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Wang D, Gao P, Wang X, Zheng T, Li X, Xu S, Kamili K, Tian G. Association of plasma homocysteine with morning blood pressure in patients with essential hypertension. Hypertens Res 2025:10.1038/s41440-025-02235-7. [PMID: 40410294 DOI: 10.1038/s41440-025-02235-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/07/2024] [Revised: 04/14/2025] [Accepted: 04/18/2025] [Indexed: 05/25/2025]
Abstract
Previous studies have shown that morning blood pressure elevation increases stroke risk. Homocysteine levels are linked to stroke, but the benefit of lowering them alone for stroke is unclear. We aimed to explore the correlation between plasma homocysteine levels and morning blood pressure. 1056 hypertensive patients who were hospitalized and received ambulatory blood pressure monitoring (ABPM) were enrolled in the study. Morning hypertension was defined as the average of blood pressure ≥135/85 mmHg during the morning period of ABPM recording. Spearman's correlation analysis, logistic regression models, subgroup analysis were performed to investigate whether homocysteine levels were independently associated with morning hypertension. Both morning systolic blood pressure and diastolic blood pressure increased with the rise of homocysteine levels. Multivariate logistic regression analysis further determined that homocysteine levels were an independent risk factor for morning hypertension: with the lowest tertile group as a reference, middle tertile group: odds ratio (OR): 2.394, 95% confidence interval (CI): 1.554-3.687; highest tertile group: OR: 4.432, 95% CI: 2.549-7.706. The area under the receiver operating characteristic curve was 0.745. In subgroup analysis, it was found that the association of homocysteine levels with morning hypertension was stronger in hypertensive patients who were older than 60 years old, female, with BMI ≥ 25 kg/m2, with a history of stroke. The plasma homocysteine levels are correlated with morning blood pressure in patients with essential hypertension, particularly among those who are older than 60 years, have a history of stroke, are female and have a BMI ≥ 25 kg/m2.
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Affiliation(s)
- Danni Wang
- Department of Cardiology, First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, China
| | - Pengjie Gao
- Department of Cardiology, First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, China
| | - Xuan Wang
- Interventional Medicine Center, Xi'an People's Hospital, Xi'an, China
| | - Tingting Zheng
- Department of Cardiology, First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, China
| | - Xiyang Li
- Department of Cardiology, First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, China
| | - Suining Xu
- Department of Cardiology, First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, China
| | - Kamila Kamili
- Department of Cardiology, First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, China
| | - Gang Tian
- Department of Cardiology, First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, China.
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Ramos-Rodríguez C, Rojas-Gomez A, Santos-Calderón LA, Ceruelo S, Ríos L, Ueland PM, Fernandez-Ballart JD, Salas-Huetos A, Murphy MM. The l-Arginine pathway may act as a mediator in the association between impaired one-carbon metabolism and hypertension. Biochimie 2025; 230:86-94. [PMID: 39549999 DOI: 10.1016/j.biochi.2024.11.006] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/29/2024] [Revised: 11/13/2024] [Accepted: 11/13/2024] [Indexed: 11/18/2024]
Abstract
Elevated fasting plasma total homocysteine (tHcy) and the methylenetetrahydrofolate reductase C677T polymorphism (rs1801133) have been associated with hypertension. Whether the l-Arginine pathway is involved, is unclear. We aimed to investigate whether the association between tHcy, the rs1801133 polymorphism and hypertension involves the l-Arginine pathway. THcy, plasma folate and cobalamin, erythrocyte glutathionine reductase activation coefficient, rs1801133 genotype, plasma l-Arginine, asymmetric dimethylarginine (ADMA) and symmetric dimethylarginine (SDMA) were determined in a cross-sectional study of 788 adults (aged 18 to 75), randomly selected from 2 town population registers. Participants participated in a medical checkup and provided a fasting blood sample. Associations between tHcy, rs1801133 genotype and l-Arginine pathway metabolites were assessed by multiple linear regression analysis and whether the tHcy and rs1801133 genotype are associated with hypertension via the l-Arginine pathway was investigated using mediation analysis. tHcy was positively associated with ADMA (B = 0.003; SE = 0.001; P < 0.001) and SDMA (B = 0.007; SE = 0.002; P < 0.001) and negatively associated with the l-Arginine/ADMA (B = -1.140; SE = 0.451; P < 0.05) and ADMA/SDMA (B = -0.006; SE = 0.003; P < 0.05) ratios. The MTHFR 677 CT vs CC genotype was negatively associated with ADMA (B = -0.013; SE = 0.007; P < 0.05) and with SDMA (B = -0.029; SE = 0.013; P < 0.05) in participants under 50 years. Each standard deviation increase (37.6) in the l-Arginine/ADMA ratio was associated with reduced hypertension risk (OR [95%CI], 0.6 [0.5, 0.8]). Mediation analysis showed that tHcy and ADMA were mediators in the association between the rs1801133 TT vs CC genotypes and hypertension. Our results support the l-Arginine pathway as a mediator in the association of impaired One-Carbon metabolism and hypertension.
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Affiliation(s)
- Carla Ramos-Rodríguez
- Unitat de Medicina Preventiva, ANUT-DSM, Facultat de Medicina i Ciències de la Salut, Universitat Rovira i Virgili, Reus, (FMCS URV), Spain; IISPV, Areas of Family and Community Medicine, Spain.
| | - Alejandra Rojas-Gomez
- Unitat de Medicina Preventiva, ANUT-DSM, Facultat de Medicina i Ciències de la Salut, Universitat Rovira i Virgili, Reus, (FMCS URV), Spain; IISPV, Areas of Family and Community Medicine, Spain.
| | - Luis A Santos-Calderón
- Unitat de Medicina Preventiva, ANUT-DSM, Facultat de Medicina i Ciències de la Salut, Universitat Rovira i Virgili, Reus, (FMCS URV), Spain; IISPV, Areas of Family and Community Medicine, Spain.
| | | | - Lídia Ríos
- Hospital Lleuger Antoni de Gimbernat de Cambrils, Spain.
| | | | - Joan D Fernandez-Ballart
- Unitat de Medicina Preventiva, ANUT-DSM, Facultat de Medicina i Ciències de la Salut, Universitat Rovira i Virgili, Reus, (FMCS URV), Spain; IISPV, Areas of Family and Community Medicine, Spain; CIBERobn ISCIII, Spain.
| | - Albert Salas-Huetos
- Unitat de Medicina Preventiva, ANUT-DSM, Facultat de Medicina i Ciències de la Salut, Universitat Rovira i Virgili, Reus, (FMCS URV), Spain; IISPV, Areas of Family and Community Medicine, Spain; CIBERobn ISCIII, Spain.
| | - Michelle M Murphy
- Unitat de Medicina Preventiva, ANUT-DSM, Facultat de Medicina i Ciències de la Salut, Universitat Rovira i Virgili, Reus, (FMCS URV), Spain; IISPV, Areas of Family and Community Medicine, Spain; CIBERobn ISCIII, Spain.
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Fewkes JJ, Dordevic AL, Murray M, Williamson G, Kellow NJ. Association between endothelial function and skin advanced glycation end-products (AGEs) accumulation in a sample of predominantly young and healthy adults. Cardiovasc Diabetol 2024; 23:332. [PMID: 39251982 PMCID: PMC11386354 DOI: 10.1186/s12933-024-02428-3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/21/2024] [Accepted: 08/31/2024] [Indexed: 09/11/2024] Open
Abstract
BACKGROUND In populations with chronic disease, skin autofluorescence (SAF), a measure of long-term fluorescent advanced glycation end-products (AGEs) accumulation in body tissues, has been associated with vascular endothelial function, measured using flow-mediated dilation (FMD). The primary aim of this study was to quantify the relationship between endothelial function and tissue accumulation of AGEs in adults from the general population to determine whether SAF could be used as a marker to predict early impairment of the endothelium. METHODS A cross-sectional study was conducted with 125 participants (median age: 28.5 y, IQR: 24.4-36.0; 54% women). Endothelial function was measured by fasting FMD. Skin AGEs were measured as SAF using an AGE Reader. Participant anthropometry, blood pressure, and blood biomarkers were also measured. Associations were evaluated using multivariable regression analysis and were adjusted for significant covariates. RESULTS FMD was inversely correlated with SAF (ρ = -0.50, P < 0.001) and chronological age (ρ = -0.51, P < 0.001). In the multivariable analysis, SAF, chronological age, and male sex were independently associated with reduced FMD (B [95% CI]; -2.60 [-4.40, -0.80]; -0.10 [-0.16, -0.03]; 1.40 [0.14, 2.67], respectively), with the multivariable model adjusted R2 = 0.31, P < 0.001. CONCLUSIONS Higher skin AGE levels, as measured by SAF, were associated with lower FMD values, in a predominantly young, healthy population. Additionally, older age and male participants exhibited significantly lower FMD values, corresponding with compromised endothelial function. These results suggest that SAF, a simple and inexpensive marker, could be used to predict endothelial impairment before the emergence of any structural artery pathophysiology or classic cardiovascular disease risk markers. TRIAL REGISTRATION The study was prospectively registered with the Australian New Zealand Clinical Trials Registry (ACTRN12621000821897) and concurrently entered into the WHO International Clinical Trials Registry Platform under the same ID number.
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Affiliation(s)
- Juanita J Fewkes
- Department of Nutrition, Dietetics and Food, Faculty of Medicine, Nursing and Health Sciences, Monash University, 264 Ferntree Gully Road, Notting Hill, 3168, Australia
- Victorian Heart Institute, Victoria Heart Hospital, 631 Blackburn Road, Clayton, VIC, 3168, Australia
| | - Aimee L Dordevic
- Department of Nutrition, Dietetics and Food, Faculty of Medicine, Nursing and Health Sciences, Monash University, 264 Ferntree Gully Road, Notting Hill, 3168, Australia
- Victorian Heart Institute, Victoria Heart Hospital, 631 Blackburn Road, Clayton, VIC, 3168, Australia
| | - Margaret Murray
- Department of Nutrition, Dietetics and Food, Faculty of Medicine, Nursing and Health Sciences, Monash University, 264 Ferntree Gully Road, Notting Hill, 3168, Australia
- School of Chemistry, Faculty of Science, Monash University, Clayton, VIC, 3800, Australia
| | - Gary Williamson
- Department of Nutrition, Dietetics and Food, Faculty of Medicine, Nursing and Health Sciences, Monash University, 264 Ferntree Gully Road, Notting Hill, 3168, Australia
- Victorian Heart Institute, Victoria Heart Hospital, 631 Blackburn Road, Clayton, VIC, 3168, Australia
| | - Nicole J Kellow
- Department of Nutrition, Dietetics and Food, Faculty of Medicine, Nursing and Health Sciences, Monash University, 264 Ferntree Gully Road, Notting Hill, 3168, Australia.
- Centre for Innate Immunity and Infectious Diseases, Hudson Institute of Medical Research, Clayton, VIC, Australia.
