 217 vs. 393 ± 57 nmol/l) and symmetric dimethylarginine (PSDMA: 644 ± 140 vs. 399 ± 70 nmol/l) but similar levels of l-arginine accompanied by significantly ( P < 0.015) increased rates of renal ADMA excretion (21 ± 9 vs. 14 ± 5 nmol/μmol creatinine) and decreased rates of renal ADMA clearance (18 ± 3 vs. 28 ± 5 ml/min). They had significantly increased plasma levels of HODE (PHODE: 309 ± 30 vs. 226 ± 24 nmol/l) and renal HODE excretion (433 ± 93 vs. 299 ± 67 nmol/μmol creatinine). For the combined group of normal and hypertensive subjects, the individual values for plasma levels of ADMA and HODE were both significantly ( P < 0.001) and inversely correlated with microvascular EDRF/NO and positively correlated with mean blood pressure. In conclusion, elevated levels of ADMA and oxidative stress in a group of hypertensive patients could contribute to the associated microvascular endothelial dysfunction and elevated blood pressure.

High altitude hypoxia and blood pressure dysregulation in adult chickens

2012 ◽  
Vol 4 (1) ◽  
pp. 69-76 ◽  
Author(s):  
E. A. Herrera ◽  
C. E. Salinas ◽  
C. E. Blanco ◽  
M. Villena ◽  
D. A. Giussani
Keyword(s):  
Blood Pressure ◽  
High Altitude ◽  
Arterial Blood Pressure ◽  
Cardiovascular Function ◽  
Dependent Manner ◽  
Cardiovascular Development ◽  
Placental Perfusion ◽  
Arterial Blood ◽  
Increased Risk

Although it is accepted that impaired placental perfusion in complicated pregnancy can slow fetal growth and programme an increased risk of cardiovascular dysfunction at adulthood, the relative contribution of reductions in fetal nutrition and in fetal oxygenation as the triggering stimulus remains unclear. By combining high altitude (HA) with the chick embryo model, we have previously isolated the direct effects of HA hypoxia on embryonic growth and cardiovascular development before hatching. This study isolated the effects of developmental hypoxia on cardiovascular function measured in vivo in conscious adult male and female chickens. Chick embryos were incubated, hatched and raised at sea level (SL, nine males and nine females) or incubated, hatched and raised at HA (seven males and seven females). At 6 months of age, vascular catheters were inserted under general anaesthesia. Five days later, basal blood gas status, basal cardiovascular function and cardiac baroreflex responses were investigated. HA chickens had significantly lower basal arterial PO2 and haemoglobin saturation, and significantly higher haematocrit than SL chickens, independent of the sex of the animal. HA chickens had significantly lower arterial blood pressure than SL chickens, independent of the sex of the animal. Although the gain of the arterial baroreflex was decreased in HA relative to SL male chickens, it was increased in HA relative to SL female chickens. We show that development at HA lowers basal arterial blood pressure and alters baroreflex sensitivity in a sex-dependent manner at adulthood.

Sign in / Sign up

Export Citation Format

Share Document