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Siervo M, Hussin AM, Calella P, Ashor A, Shannon OM, Mendes I, Stephan BC, Zheng D, Hill T, Mathers JC. Associations between Aging and Vitamin D Status with Whole-Body Nitric Oxide Production and Markers of Endothelial Function. J Nutr 2024; 154:469-478. [PMID: 38048992 DOI: 10.1016/j.tjnut.2023.12.002] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/17/2023] [Revised: 11/23/2023] [Accepted: 12/01/2023] [Indexed: 12/06/2023] Open
Abstract
BACKGROUND Aging and vitamin D deficiency have been associated with reduced nitric oxide (NO) synthesis and impaired endothelial function (EF) but the evidence in humans remains weak. OBJECTIVES Two independent cross-sectional studies were designed to evaluate the association between age, sex, and plasma vitamin D concentrations with physiological and biochemical biomarkers of NO synthesis and EF in young and older healthy participants (Study 1) and in overweight and obese postmenopausal females (Study 2). METHODS In Study 1, 40 young (20-49 y) and older (50-75 y) males and females (10 participants per age and sex group) were included. Resting blood pressure and ear-to-finger peripheral pulse wave velocity (PWV) were measured. A stable-isotopic method was used to determine whole-body NO production. Plasma 25-hydroxyvitamin D (25(OH)D), nitrate, nitrite, and asymmetric dimethylarginine (ADMA) concentrations were determined. In Study 2, 80 older overweight and obese females (age 61.2 ± 6.2 y, body mass index 29.5 ± 4.4 kg/m2) were recruited. Postocclusion reactive hyperemia (PORH) and peripheral PWV were measured. Plasma concentrations of 25(OH)D, nitrate, cyclic guanosine monophosphate, 3-nitrotyrosine (3-NT), endothelin-1, vascular endothelial growth factor, and ADMA were determined. RESULTS In Study 1, whole-body NO production was significantly greater in young compared with older participants (0.61 ± 0.30 μmol·h-1·kg-1 compared with 0.39 ± 0.10 μmol·h-1·kg-1, P = 0.01) but there was no evidence of a sex difference (P = 0.81). Plasma 25(OH)D concentration was not associated with PWV (r = 0.18, P = 0.28) or whole-body NO production (r = -0.20, P = 0.22). Plasma ADMA concentration was associated positively with age (r = 0.35, P = 0.03) and negatively with whole-body NO production (r = -0.33, P = 0.04). In Study 2, age was associated with lower PORH (r = -0.28, P = 0.02) and greater ADMA concentrations (r = 0.22, P = 0.04). Plasma 25(OH)D concentration was inversely associated with 3-NT concentrations (r = -0.31, P = 0.004). CONCLUSIONS Older age was associated with lower whole-body NO production. Plasma vitamin D concentrations were not associated with NO production or markers of EF but showed a weak, significant correlation with oxidative stress in postmenopausal overweight females.
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Affiliation(s)
- Mario Siervo
- School of Population Health, Curtin University, Perth, WA, Australia; Curtin Dementia Centre of Excellence, Enable Institute, Curtin University, Perth, WA, Australia.
| | - Azizah Mat Hussin
- Human Nutrition & Exercise Research Centre, Centre for Healthier Lives, Population Health Sciences Institute, Newcastle University, Newcastle, United Kingdom; Institute of Medical Science Technology-Universiti Kuala Lumpur, Kuala Lumpur, Malaysia
| | - Patrizia Calella
- Department of Movement Sciences and Wellbeing, University of Naples "Parthenope," Naples, Italy
| | - Ammar Ashor
- Department of Internal Medicine, College of Medicine, University of Al-Mustansiriyah, Baghdad, Iraq
| | - Oliver M Shannon
- Human Nutrition & Exercise Research Centre, Centre for Healthier Lives, Population Health Sciences Institute, Newcastle University, Newcastle, United Kingdom
| | - Ines Mendes
- Human Nutrition & Exercise Research Centre, Centre for Healthier Lives, Population Health Sciences Institute, Newcastle University, Newcastle, United Kingdom
| | - Blossom Cm Stephan
- Curtin Dementia Centre of Excellence, Enable Institute, Curtin University, Perth, WA, Australia
| | - Dingchang Zheng
- Research Centre for Intelligent Healthcare, Coventry University, Coventry, United Kingdom
| | - Tom Hill
- Human Nutrition & Exercise Research Centre, Centre for Healthier Lives, Population Health Sciences Institute, Newcastle University, Newcastle, United Kingdom
| | - John C Mathers
- Human Nutrition & Exercise Research Centre, Centre for Healthier Lives, Population Health Sciences Institute, Newcastle University, Newcastle, United Kingdom
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Park J, Kim J, Kang J, Choi J, Kim JE, Min KJ, Choi SW, Cho JY, Lee M, Choi JY. A 6-month exercise intervention clinical trial in women: effects of physical activity on multi-omics biomarkers and health during the first wave of COVID-19 in Korea. BMC Sports Sci Med Rehabil 2024; 16:30. [PMID: 38287431 PMCID: PMC10826212 DOI: 10.1186/s13102-024-00824-6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/15/2022] [Accepted: 01/24/2024] [Indexed: 01/31/2024]
Abstract
BACKGROUND Coronavirus disease 2019 (COVID-19) was first reported in December 2019 and the first case in Korea was confirmed on January 20, 2020. Due to the absence of therapeutic agents and vaccines, the Korean government implemented social distancing on February 29, 2020. This study aimed to examine the effect of physical activity (PA) on health through changes in multi-omics biomarkers with a 6-month of exercise intervention during the first wave of COVID-19 in Korea. METHODS Twenty-seven healthy middle-aged women were recruited and 14 subjects completed the exercise intervention. The mean age (± SD) was 46.3 (± 5.33) and the mean BMI (± SD) was 24.9 (± 3.88). A total of three blood and stool samples were collected at enrollment, after period 1, and after period 2 (3-month intervals). The amount of PA was measured with an accelerometer and by questionnaire. Clinical variables were used, including blood pressure, grip strength, flexibility, and blood glucose levels and lipid markers obtained from laboratory tests. The concentration of blood metabolites was measured by targeted metabolomics. Fecal microbiome data were obtained by 16 S rRNA gene amplicon sequencing. RESULTS During the second half period (period 2), Coronavirus disease 2019 occurred and spread out in Korea, and PA decreased compared with the first half period (period 1) (185.9 ± 168.73 min/week to 102.5 ± 82.30 min/week; p = 0.0101). Blood pressure, hemoglobin A1c (HbA1c), and low-density lipoprotein cholesterol (LDL-C) decreased in period 1 (p < 0.05) and tended to increase again during period 2 (p < 0.05). Forty metabolites were changed significantly during period 1 (FDR p < 0.05), and we found that 6 of them were correlated with changes in blood pressure, HbA1c, and LDL-C via network analysis. CONCLUSIONS Our results may suggest that exercise improves health through changes in biomarkers at multi-omics levels. However, reduced PA due to COVID-19 can adversely affect health, emphasizing the necessity for sustained exercise and support for home-based fitness to maintain health. TRIAL REGISTRATION The trial is retrospectively registered on ClinicalTrials.gov (NCT05927675; June 30, 2023).
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Affiliation(s)
- JooYong Park
- Department of Big Data Medical Convergence, Eulji University, Seongnam-Si, Gyeonggi-Do, Korea
- Department of Biomedical Sciences Graduate School, Seoul National University, 103 Daehak-ro, Jongno-gu, Seoul, 03080, Korea
| | - Jaemyung Kim
- School of Biological and Population Health Sciences, Oregon State University, Corvallis, OR, USA
| | - Jihyun Kang
- Department of Biomedical Sciences Graduate School, Seoul National University, 103 Daehak-ro, Jongno-gu, Seoul, 03080, Korea
- Department of Clinical Pharmacology and Therapeutics, Seoul National University College of Medicine and Hospital, Seoul, Korea
| | - Jaesung Choi
- Institute of Health Policy and Management, Seoul National University Medical Research Center, Seoul, Korea
| | - Ji-Eun Kim
- Department of Biomedical Sciences Graduate School, Seoul National University, 103 Daehak-ro, Jongno-gu, Seoul, 03080, Korea
| | | | | | - Joo-Youn Cho
- Department of Biomedical Sciences Graduate School, Seoul National University, 103 Daehak-ro, Jongno-gu, Seoul, 03080, Korea
- Department of Clinical Pharmacology and Therapeutics, Seoul National University College of Medicine and Hospital, Seoul, Korea
| | - Miyoung Lee
- College of Physical Education and Sport Science, Kookmin University, 77 Jeongneung-ro, Seongbuk-gu, Seoul, 02707, Korea.
| | - Ji-Yeob Choi
- Department of Biomedical Sciences Graduate School, Seoul National University, 103 Daehak-ro, Jongno-gu, Seoul, 03080, Korea.
- Institute of Health Policy and Management, Seoul National University Medical Research Center, Seoul, Korea.
- Cancer Research Institute, Seoul National University, Seoul, Korea.
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Bulut F, Türksever Tetiker A, Çelikkol A, Şafak AS, Topçu B, Ballica B. Plasma Asymmetrıc Dımethylargınıne (ADMA) and Nıtrıc Oxıde (NO) Levels ın Patıents wıth Chronıc Pansınusıtıs. Indian J Otolaryngol Head Neck Surg 2022; 74:1591-1596. [PMID: 36452608 PMCID: PMC9702502 DOI: 10.1007/s12070-021-02720-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/07/2021] [Accepted: 06/27/2021] [Indexed: 11/28/2022] Open
Abstract
Chronic pansinusitis is a mucosal inflammation of the nose and all paranasal sinuses with severe inflammation of the upper airways. Asymmetric dimethylarginine (ADMA) is associated with oxidative stress. In this study, we aimed to examine the plasma levels and importance of ADMA and nitric oxide (NO) in patients with chronic pansinusitis. The study was conducted with a total of 64 patients. The study group included a total of 40 patients with chronic pansinusitis. (18 females, 22 males) (mean age 32.27 ± 10.02). The control group consisted of 24 patients (11 females and 13 males). The mean age of the patients in the control group was 31.35 ± 6.05 years. Nasal endoscopic examinations were performed in patients with a history of chronic pansinusitis and symptoms of chronic pansinusitis. Later, the diagnosis of chronic pansinusitis was confirmed with coronal paranasal sinus Computed tomography scans. Plasma ADMA levels were measured by ELISA method and NO levels were measured by Griess method. Plasma ADMA and NO levels of the patients and healthy volunteers were measured and the mean plasma levels of the two groups were compared. ADMA levels were significantly higher in the group with chronic pansinusitis compared to the control group (1.23 ± 0.41 μM and 0.28 ± 0.06 μM, respectively) (p < 0.001), while NO levels were significantly lower in the patient group compared to the control group (7.06 ± 1.07 μM and 12.25 ± 0.95, μM, respectively) (p < 0.001). Our results show that the increase in ADMA levels and the decrease in NO levels are associated with chronic pansinusitis. According to these results, increased plasma levels of ADMA in chronic pansinusitis may be useful in clinical use as a sign of increased oxidative stress.
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Affiliation(s)
- Fuat Bulut
- Private Çorlu REYAP Hospital, Department of Otorhinolaryngology, Istanbul Rumeli University, Istanbul, Turkey
| | | | - Aliye Çelikkol
- Department of Medical Biochemistry, Faculty of Medicine, Tekirdağ Namık Kemal University, Tekirdağ, Turkey
| | - Ayşe Sezim Şafak
- Private Kurtköy Ersoy Hospital, Department of Otorhinolaryngology, Istanbul Yeni Yüzyıl Üniversity, Istanbul, Turkey
| | - Birol Topçu
- Department of Biostatistics, Faculty of Medicine, Tekirdağ Namık Kemal University, Tekirdağ, Turkey
| | - Basak Ballica
- Istanbul Bahcesehir University, Faculty of Medicine, Istanbul, Turkey
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Noronha IL, Santa-Catharina GP, Andrade L, Coelho VA, Jacob-Filho W, Elias RM. Glomerular filtration in the aging population. Front Med (Lausanne) 2022; 9:769329. [PMID: 36186775 PMCID: PMC9519889 DOI: 10.3389/fmed.2022.769329] [Citation(s) in RCA: 31] [Impact Index Per Article: 10.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/01/2021] [Accepted: 08/24/2022] [Indexed: 12/11/2022] Open
Abstract
In the last decades, improvements in the average life expectancy in the world population have been associated with a significant increase in the proportion of elderly people, in parallel with a higher prevalence of non-communicable diseases, such as hypertension and diabetes. As the kidney is a common target organ of a variety of diseases, an adequate evaluation of renal function in the approach of this population is of special relevance. It is also known that the kidneys undergo aging-related changes expressed by a decline in the glomerular filtration rate (GFR), reflecting the loss of kidney function, either by a natural senescence process associated with healthy aging or by the length of exposure to diseases with potential kidney damage. Accurate assessment of renal function in the older population is of particular importance to evaluate the degree of kidney function loss, enabling tailored therapeutic interventions. The present review addresses a relevant topic, which is the effects of aging on renal function. In order to do that, we analyze and discuss age-related structural and functional changes. The text also examines the different options for evaluating GFR, from the use of direct methods to the implementation of several estimating equations. Finally, this manuscript supports clinicians in the interpretation of GFR changes associated with age and the management of the older patients with decreased kidney function.
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Affiliation(s)
- Irene L. Noronha
- Renal Division, Hospital das Clinicas, University of São Paulo Medical School, São Paulo, Brazil
- Laboratory of Cellular, Genetic and Molecular Nephrology, University of São Paulo Medical School, São Paulo, Brazil
- *Correspondence: Irene L. Noronha
| | | | - Lucia Andrade
- Renal Division, Hospital das Clinicas, University of São Paulo Medical School, São Paulo, Brazil
| | - Venceslau A. Coelho
- Geriatric Division, Hospital das Clinicas, University of São Paulo Medical School, São Paulo, Brazil
| | - Wilson Jacob-Filho
- Geriatric Division, Hospital das Clinicas, University of São Paulo Medical School, São Paulo, Brazil
| | - Rosilene M. Elias
- Renal Division, Hospital das Clinicas, University of São Paulo Medical School, São Paulo, Brazil
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Fujie S, Sanada K, Hamaoka T, Iemitsu M. Time-dependent relationships between exercise training-induced changes in nitric oxide production and hormone regulation. Exp Gerontol 2022; 166:111888. [PMID: 35820510 DOI: 10.1016/j.exger.2022.111888] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/18/2022] [Revised: 06/07/2022] [Accepted: 07/01/2022] [Indexed: 11/27/2022]
Abstract
Aerobic exercise training (AT) reduces aging-induced deterioration of arterial stiffness and is associated with arterial nitric oxide (NO) production via changes in apelin and adropin as NO-upregulating hormones, and asymmetric dimethylarginine (ADMA) as a NO-downregulating hormone. However, the time-dependent effects of AT on NO production via NO-regulating hormones remain unclear. This study aimed to determine whether AT-induced changes in the time course of NO production via NO-regulating hormones, participate in the AT-induced improvement in central arterial stiffening with advancing age. Methods: Thirty-three healthy Japanese middle-aged and older subjects (67 ± 1 years) were randomly divided into two groups: AT intervention and sedentary controls. Subjects in the training group completed 8-week of AT. Carotid-femoral pulse wave velocity as an index of central arterial stiffness and plasma nitrate/nitrite levels significantly changed from baseline at weeks 6 (P < 0.05) and 8 (P < 0.01). Interestingly, circulating apelin and adropin levels gradually increased during AT intervention and significantly increased from baseline at weeks 4, 6, and 8 (P < 0.01). Additionally, plasma ADMA levels significantly decreased at 8-week AT intervention (P < 0.01). These results suggest that AT-induced changes in the time course of NO production via NO-regulating hormones may participate in AT-induced improvements of central arterial stiffening with advancing age.
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Affiliation(s)
- Shumpei Fujie
- Faculty of Sport and Health Science, Ritsumeikan University, Shiga, Japan
| | - Kiyoshi Sanada
- Faculty of Sport and Health Science, Ritsumeikan University, Shiga, Japan
| | - Takafumi Hamaoka
- Sports Medicine for Health Promotion, Tokyo Medical University, Tokyo, Japan
| | - Motoyuki Iemitsu
- Faculty of Sport and Health Science, Ritsumeikan University, Shiga, Japan.
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Singh R, Nasci VL, Guthrie G, Ertuglu LA, Butt MK, Kirabo A, Gohar EY. Emerging Roles for G Protein-Coupled Estrogen Receptor 1 in Cardio-Renal Health: Implications for Aging. Biomolecules 2022; 12:412. [PMID: 35327604 PMCID: PMC8946600 DOI: 10.3390/biom12030412] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/29/2022] [Revised: 02/25/2022] [Accepted: 03/01/2022] [Indexed: 02/05/2023] Open
Abstract
Cardiovascular (CV) and renal diseases are increasingly prevalent in the United States and globally. CV-related mortality is the leading cause of death in the United States, while renal-related mortality is the 8th. Despite advanced therapeutics, both diseases persist, warranting continued exploration of disease mechanisms to develop novel therapeutics and advance clinical outcomes for cardio-renal health. CV and renal diseases increase with age, and there are sex differences evident in both the prevalence and progression of CV and renal disease. These age and sex differences seen in cardio-renal health implicate sex hormones as potentially important regulators to be studied. One such regulator is G protein-coupled estrogen receptor 1 (GPER1). GPER1 has been implicated in estrogen signaling and is expressed in a variety of tissues including the heart, vasculature, and kidney. GPER1 has been shown to be protective against CV and renal diseases in different experimental animal models. GPER1 actions involve multiple signaling pathways: interaction with aldosterone and endothelin-1 signaling, stimulation of the release of nitric oxide, and reduction in oxidative stress, inflammation, and immune infiltration. This review will discuss the current literature regarding GPER1 and cardio-renal health, particularly in the context of aging. Improving our understanding of GPER1-evoked mechanisms may reveal novel therapeutics aimed at improving cardio-renal health and clinical outcomes in the elderly.
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Affiliation(s)
- Ravneet Singh
- Division of Nephrology and Hypertension, Vanderbilt University Medical Center, Medical Research Building IV, Nashville, TN 37232, USA; (R.S.); (V.L.N.)
| | - Victoria L. Nasci
- Division of Nephrology and Hypertension, Vanderbilt University Medical Center, Medical Research Building IV, Nashville, TN 37232, USA; (R.S.); (V.L.N.)
| | - Ginger Guthrie
- Division of Nephrology, Department of Medicine, University of Alabama at Birmingham, Birmingham, AL 35233, USA; (G.G.); (M.K.B.)
| | - Lale A. Ertuglu
- Division of Clinical Pharmacology, Vanderbilt University Medical Center, Nashville, TN 37232, USA; (L.A.E.); (A.K.)
| | - Maryam K. Butt
- Division of Nephrology, Department of Medicine, University of Alabama at Birmingham, Birmingham, AL 35233, USA; (G.G.); (M.K.B.)
| | - Annet Kirabo
- Division of Clinical Pharmacology, Vanderbilt University Medical Center, Nashville, TN 37232, USA; (L.A.E.); (A.K.)
| | - Eman Y. Gohar
- Division of Nephrology and Hypertension, Vanderbilt University Medical Center, Medical Research Building IV, Nashville, TN 37232, USA; (R.S.); (V.L.N.)
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10
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Assar ME, Angulo J, García-Rojo E, Sevilleja-Ortiz A, García-Gómez B, Fernández A, Sánchez-Ferrer A, La Fuente JM, Romero-Otero J, Rodríguez-Mañas L. Early manifestation of aging-related vascular dysfunction in human penile vasculature-A potential explanation for the role of erectile dysfunction as a harbinger of systemic vascular disease. GeroScience 2022; 44:485-501. [PMID: 34962617 PMCID: PMC8811115 DOI: 10.1007/s11357-021-00507-x] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/26/2021] [Accepted: 12/22/2021] [Indexed: 01/05/2023] Open
Abstract
Advanced age is related to functional alterations of human vasculature, but erectile dysfunction precedes systemic manifestations of vascular disease. The current study aimed to simultaneously evaluate the influence of aging on vascular function (relaxation and contraction responses) in systemic human vascular territories: aorta (HA) and resistance mesenteric arteries (HMA) and human corpus cavernosum (HCC) and penile resistance arteries (HPRA). Associations of oxidative stress and inflammation circulating biomarkers with age and functional responses were also determined. Vascular specimens were obtained from 76 organ donors (age range 18-87). Four age-groups were established: < 40, 40-55, 56-65 and > 65 years old. Increasing age was associated with a decline in endothelium-dependent relaxation induced by BK in HMA (r = -0.597, p = 0.0001), or by ACh in HCC (r = -0.505, p = 0.0022), and HPRA (r = -0.601, p = 0.0012). Significant impairment was detected at > 65 years old in HMA but earlier in penile vasculature (> 55 years old). Age-related reduction to H2O2-vasodilatory response started before in HCC (56-65 years old) than in HA (> 65 years old). In contrast to relaxation responses, aging-related hypercontractility to adrenergic stimulation was homogeneous: contractions significantly increased in subjects > 55 years old in all tested vessels. Although not significantly age related, circulating levels of ADMA (r = -0.681, p = 0.0052) and TNF-α (r = -0.537, p = 0.0385) were negatively correlated with endothelial vasodilation in HMA but not in HCC or HPRA. Penile vasculature exhibits an early impairment of endothelium-dependent and H2O2-induced vasodilations when compared to mesenteric microcirculation and aorta. Therefore, functional susceptibility of penile vasculature to the aging process may account for anticipation of erectile dysfunction to systemic manifestations of vascular disease.
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Affiliation(s)
- Mariam El Assar
- Fundación de Investigación Biomédica, del Hospital Universitario de Getafe, Getafe, Spain
- Centro de Investigación Biomédica en Red de Fragilidad Y Envejecimiento Saludable (CIBERFES), Instituto de Salud Carlos III, Madrid, Spain
| | - Javier Angulo
- Centro de Investigación Biomédica en Red de Fragilidad Y Envejecimiento Saludable (CIBERFES), Instituto de Salud Carlos III, Madrid, Spain
- Servicio de Histología-Investigación, Unidad de Investigación Traslacional en Cardiología (IRYCIS-UFV), Hospital Universitario Ramón Y Cajal, Madrid, Spain
| | - Esther García-Rojo
- Department of Urology, Hospital Universitario 12 de Octubre, Instituto de Investigación Sanitaria Hospital, 12 de Octubre (imas12), Madrid, Spain
| | - Alejandro Sevilleja-Ortiz
- Servicio de Histología-Investigación, Unidad de Investigación Traslacional en Cardiología (IRYCIS-UFV), Hospital Universitario Ramón Y Cajal, Madrid, Spain
| | - Borja García-Gómez
- Department of Urology, Hospital Universitario 12 de Octubre, Instituto de Investigación Sanitaria Hospital, 12 de Octubre (imas12), Madrid, Spain
| | - Argentina Fernández
- Servicio de Histología-Investigación, Unidad de Investigación Traslacional en Cardiología (IRYCIS-UFV), Hospital Universitario Ramón Y Cajal, Madrid, Spain
| | - Alberto Sánchez-Ferrer
- Fundación de Investigación Biomédica, del Hospital Universitario de Getafe, Getafe, Spain
| | - José M La Fuente
- Serviço de Urologia, Hospital Geral Santo Antonio, Porto, Portugal
| | - Javier Romero-Otero
- Department of Urology, Hospital Universitario 12 de Octubre, Instituto de Investigación Sanitaria Hospital, 12 de Octubre (imas12), Madrid, Spain
| | - Leocadio Rodríguez-Mañas
- Fundación de Investigación Biomédica, del Hospital Universitario de Getafe, Getafe, Spain.
- Centro de Investigación Biomédica en Red de Fragilidad Y Envejecimiento Saludable (CIBERFES), Instituto de Salud Carlos III, Madrid, Spain.
- Division of Geriatric Medicine, Servicio de Geriatría, Hospital Universitario de Getafe, Ctra de Toledo km 12, 500, 8905, Getafe, Spain.
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11
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Amino Acid and Phospholipid Metabolism as an Indicator of Inflammation and Subtle Cardiomyopathy in Patients with Marfan Syndrome. Metabolites 2021; 11:metabo11120805. [PMID: 34940564 PMCID: PMC8707072 DOI: 10.3390/metabo11120805] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/29/2021] [Revised: 11/19/2021] [Accepted: 11/26/2021] [Indexed: 11/16/2022] Open
Abstract
Patients with Marfan syndrome (MFS) have an increased risk of aortic aneurysm formation, dissection and development of a subtle cardiomyopathy. We analyzed amino acid and lipid metabolic pathways in MFS patients, seeking biomarker patterns as potential monitoring tools of cardiovascular risk with deterioration of myocardial function. We assessed myocardial function in 24 adult MFS patients and compared traditional laboratory values and mass spectrometry-based amino acid, phospholipid and acylcarnitine metabolomes in patients with those in healthy controls. Analytes for which values differed between patients and controls were subjected to regression analysis. A high proportion of patients had signs of impaired diastolic function and elevated serum levels of NT-proBNP. Patients had lower serum levels of taurine, histidine and PCaeC42:3 than controls. The evidence of diastolic dysfunction, aortic root dimensions and history of aortic root surgery correlated with NT-proBNP and taurine levels. Alterations in serum levels of metabolism derived analytes link MFS pathophysiology with inflammation, oxidative stress and incipient cardiomyopathy.
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12
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Unlu A, Eryavuz Onmaz D, Abusoglu S, Abusoglu G. HPLC and LC-MS/MS measurement methods for the quantification of asymmetric dimethylarginine (ADMA) and related metabolites. TURKISH JOURNAL OF BIOCHEMISTRY 2021; 46:327-347. [DOI: 10.1515/tjb-2020-0150] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/03/2025]
Abstract
Abstract
Methyl arginine derivatives such as asymmetric dimethylarginine (ADMA), symmetric dimethylarginine (SDMA), L-N-monomethyl arginine (L-NMMA) are formed by proteolytic catalysis following methylation of arginine residues in proteins. These metabolites reduce NO production. Methylated arginines are an important biomarker for various diseases such as cardiovascular and renal diseases. Therefore, many methods have been developed to reliably and accurately measure the levels of these metabolites. This review, HPLC and LC-MS/MS methods developed for the measurement of methylarginine derivatives are discussed. In HPLC methods, solid phase extraction, derivatization and subsequent separation by reverse phase chromatography were performed. Since these metabolites are polar, they are difficult to retain in conventional reverse phase columns. In addition, as serum levels of these metabolites are low, sensitivity problems have been observed in HPLC methods. Derivatization has been applied to eliminate these problems. However, there have been problems with the stability of derivatives formed. Another important problem is that the separation of stereoisomer ADMA and SDMA can only be achieved chromatographically. Tandem mass spectrometric methods are accurate, selective, sensitive and rapid since analytes are separated depending on m/z ratios rather than chromatographic separation. Therefore, tandem mass spectrometry methods might be considered as the goal standard for these analytes.
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Affiliation(s)
- Ali Unlu
- Department of Biochemistry , Selcuk University Faculty of Medicine , Konya , Turkey
| | - Duygu Eryavuz Onmaz
- Department of Biochemistry , Selcuk University Faculty of Medicine , Konya , Turkey
| | - Sedat Abusoglu
- Department of Biochemistry , Selcuk University Faculty of Medicine , Konya , Turkey
| | - Gulsum Abusoglu
- Department of Medical Laboratory Techniques , Selcuk University Vocational School of Health , Konya , Turkey
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13
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Kyrillos FA, Motawea M, Abd-El-Aziz M, Al-Bayoumy A, Amer T, El-Nahas M. Plasma levels of Asymmetric Di Methyl Arginine and endothelial dysfunction in diabetic subjects with neuropathic foot ulcer. Foot (Edinb) 2021; 48:101837. [PMID: 34388426 DOI: 10.1016/j.foot.2021.101837] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/27/2019] [Revised: 04/23/2021] [Accepted: 05/22/2021] [Indexed: 02/04/2023]
Abstract
OBJECTIVE Asymmetric dimethyl arginine (ADMA) is an amino acid that acts as an endogenous competitive inhibitor of Nitric oxide synthase, leading to endothelial dysfunction (ED). The aim of this study was to evaluate the relationship between plasma ADMA (p-ADMA) level and ED in diabetic subjects with neuropathic foot ulcer (NFU), and the possible predictors of p-ADMA level. MATERIALS AND METHODS 80 diabetic subjects of matched age, sex and BMI were included; 40 with NFU (G1), 20 with peripheral nerve dysfunction (PND) (G2) and 20 without PND (G3), plus 20 matched healthy subjects (G4). Flow-mediated-dilatation (FMD) of brachial artery and Carotid-intima-media-thickness (CIMT) were measured to evaluate ED and subclinical atherosclerosis, respectively. RESULTS G1&2 had a significantly lower FMD than G3&4 [-5.09 (-22.5 to 22.92), 4.67 (-15 to 23.91) vs. 15.74 (8.33-36.59) and 20.1 (10.0-46.15)%, respectively] (p < 0.001), and higher CIMT [0.9 (0.6-1.5), 0.9 (0.6-1.3) vs. 0.6 (0.5-0.8) and 0.7 (0.5-0.9) cm, respectively] (p < 0.001, r = 0.237, p = 0.034, r = 0.330, p = 0.003, respectively), with no significant correlation with FMD (r = -0.176, p = 0.118). FMD was inversely and strongly related to CIMT (r = -0.520, p < 0.001). p-ADMA levels were significantly higher in uncontrolled hypertensive patients in comparison to controlled and normotensive subjects [717 (286-3611) vs. 648 (335-874) and 686 (526-857) ng/L, respectively] (p = 0.026). Metformin users and hypertensive subjects on ACEIs or ARBs had the lowest p-ADMA levels than the non-users (p < 0.001, p = 0.007, respectively). CONCLUSION The remarkable ED in diabetic subjects with NFU is unlikely to be due to alteration in p-ADMA. Further studies are needed in order to conclude a causal association between p-ADMA and ED in this group of patients.
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Affiliation(s)
- Fady Azmy Kyrillos
- Faculty of Medicine, Mansoura University, Algomhoria Street, 35516, Egypt.
| | - Mohamad Motawea
- Faculty of Medicine, Mansoura University, Algomhoria Street, 35516, Egypt.
| | | | - Azza Al-Bayoumy
- Faculty of Medicine, Mansoura University, Algomhoria Street, 35516, Egypt.
| | - Talal Amer
- Faculty of Medicine, Mansoura University, Algomhoria Street, 35516, Egypt.
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14
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Kunz HE, Dorschner JM, Berent TE, Meyer T, Wang X, Jatoi A, Kumar R, Lanza IR. Methylarginine metabolites are associated with attenuated muscle protein synthesis in cancer-associated muscle wasting. J Biol Chem 2021; 295:17441-17459. [PMID: 33453990 DOI: 10.1074/jbc.ra120.014884] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/17/2020] [Revised: 09/22/2020] [Indexed: 12/14/2022] Open
Abstract
Cancer cachexia is characterized by reductions in peripheral lean muscle mass. Prior studies have primarily focused on increased protein breakdown as the driver of cancer-associated muscle wasting. Therapeutic interventions targeting catabolic pathways have, however, largely failed to preserve muscle mass in cachexia, suggesting that other mechanisms might be involved. In pursuit of novel pathways, we used untargeted metabolomics to search for metabolite signatures that may be linked with muscle atrophy. We injected 7-week-old C57/BL6 mice with LLC1 tumor cells or vehicle. After 21 days, tumor-bearing mice exhibited reduced body and muscle mass and impaired grip strength compared with controls, which was accompanied by lower synthesis rates of mixed muscle protein and the myofibrillar and sarcoplasmic muscle fractions. Reductions in protein synthesis were accompanied by mitochondrial enlargement and reduced coupling efficiency in tumor-bearing mice. To generate mechanistic insights into impaired protein synthesis, we performed untargeted metabolomic analyses of plasma and muscle and found increased concentrations of two methylarginines, asymmetric dimethylarginine (ADMA) and NG-monomethyl-l-arginine, in tumor-bearing mice compared with control mice. Compared with healthy controls, human cancer patients were also found to have higher levels of ADMA in the skeletal muscle. Treatment of C2C12 myotubes with ADMA impaired protein synthesis and reduced mitochondrial protein quality. These results suggest that increased levels of ADMA and mitochondrial changes may contribute to impaired muscle protein synthesis in cancer cachexia and could point to novel therapeutic targets by which to mitigate cancer cachexia.
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Affiliation(s)
- Hawley E Kunz
- Endocrine Research Unit, Division of Endocrinology, Department of Internal Medicine, Mayo Clinic, Rochester, Minnesota, USA
| | - Jessica M Dorschner
- Nephrology and Hypertension Research Unit, Division of Nephrology and Hypertension, Department of Internal Medicine, Mayo Clinic, Rochester, Minnesota, USA
| | - Taylor E Berent
- Nephrology and Hypertension Research Unit, Division of Nephrology and Hypertension, Department of Internal Medicine, Mayo Clinic, Rochester, Minnesota, USA
| | - Thomas Meyer
- Nephrology and Hypertension Research Unit, Division of Nephrology and Hypertension, Department of Internal Medicine, Mayo Clinic, Rochester, Minnesota, USA
| | - Xuewei Wang
- Biomedical Statistics and Informatics, Department of Health Sciences Research, Mayo Clinic, Rochester, Minnesota, USA
| | - Aminah Jatoi
- Department of Medical Oncology, Mayo Clinic, Rochester, Minnesota, USA
| | - Rajiv Kumar
- Nephrology and Hypertension Research Unit, Division of Nephrology and Hypertension, Department of Internal Medicine, Mayo Clinic, Rochester, Minnesota, USA; Department of Biochemistry and Molecular Biology, Mayo Clinic, Rochester, Minnesota, USA.
| | - Ian R Lanza
- Endocrine Research Unit, Division of Endocrinology, Department of Internal Medicine, Mayo Clinic, Rochester, Minnesota, USA.
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15
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Shimomura M, Fujie S, Sanada K, Kajimoto H, Hamaoka T, Iemitsu M. Relationship between plasma asymmetric dimethylarginine and nitric oxide levels affects aerobic exercise training-induced reduction of arterial stiffness in middle-aged and older adults. Phys Act Nutr 2021; 25:16-22. [PMID: 33887824 PMCID: PMC8076586 DOI: 10.20463/pan.2021.0003] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/29/2021] [Accepted: 03/11/2021] [Indexed: 11/22/2022] Open
Abstract
Purpose Aerobic exercise training (AT) reverses aging-induced deterioration of arterial stiffness via increased arterial nitric oxide (NO) production. Asymmetric dimethylarginine (ADMA), an endogenous inhibitor of NO synthase, was decreased by AT. However, whether AT-induced changes in ADMA levels are related to changes in nitrite/nitrate (NOx) levels remains unclear. Accordingly, we aimed to clarify whether the relationship between plasma ADMA and NOx levels affected the AT-induced reduction of arterial stiffness in middle-aged and older adults. Methods Thirty-one healthy middle-aged and older male and female subjects (66.4 ± 1.3 years) were randomly divided into two groups: exercise intervention and sedentary controls. Subjects in the training group completed an 8-week AT (60%-70% peak oxygen uptake [V̇O2peak] for 45 min, 3 days/week). Results AT significantly increased V̇O2peak (P < 0.05) and decreased carotid β-stiffness (P < 0.01). Moreover, plasma ADMA levels were significantly decreased while plasma NOx levels and NOx/ADMA ratio were significantly increased by AT (P < 0.01). Additionally, no sex differences in AT-induced changes of circulating ADMA and NOx levels, NOx/ADMA ratio, and carotid β-stiffness were observed. Furthermore, the AT-induced increase in circulating ADMA levels was negatively correlated with an increase in circulating NOx levels (r = -0.414, P < 0.05), and the AT-induced increase in NOx/ADMA ratio was negatively correlated with a decrease in carotid β-stiffness (r = -0.514, P < 0.01). Conclusion These results suggest that the increase in circulating NOx with reduction of ADMA elicited by AT is associated with a decrease in arterial stiffness regardless of sex in middle-aged and older adults.
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Affiliation(s)
- Mio Shimomura
- Faculty of Sport and Health Science, Ritsumeikan University, Shiga, Japan
| | - Shumpei Fujie
- Faculty of Sport and Health Science, Ritsumeikan University, Shiga, Japan
| | - Kiyoshi Sanada
- Faculty of Sport and Health Science, Ritsumeikan University, Shiga, Japan
| | - Hiroki Kajimoto
- Faculty of Sport and Health Science, Ritsumeikan University, Shiga, Japan
| | - Takafumi Hamaoka
- Sports Medicine for Health Promotion, Tokyo Medical University, Tokyo, Japan
| | - Motoyuki Iemitsu
- Faculty of Sport and Health Science, Ritsumeikan University, Shiga, Japan
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16
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Gamil S, Erdmann J, Schwedhelm E, Bakheit KH, Abdalrahman IBB, Mohamed AO. Increased Serum Levels of Asymmetric Dimethylarginine and Symmetric Dimethylarginine and Decreased Levels of Arginine in Sudanese Patients with Essential Hypertension. Kidney Blood Press Res 2020; 45:727-736. [PMID: 32814314 DOI: 10.1159/000508695] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/13/2019] [Accepted: 05/14/2020] [Indexed: 11/19/2022] Open
Abstract
INTRODUCTION Essential hypertension (EH) is a disease caused by various environmental and genetic factors. Nitric oxide (NO) is important for the functional integrity of the endothelium. It is produced in endothelial cells by endothelial NO synthase (eNOS) that mediates the conversion of the amino acid arginine into NO and citrulline. Asymmetric dimethylarginine (ADMA) acts as an inhibitor of eNOS. In contrast, symmetric dimethylarginine (SDMA) has no direct effect on eNOS but plays an important role competing with arginine for transport across the amino acid transporter. ADMA and SDMA have been found to play a central role in the development of cardiovascular diseases. Serum ADMA levels may serve as a future diagnostic marker and a target of therapy in hypertensive patients in the Sudanese population. This study aimed to investigate the relation between serum arginine, ADMA, and SDMA levels with EH in the Sudanese population. METHODS Patients (n = 260) with established hypertension and controls (n = 144) with normal blood pressure were included in this case-control study. Serum blood samples were analyzed for arginine, ADMA, and SDMA, using high-performance liquid chromatography-tandem mass spectrometry. Other laboratory data were measured using routine methods. Mann-Whitney's U test and χ2 tests were used for continuous and categorical data, respectively. A multivariate logistic regression analysis was conducted to investigate the independent effect of multiple variables on the development of hypertension. RESULTS Serum arginine levels were significantly lower in the patient group than in the control group (p < 0.001). ADMA and SDMA levels were significantly higher in the patient group than the control group (p < 0.001, p = 0.001, respectively). Multivariate logistic regression analysis showed that only older age, being a male, and arginine levels are independent factors controlling the development of hypertension (p < 0.001, p < 0.001, and p = 0.046, respectively). ADMA and SDMA levels were not independent factors for the development of hypertension. CONCLUSIONS This study demonstrated increased serum levels of ADMA and SDMA and decreased arginine levels in Sudanese patients with EH. Lowering serum ADMA levels or increasing the arginine levels might be a novel therapeutic target in these individuals.
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Affiliation(s)
- Sahar Gamil
- Department of Biochemistry, Faculty of Medicine, University of Khartoum, Khartoum, Sudan,
| | - Jeanette Erdmann
- Institute for Cardiogenetics, University of Lübeck, Lübeck, Germany.,DZHK (German Research Centre for Cardiovascular Research), partner site Hamburg/Kiel/Lübeck, Hamburg/Kiel/Lübeck, Germany.,University Heart Center Lübeck, Lübeck, Germany
| | - Edzard Schwedhelm
- DZHK (German Research Centre for Cardiovascular Research), partner site Hamburg/Kiel/Lübeck, Hamburg/Kiel/Lübeck, Germany.,Department of Clinical Pharmacology and Toxicology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | | | - Ihab B B Abdalrahman
- Department of Medicine, Faculty of Medicine, University of Khartoum, Khartoum, Sudan
| | - Abdelrahim O Mohamed
- Department of Biochemistry, Faculty of Medicine, University of Khartoum, Khartoum, Sudan
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Michel M, Dubowy KO, Entenmann A, Karall D, Adam MG, Zlamy M, Odri Komazec I, Geiger R, Niederwanger C, Salvador C, Müller U, Laser KT, Scholl-Bürgi S. Targeted metabolomic analysis of serum amino acids in the adult Fontan patient with a dominant left ventricle. Sci Rep 2020; 10:8930. [PMID: 32488174 PMCID: PMC7265548 DOI: 10.1038/s41598-020-65852-x] [Citation(s) in RCA: 26] [Impact Index Per Article: 5.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/31/2019] [Accepted: 05/11/2020] [Indexed: 12/12/2022] Open
Abstract
Growing interest lies in the assessment of the metabolic status of patients with a univentricular circulation after Fontan operation, especially in changes of amino acid metabolism. Using targeted metabolomic examinations, we investigated amino acid metabolism in a homogeneous adult Fontan-patient group with a dominant left ventricle, seeking biomarker patterns that might permit better understanding of Fontan pathophysiology and early detection of subtle ventricular or circulatory dysfunction. We compared serum amino acid levels (42 analytes; AbsoluteIDQ p180 kit, Biocrates Life Sciences, Innsbruck, Austria) in 20 adult Fontan patients with a dominant left ventricle and those in age- and sex-matched biventricular controls. Serum concentrations of asymmetric dimethylarginine, methionine sulfoxide, glutamic acid, and trans-4-hydroxyproline and the methionine sulfoxide/methionine ratio (Met-SO/Met) were significantly higher and serum concentrations of asparagine, histidine, taurine, and threonine were significantly lower in patients than in controls. Met-SO/Met values exhibited a significant negative correlation with oxygen uptake during exercise. The alterations in amino acid metabolome that we found in Fontan patients suggest links between Fontan pathophysiology, altered cell energy metabolism, oxidative stress, and endothelial dysfunction like those found in biventricular patients with congestive heart failure. Studies of extended amino acid metabolism may allow better understanding of Fontan pathophysiology that will permit early detection of subtle ventricular or circulatory dysfunction in Fontan patients.
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Affiliation(s)
- Miriam Michel
- Department of Pediatrics III, Division of Pediatric Cardiology, Medical University of Innsbruck, Anichstraße 35, 6020, Innsbruck, Austria. .,Center of Pediatric Cardiology and Congenital Heart Disease, Heart and Diabetes Center North Rhine-Westphalia, Ruhr-University of Bochum, Georgstraße 11, 32545, Bad Oeynhausen, Germany.
| | - Karl-Otto Dubowy
- Center of Pediatric Cardiology and Congenital Heart Disease, Heart and Diabetes Center North Rhine-Westphalia, Ruhr-University of Bochum, Georgstraße 11, 32545, Bad Oeynhausen, Germany
| | - Andreas Entenmann
- Department of Pediatrics I, Division of Gastroenterology and Hepatology, Medical University of Innsbruck, Anichstraße 35, 6020, Innsbruck, Austria
| | - Daniela Karall
- Department of Pediatrics I, Division of Inherited Metabolic Disorders, Medical University of Innsbruck, Anichstraße 35, 6020, Innsbruck, Austria
| | - Mark Gordian Adam
- Biocrates Life Sciences AG, Eduard-Bodem-Gasse 8, 6020, Innsbruck, Austria
| | - Manuela Zlamy
- Department of Pediatrics I, Division of Inherited Metabolic Disorders, Medical University of Innsbruck, Anichstraße 35, 6020, Innsbruck, Austria
| | - Irena Odri Komazec
- Department of Pediatrics III, Division of Pediatric Cardiology, Medical University of Innsbruck, Anichstraße 35, 6020, Innsbruck, Austria
| | - Ralf Geiger
- Department of Pediatrics III, Division of Pediatric Cardiology, Medical University of Innsbruck, Anichstraße 35, 6020, Innsbruck, Austria
| | - Christian Niederwanger
- Department of Pediatrics I, Division of Inherited Metabolic Disorders, Medical University of Innsbruck, Anichstraße 35, 6020, Innsbruck, Austria
| | - Christina Salvador
- Department of Pediatrics I, Division of Inherited Metabolic Disorders, Medical University of Innsbruck, Anichstraße 35, 6020, Innsbruck, Austria
| | - Udo Müller
- Biocrates Life Sciences AG, Eduard-Bodem-Gasse 8, 6020, Innsbruck, Austria
| | - Kai Thorsten Laser
- Center of Pediatric Cardiology and Congenital Heart Disease, Heart and Diabetes Center North Rhine-Westphalia, Ruhr-University of Bochum, Georgstraße 11, 32545, Bad Oeynhausen, Germany
| | - Sabine Scholl-Bürgi
- Department of Pediatrics I, Division of Inherited Metabolic Disorders, Medical University of Innsbruck, Anichstraße 35, 6020, Innsbruck, Austria
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DDAH-2 alleviates contrast medium iopromide-induced acute kidney injury through nitric oxide synthase. Clin Sci (Lond) 2020; 133:2361-2378. [PMID: 31763675 DOI: 10.1042/cs20190455] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/02/2019] [Revised: 11/21/2019] [Accepted: 11/25/2019] [Indexed: 12/27/2022]
Abstract
BACKGROUND Contrast medium-induced acute kidney injury (CI-AKI) is one of the most common causes of hospital-acquired acute renal failure. However, the pathogenesis of CI-AKI remains unclear. Asymmetric dimethylarginine (ADMA) is an endogenous nitric oxide synthase (NOS) inhibitor that is largely metabolised by dimethylarginine dimethylaminohydroxylase (DDAH) in humans. Two isoforms of DDAH exist, namely, DDAH-1 and DDAH-2. In the present study, we examined whether the DDAH-2/ADMA/NOS pathway is involved in the pathogenesis of CI-AKI. METHODS AND RESULTS Exposure to the contrast medium iopromide led to increase in creatinine and blood urea nitrogen (BUN) levels, accumulation of ADMA, increase in reactive oxygen species (ROS) generation, and an inflammatory response in mice kidney tissue. The injection of adenovirus-harbouring DDAH-2 lowered renal ADMA levels and had a reno-protective effect against contrast-medium injury by decreasing cell apoptosis, ROS, and fibrosis. By contrast, contrast medium-induced renal injury was exacerbated in heterozygous DDAH-2 knockout mice. In the in vitro study, overexpression of DDAH-2 increased the levels of nitrite and intracellular cGMP, while the DDAH-2 knockdown induced the opposite effect. These findings were also observed in the in vivo sample. CONCLUSIONS Our findings provide the first evidence that the DDAH-2/ADMA/NOS pathway is involved in the pathogenesis of CI-AKI and that the protective effect of DDAH-2 probably arises from the modulation of NOS activity, oxidative stress, and the inflammatory process.
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Amarasekera AT, Chang D. Buddhist meditation for vascular function: A narrative review. Integr Med Res 2019; 8:252-256. [PMID: 31799114 PMCID: PMC6881634 DOI: 10.1016/j.imr.2019.11.002] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/07/2019] [Revised: 10/30/2019] [Accepted: 11/01/2019] [Indexed: 02/07/2023] Open
Abstract
Background High blood pressure represents an important risk factor for diseases related to cardiovascular system and is directly associated with high oxidative stress, inflammation and vascular endothelial dysfunction. Recently, there is promising data available to suggest that meditation-based low-cost and low-risk lifestyle modification strategies may provide beneficial effects on chronic inflammation, oxidative stress and maintenance of blood pressure, both in young and older adults. This review aims to summarize the evidence regarding the effectiveness of Buddhist meditation for vascular endothelial function and blood pressure. Method A search was conducted using Ovid MEDLINE, Scopus, CINAHL and PsycINFO for articles published from 1990 to 2018. Results Relevant articles (n = 407) were reviewed and 5 met selection criteria. Several lines of studies have provided compelling data showing that Buddhist meditation approach was effective in improving inflammation and vascular function (endothelial vasodilation and arterial stiffness) in both young and elderly cohorts. Particularly, Buddhist meditation approach has shown to be effective in reducing plasma inflammatory markers, increasing nitric oxide concentration and improving vascular endothelial function and glycemic control, which in turn can be favorable factors for demonstrated positive effects of Buddhist meditation on blood pressure and vascular function. Conclusion This paper presents brief overview of clinical outcomes of complementary therapeutic approach of Buddhist meditation in vascular function. In future, well-structured systematic reviews are essential to report specificity of Buddhist mindfulness-based approach on vascular function, blood pressure and other cardiovascular risk factors.
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Affiliation(s)
- Anjalee Thanuja Amarasekera
- Western Sydney Nursing and Midwifery Research Centre, School of Nursing and Midwifery, Western Sydney University, Sydney, New South Wales, Australia.,Western Sydney Local Health District, Sydney, New South Wales, Australia
| | - Dennis Chang
- NICM Health Research Institute, Western Sydney University, Sydney, New South Wales, Australia
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Oliva-Damaso E, Oliva-Damaso N, Rodriguez-Esparragon F, Payan J, Baamonde-Laborda E, Gonzalez-Cabrera F, Santana-Estupiñan R, Rodriguez-Perez JC. Asymmetric (ADMA) and Symmetric (SDMA) Dimethylarginines in Chronic Kidney Disease: A Clinical Approach. Int J Mol Sci 2019; 20:E3668. [PMID: 31357472 PMCID: PMC6696355 DOI: 10.3390/ijms20153668] [Citation(s) in RCA: 81] [Impact Index Per Article: 13.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/30/2019] [Revised: 07/18/2019] [Accepted: 07/19/2019] [Indexed: 01/19/2023] Open
Abstract
Asymmetric dimethylarginine (ADMA) and its enantiomer, Symmetric dimethylarginine (SDMA), are naturally occurring amino acids that were first isolated and characterized in human urine in 1970. ADMA is the most potent endogenous inhibitor of nitric oxide synthase (NOS), with higher levels in patients with end-stage renal disease (ESRD). ADMA has shown to be a significant predictor of cardiovascular outcome and mortality among dialysis patients. On the other hand, although initially SDMA was thought to be an innocuous molecule, we now know that it is an outstanding marker of renal function both in human and in animal models, with ESRD patients on dialysis showing the highest SDMA levels. Today, we know that ADMA and SDMA are not only uremic toxins but also independent risk markers for mortality and cardiovascular disease (CVD). In this review, we summarize the role of both ADMA and SDMA in chronic kidney disease along with other cardiovascular risk factors.
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Affiliation(s)
- Elena Oliva-Damaso
- Department of Nephrology, Hospital Universitario de Gran Canaria Doctor Negrín, 35010 Las Palmas de Gran Canaria, Spain.
| | - Nestor Oliva-Damaso
- Department of Medicine, Division of Nephrology, Hospital Costa del Sol, 29603 Marbella, Spain
| | - Francisco Rodriguez-Esparragon
- Department of Investigation, Hospital Universitario de Gran Canaria Doctor Negrín, 35010 Las Palmas de Gran Canaria, Spain
| | - Juan Payan
- Department of Medicine, Division of Nephrology, Hospital Costa del Sol, 29603 Marbella, Spain
| | - Eduardo Baamonde-Laborda
- Department of Nephrology, Hospital Universitario de Gran Canaria Doctor Negrín, 35010 Las Palmas de Gran Canaria, Spain
| | - Fayna Gonzalez-Cabrera
- Department of Nephrology, Hospital Universitario de Gran Canaria Doctor Negrín, 35010 Las Palmas de Gran Canaria, Spain
| | - Raquel Santana-Estupiñan
- Department of Nephrology, Hospital Universitario de Gran Canaria Doctor Negrín, 35010 Las Palmas de Gran Canaria, Spain
| | - Jose Carlos Rodriguez-Perez
- Department of Nephrology, Hospital Universitario de Gran Canaria Doctor Negrín, 35010 Las Palmas de Gran Canaria, Spain
- Department of Medical and Surgical Sciences, Universidad de Las Palmas de Gran Canaria, 35001 Las Palmas de Gran Canaria, Spain
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Toba H, Lindsey ML. Extracellular matrix roles in cardiorenal fibrosis: Potential therapeutic targets for CVD and CKD in the elderly. Pharmacol Ther 2019; 193:99-120. [PMID: 30149103 PMCID: PMC6309764 DOI: 10.1016/j.pharmthera.2018.08.014] [Citation(s) in RCA: 35] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
Whereas hypertension, diabetes, and dyslipidemia are age-related risk factors for cardiovascular disease (CVD) and chronic kidney disease (CKD), aging alone is an independent risk factor. With advancing age, the heart and kidney gradually but significantly undergo inflammation and subsequent fibrosis, which eventually results in an irreversible decline in organ physiology. Through cardiorenal network interactions, cardiac dysfunction leads to and responds to renal injury, and both facilitate aging effects. Thus, a comprehensive strategy is needed to evaluate the cardiorenal aging network. Common hallmarks shared across systems include extracellular matrix (ECM) accumulation, along with upregulation of matrix metalloproteinases (MMPs) including MMP-9. The wide range of MMP-9 substrates, including ECM components and inflammatory cytokines, implicates MMP-9 in a variety of pathological and age-related processes. In particular, there is strong evidence that inflammatory cell-derived MMP-9 exacerbates cardiorenal aging. This review explores the potential therapeutic targets against CVD and CKD in the elderly, focusing on ECM and MMP roles.
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Affiliation(s)
- Hiroe Toba
- Department of Clinical Pharmacology, Division of Pathological Sciences, Kyoto Pharmaceutical University, Kyoto, Japan.
| | - Merry L Lindsey
- Mississippi Center for Heart Research, Department of Physiology and Biophysics, University of Mississippi Medical Center, and Research Service, G.V. (Sonny) Montgomery Veterans Affairs Medical Center, Jackson, MS, USA.
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Han S, Aydin MM, Akansel S, Usanmaz SE, Akçali C, Uludağ MO, Demirel Yilmaz E. Age- and sex-dependent alteration of functions and epigenetic modifications of vessel and endothelium related biomarkers. Turk J Biol 2018; 42:286-296. [PMID: 30814892 DOI: 10.3906/biy-1803-59] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/03/2022] Open
Abstract
Aging is a main risk factor for development of cardiovascular diseases associated with the impairment of endothelial function in both sexes. In the present study, age-related changes in vascular responsiveness, epigenetic modifications of vessel wall, and blood biomarkers related to endothelial functions were examined in an age- and sex-dependent manner. Acetylcholine (ACh)-induced relaxations of the aorta were decreased in 3-, 6-, and 12-month-old rats compared to those in 1-month-old female rats. In males, maximum relaxations related to ACh were higher in 1- and 6-month-old rats than in 3- and 12-month-old rats. Plasma levels of nitric oxide (NO) and asymmetric dimethylarginine (ADMA) decreased with age in female rats, and total antioxidant capacity (TAC) and hydrogen sulfide (H 2S) levels displayed biphasic alterations. In male rats, plasma levels of NO, TAC, and ADMA decreased with age, and H2S levels increased. Aging also caused a sex-dependent alteration in epigenetic modification of vessels. Expressions of H3K27me2, H3K27me3, H3K36me2, and H3K36me3 were much higher in vessels of 12-month-old female rats compared to those in younger age groups. These results indicate that vascular functions, epigenetic modifications of vessels, and plasma levels of endothelium-related biomarkers are affected by age and sex. These findings could be important for the assessment of vascular status over the course of the life span.
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Affiliation(s)
- Sevtap Han
- Department of Pharmacology, Faculty of Pharmacy, Gazi University , Ankara , Turkey
| | - Muammer Merve Aydin
- Department of Biophysics, Faculty of Medicine, Ankara University , Ankara , Turkey
| | - Serdar Akansel
- Department of Medical Pharmacology, Faculty of Medicine, Ankara University , Turkey
| | - Suzan Emel Usanmaz
- Department of Medical Pharmacology, Faculty of Medicine, Ankara University , Turkey
| | - Can Akçali
- Department of Biophysics, Faculty of Medicine, Ankara University , Ankara , Turkey
| | - Mecit Orhan Uludağ
- Department of Pharmacology, Faculty of Pharmacy, Gazi University , Ankara , Turkey
| | - Emine Demirel Yilmaz
- Department of Medical Pharmacology, Faculty of Medicine, Ankara University , Turkey
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Li Z, Wang Z. Aging Kidney and Aging-Related Disease. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2018; 1086:169-187. [PMID: 30232759 DOI: 10.1007/978-981-13-1117-8_11] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
With the development of society and improvement of health care, the life span is much longer than before, which brings serious aging problems. Among all the aging problems, renal aging grows to be nonnegligible issue. The aging process of kidney is always accompanied with structural and functional changes. Molecular changes, including Klotho and Sirtuins, are the basic causes of phenotypical changes. Cell senescence and cell autophagy play fundamental roles in the process of renal aging. To effectively intervene in the process of renal aging, different methods have been tried separately, which could produce different effects. Effective intervention of renal aging could be meaningful for healthy state of the whole body.
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Affiliation(s)
- Zhongchi Li
- MOE Key Laboratory of Protein Sciences, School of Pharmaceutical Sciences, Tsinghua University, Beijing, China
| | - Zhao Wang
- School of Pharmaceutical Sciences, Tsinghua University, Beijing, China.
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Nair N, Gongora E. Oxidative Stress and Cardiovascular Aging: Interaction Between NRF-2 and ADMA. Curr Cardiol Rev 2017; 13:183-188. [PMID: 28215178 PMCID: PMC5633712 DOI: 10.2174/1573403x13666170216150955] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/13/2016] [Revised: 01/10/2017] [Accepted: 02/10/2017] [Indexed: 01/26/2023] Open
Abstract
Background: The concept of antioxidant therapies assumes high importance as oxidative stress is associated with cardiovascular aging via endothelial dysfunction. This review focuses on exploring the interaction between nrf-2 and ADMA in influencing the nitric oxide pathway and cardiovascular function. Objective: A systematic review of literature from 1990 to 2016 was conducted using Pubmed and Google Scholar. The literature suggests a strong influence of nrf-2 activation on up regulation of DDAH I which degrades ADMA, the endogenous inhibitor of nitric oxide synthase. The resulting decrease of ADMA would in turn enhance nitric oxide (NO) production. This would support endothelial function by adequate NO production and homeostasis of endothelial function. Conclusion: As NO production has many positive pleiotropic effects in the cardiovascular system, such an interaction could be utilized for designing molecular therapeutics. The targets for therapy need not be limited to activation of nrf-2. Modulation of molecules downstream such as DDAH I can be used to regulate ADMA levels. Most current literature is supported by animal studies. The concept of antioxidant therapies needs to be tested in well-defined randomized control trials. The biochemical basis of nrf-2 activation needs to be substantiated in human studies.
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Affiliation(s)
- Nandini Nair
- Division of Cardiology, Department of Internal Medicine, Texas Tech University Health Sciences Center, Lubbock, TX 79430, United States
| | - Enrique Gongora
- Memorial Cardiac and Vascular Institute, Hollywood, FL 33031, United States
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Symmetric dimethylarginine (SDMA) outperforms asymmetric dimethylarginine (ADMA) and other methylarginines as predictor of renal and cardiovascular outcome in non-dialysis chronic kidney disease. Clin Res Cardiol 2017; 107:201-213. [DOI: 10.1007/s00392-017-1172-4] [Citation(s) in RCA: 57] [Impact Index Per Article: 7.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/24/2017] [Accepted: 10/20/2017] [Indexed: 10/18/2022]
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Abstract
Although the endothelium has a number of important functions, the term endothelial dysfunction is commonly used to describe impairment in its vasodilatory capacity. It is increasingly recognized that this is related to hypertension, although whether it predates essential hypertension or is a consequence of it is still unknown. In this review, we explore the mechanisms of endothelial dysfunction in essential hypertension, its prognostic significance and methods of pharmacological reversal.
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Abstract
Epidemiological studies have shown that ageing is a major non-reversible risk factor for cardiovascular disease. Vascular ageing starts early in life and is characterized by a gradual change of vascular structure and function resulting in increased arterial stiffening. At the present review we discuss the role of the most important molecular pathways involved in vascular ageing, their association with arterial stiffening and possible novel therapeutic targets that may delay this otherwise irreversible degenerating process. Specifically, we discuss the role of oxidative stress, telomere shortening, and ubiquitin proteasome system in endothelial cell senescence and dysfunction in vascular inflammation and in arterial stiffening. Further, we summarize the most important molecular mechanisms regulating vascular ageing including sirtuin 1, telomerase, klotho, JunD, and amyloid beta 1-40 peptide.
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Affiliation(s)
- Ageliki Laina
- Department of Clinical Therapeutics, Alexandra Hospital, University of Athens, Athens, Greece
| | - Konstantinos Stellos
- Institute of Cardiovascular Regeneration, Center of Molecular Medicine, Goethe University Frankfurt, Frankfurt, Germany; Department of Cardiology, Center of Internal Medicine, Goethe University Frankfurt, Frankfurt, Germany; German Center of Cardiovascular Research (Deutsches Zentrum für Herz-Kreislaufforschung; DZHK), Rhein-Main Partner Site, Frankfurt, Germany
| | - Kimon Stamatelopoulos
- Department of Clinical Therapeutics, Alexandra Hospital, University of Athens, Athens, Greece.
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28
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Alshahawey M, Shahin SM, Elsaid TW, Sabri NA. Effect of Febuxostat on the Endothelial Dysfunction in Hemodialysis Patients: A Randomized, Placebo-Controlled, Double-Blinded Study. Am J Nephrol 2017; 45:452-459. [PMID: 28463849 DOI: 10.1159/000471893] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/24/2017] [Accepted: 03/03/2017] [Indexed: 01/22/2023]
Abstract
BACKGROUND Endothelial dysfunction is an important risk factor for cardiovascular diseases to occur in end-stage renal disease patients. Febuxostat, being a novel xanthine oxidase inhibitor, is apparently having a beneficial role in improving the endothelial dysfunction; however, data among hemodialysis patients are still limited. METHODS A prospective, placebo-controlled, block-randomized, double-blinded study was carried out to evaluate the effect of oral febuxostat on the endothelial dysfunction in hemodialysis patients. Fifty-seven eligible hemodialysis patients were randomly assigned to either the drug group (40 mg thrice weekly) or the placebo group. Serum Asymmetric dimethylarginine (ADMA), Serum uric acid (UA), and serum high sensitivity C-reactive protein (hsCRP) were measured at baseline and at the end of a 2-month study. Serum alanine aminotransferase (ALT), serum aspartate aminotransferase (AST), and the occurrence of pancytopenia were tested as safety parameters at baseline and at the end of study. RESULTS Serum UA significantly decreased from 7.5 ± 0.8 to 5.1 ± 1.2 mg/dL in the febuxostat group, while it did not change significantly in the placebo group. Treatment with febuxostat resulted in a significant decrease in the serum ADMA level from 1.027 ± 0.116 to 0.944 ± 0.104 µmol/L and the serum hsCRP level from 12.5 ± 1.65 to 12.1 ± 1.70 mg/L. Testing of serum ALT, serum AST, and pancytopenia revealed no significant difference in both groups. CONCLUSION Febuxostat appears to improve hyperuricemia and endothelial dysfunction and ameliorate inflammation in hemodialysis patients with no safety concerns.
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29
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Ganz T, Wainstein J, Gilad S, Limor R, Boaz M, Stern N. Serum asymmetric dimethylarginine and arginine levels predict microvascular and macrovascular complications in type 2 diabetes mellitus. Diabetes Metab Res Rev 2017; 33. [PMID: 27393712 DOI: 10.1002/dmrr.2836] [Citation(s) in RCA: 37] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/27/2016] [Revised: 06/06/2016] [Accepted: 06/29/2016] [Indexed: 12/26/2022]
Abstract
BACKGROUND Increased oxidative stress in diabetes increases nitric oxide (NO) oxidation and low l-arginine (Arg) could further reduce NO and impair vascular function, thereby accelerating, in the long run, vascular complications. We therefore measured Arg and asymmetric dimethylarginine (ADMA) levels in patients with type 2 diabetes mellitus (T2DM) and healthy controls. Additionally, we observed the diabetic individuals over time to see if Arg and asymmetric dimethylarginine predicted T2DM complications. METHODS We examined baseline serum Arg and ADMA levels in a cohort of 105 participants with type 2 diabetes and compared them with an age- and weight-matched nondiabetic group of 137 individuals who served as a reference population. Additionally, we assessed whether Arg and/or ADMA predicted macrovascular and microvascular complications over 6 years of follow-up. RESULTS Serum Arg was lower in individuals with T2DM than in controls (64 ± 28 vs 75 ± 31 μmol/L; P = .009) and inversely related to hemoglobin A1c (r = -0.2; P = .002). Over follow-up, we observed that participants with T2DM in the lowest quartile of Arg had increased risk for the subsequent evolution of nephropathy, peripheral neuropathy, and composite microvascular complications (odds ratio [OR] = 5.5; 95% confidence interval [CI] -1.9 to 16; P = .002). The highest ADMA quartile was associated with increased risk for both microvascular (OR = 4.5; 95% CI -1.4 to 14.1; P = .009) and 6.5-year incident macrovascular complications (OR = 8.3; 95% CI 1.9-35.5; P = .004). CONCLUSION l-Arginine levels are lower in individuals with T2DM than in matched controls. Both low Arg and high ADMA, independent of each other and adjusted for classical risk factors, predict the incidence of microvascular complications.
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Affiliation(s)
- Tali Ganz
- Diabetes Unit, Wolfson Medical Center, Holon, Israel
- Sackler Faculty of Medicine, Tel Aviv University, Ramat Aviv, Israel
| | - Julio Wainstein
- Diabetes Unit, Wolfson Medical Center, Holon, Israel
- Sackler Faculty of Medicine, Tel Aviv University, Ramat Aviv, Israel
| | - Suzan Gilad
- The Institute of Endocrinology, Metabolism and Hypertension, Tel Aviv-Sourasky Medical Center, Tel Aviv, Israel
| | - Rona Limor
- The Institute of Endocrinology, Metabolism and Hypertension, Tel Aviv-Sourasky Medical Center, Tel Aviv, Israel
| | - Mona Boaz
- Department of Nutrition Sciences, Ariel University, Ariel, Israel
- Epidemilogy and Research Unit, Wolfson Medical Center, Holon, Israel
| | - Naftali Stern
- Sackler Faculty of Medicine, Tel Aviv University, Ramat Aviv, Israel
- The Institute of Endocrinology, Metabolism and Hypertension, Tel Aviv-Sourasky Medical Center, Tel Aviv, Israel
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Bode-Böger SM, Scalera F, Martens-Lobenhoffer J. Asymmetric dimethylarginine (ADMA) accelerates cell senescence. Vasc Med 2016. [DOI: 10.1191/1358863x05vm606oa] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/05/2022]
Abstract
Asymmetric dimethylarginine (ADMA) is an endogenous inhibitor of nitric oxide synthase and its accumulation has been associated with cardiovascular disease. We aimed to investigate the role of ADMA in endothelial cell senescence. Endothelial cells were cultured until the tenth passage. ADMA was replaced every 48 hours starting at the fourth passage. ADMA significantly accelerated senescence-associated β-galactosidase activity. Additionally, the shortening of telomere length was significantly speeded up and telomerase activity was significantly reduced. This effect was associated with an increase of oxidative stress: both allantoin, a marker of oxygen free radical generation, and intracellular reactive oxygen species increased significantly after ADMA treatment compared with control, whereas nitric oxide synthesis decreased. Furthermore, ADMA-increased oxidative stress was accompanied by a decrease in the activity of dimethylarginine dimethylaminohydrolase, the enzyme that degrades ADMA, which could be prevented by the antioxidant pyrroli-dine dithiocarbamate. Exogenous ADMA also stimulated secretion of monocyte chemotactic protein-1 and interleukin-8. Co-incubation with the methyltransferase inhibitor S-adenosylhomocysteine abolished the effects of ADMA. These data suggest that ADMA accelerates senescence, probably via increased oxygen radical formation by inhibiting nitric oxide elaboration. This study provides evidence that modest changes of intracellular ADMA levels are associated with significant effects on slowing down endothelial senescence.
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Affiliation(s)
- Stefanie M Bode-Böger
- Institute of Clinical Pharmacology, University Hospital Otto-von-Guericke University, Magdeburg, Germany,
| | - Fortunato Scalera
- Institute of Clinical Pharmacology, University Hospital Otto-von-Guericke University, Magdeburg, Germany
| | - Jens Martens-Lobenhoffer
- Institute of Clinical Pharmacology, University Hospital Otto-von-Guericke University, Magdeburg, Germany
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31
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Abstract
Individuals age >65 years old are the fastest expanding population demographic throughout the developed world. Consequently, more aged patients than before are receiving diagnoses of impaired renal function and nephrosclerosis-age-associated histologic changes in the kidneys. Recent studies have shown that the aged kidney undergoes a range of structural changes and has altered transcriptomic, hemodynamic, and physiologic behavior at rest and in response to renal insults. These changes impair the ability of the kidney to withstand and recover from injury, contributing to the high susceptibility of the aged population to AKI and their increased propensity to develop subsequent progressive CKD. In this review, we examine these features of the aged kidney and explore the various validated and putative pathways contributing to the changes observed with aging in both experimental animal models and humans. We also discuss the potential for additional study to increase understanding of the aged kidney and lead to novel therapeutic strategies.
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Affiliation(s)
- Eoin D O'Sullivan
- Department of Renal Medicine, Royal Infirmary of Edinburgh, Edinburgh, United Kingdom;
| | - Jeremy Hughes
- Department of Renal Medicine, Royal Infirmary of Edinburgh, Edinburgh, United Kingdom.,MRC Centre for Inflammation Research, Queen's Medical Research Institute, University of Edinburgh, Edinburgh, United Kingdom; and
| | - David A Ferenbach
- Department of Renal Medicine, Royal Infirmary of Edinburgh, Edinburgh, United Kingdom.,MRC Centre for Inflammation Research, Queen's Medical Research Institute, University of Edinburgh, Edinburgh, United Kingdom; and.,Renal and.,Biomedical Engineering Divisions, Brigham and Women's Hospital, Department of Medicine, Harvard Medical School, Boston, Massachusetts
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32
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Lu TM, Hsu CP, Chang CF, Lin CC, Lee TS, Lin SJ, Chan WL. Asymmetric dimethylarginine predicts the risk of contrast-induced acute kidney injury in patients undergoing cardiac catheterization. Atherosclerosis 2016; 254:161-166. [DOI: 10.1016/j.atherosclerosis.2016.10.010] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/22/2016] [Revised: 09/17/2016] [Accepted: 10/05/2016] [Indexed: 11/24/2022]
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Bi X, Niu J, Ding W, Zhang M, Yang M, Gu Y. Angiopoietin-1 attenuates angiotensin II-induced ER stress in glomerular endothelial cells via a Tie2 receptor/ERK1/2-p38 MAPK-dependent mechanism. Mol Cell Endocrinol 2016; 428:118-32. [PMID: 27033326 DOI: 10.1016/j.mce.2016.03.027] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/22/2015] [Revised: 03/13/2016] [Accepted: 03/21/2016] [Indexed: 12/11/2022]
Abstract
Research has indicated that endoplasmic reticulum (ER) stress in endothelial cells affects vascular pathologies and induces cellular dysfunction and apoptosis. Angiopoietin1 (Angpt1) has been shown to have therapeutic potential in some vascular diseases, including chronic kidney disease. This study showed that Angpt1 is a powerful factor that attenuated ER stress-induced cellular dysfunction and apoptosis in glomerular endothelial cells (GEnCs). Furthermore, Angpt1 significantly decreased the angiotensin II (Ang II)-induced expression of the ER stress response proteins GRP78, GRP94, p-PERK and CHOP. These results suggest that the Angpt1-mediated cellular protection may occur downstream of the ER stress response. In addition, both specific inhibitors and siRNAs for Tie2 reversed these changes, implying the importance of Tie2 receptor activation in the signalling pathways that prevent ER stress. The protective effects of Angpt1 are related to the activation of two downstream signalling pathways, ERK1/2 and p38 MAPK. The inhibition of these pathways with specific inhibitors, PD98059 and SB203580, respectively, partially increased the expression of chaperones that assist in folding proteins in the ER and reduce the protective effects of Angpt1. In conclusion, Angpt1 attenuated ER stress-induced cellular dysfunction and apoptosis via the Tie2 receptor/ERK1/2-p38 MAPK pathways in GEnCs. This study may provide insights into a novel underlying mechanism and a strategy for alleviating ER stress-induced injury.
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Affiliation(s)
- Xiao Bi
- Division of Nephrology, Shanghai Fifth People's Hospital, Fudan University, Shanghai, China
| | - Jianying Niu
- Division of Nephrology, Shanghai Fifth People's Hospital, Fudan University, Shanghai, China
| | - Wei Ding
- Division of Nephrology, Shanghai Fifth People's Hospital, Fudan University, Shanghai, China
| | - Minmin Zhang
- Division of Nephrology, Huashan Hospital, Fudan University, Shanghai, China
| | - Min Yang
- Division of Nephrology, Shanghai Fifth People's Hospital, Fudan University, Shanghai, China.
| | - Yong Gu
- Division of Nephrology, Huashan Hospital, Fudan University, Shanghai, China.
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Mirmiran P, Bahadoran Z, Ghasemi A, Azizi F. The Association of Dietary l-Arginine Intake and Serum Nitric Oxide Metabolites in Adults: A Population-Based Study. Nutrients 2016; 8:nu8050311. [PMID: 27213443 PMCID: PMC4882723 DOI: 10.3390/nu8050311] [Citation(s) in RCA: 22] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/04/2016] [Revised: 05/11/2016] [Accepted: 05/16/2016] [Indexed: 12/20/2022] Open
Abstract
This study was conducted to investigate whether regular dietary intake of l-arginine is associated with serum nitrate + nitrite (NOx). In this cross-sectional study, 2771 men and women, who had participated in the third examination of the Tehran Lipid and Glucose Study (2006–2008), were recruited. Demographics, anthropometrics and biochemical variables were evaluated. Dietary data were collected using a validated 168-food item semi-quantitative food frequency questionnaire and dietary intake of l-arginine was calculated. To determine any association between dietary l-arginine and serum NOx, linear regression models with adjustment for potential confounders were used. Mean age of participants (39.2% men) was 45.9 ± 15.9 years. After adjustment for all potential confounding variables, a significant positive association was observed between l-arginine intake and serum NOx concentrations in the fourth quartile of l-arginine (β = 6.63, 95% CI = 4.14, 9.12, p for trend = 0.001), an association stronger in women. Further analysis, stratified by age, body mass index and hypertension status categories, showed a greater association in middle-aged and older adults (β = 9.12, 95% CI = 3.99, 13.6 and β = 12.1, 95% CI = 6.48, 17.7, respectively). l-arginine intakes were also strongly associated with serum NOx levels in overweight and obese subjects in the upper quartile (β = 10.7, 95% CI = 5.43, 16.0 and β = 11.0, 95% CI = 4.29, 17.5); a greater association was also observed between l-arginine intakes and serum NOx in non-hypertensive (HTN) compared to HTN subjects (β = 2.65, 95% CI = 2.1–3.2 vs. β = 1.25, 95% CI = −1.64–4.15). Dietary l-arginine intakes were associated to serum NOx and this association may be affected by sex, age, body mass index, and hypertension status.
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Affiliation(s)
- Parvin Mirmiran
- Nutrition and Endocrine Research Center, Research Institute for Endocrine Sciences, Shahid Beheshti University of Medical Sciences, Tehran 19395-4763, Iran.
| | - Zahra Bahadoran
- Nutrition and Endocrine Research Center, Research Institute for Endocrine Sciences, Shahid Beheshti University of Medical Sciences, Tehran 19395-4763, Iran.
| | - Asghar Ghasemi
- Endocrine Physiology Research Center, Research Institute for Endocrine Sciences, Shahid Beheshti University of Medical Sciences, Tehran 19395-4763, Iran.
| | - Fereidoun Azizi
- Endocrine Research Center, Research Institute for Endocrine Sciences, Shahid Beheshti University of Medical Sciences, Tehran 19395-4763, Iran.
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Nitric oxide synthesis capacity, ambulatory blood pressure and end organ damage in a black and white population: the SABPA study. Amino Acids 2015; 48:801-810. [PMID: 26573539 DOI: 10.1007/s00726-015-2128-5] [Citation(s) in RCA: 18] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/10/2015] [Accepted: 11/04/2015] [Indexed: 10/22/2022]
Abstract
Nitric oxide (NO) synthesis capacity is determined by the availability of substrate(s) such as L-arginine and the influence of nitric oxide synthase (NOS) inhibitors, asymmetric dimethylarginine (ADMA) and symmetric dimethylarginine (SDMA). These factors may be important in black South Africans with a very high prevalence of hypertension. We compared ambulatory blood pressure (BP), markers of end organ damage and NO synthesis capacity markers [L-arginine, L-homoarginine, L-citrulline, L-arginine:ADMA, ADMA, SDMA and dimethylarginine (DMA)], between black and white teachers (n = 390). Associations of nighttime BP and markers of end organ damage with NO synthesis capacity markers were also investigated. Although black men and women had higher BP and albumin-to-creatinine ratio (ACR) (all p < 0.001), they also had higher L-arginine, L-homoarginine, L-arginine:ADMA and lower SDMA and DMA levels (all p < 0.05). Only in white men ADMA concentrations associated positively with nighttime systolic blood pressure (R (2) = 0.20, β = 0.26, p = 0.009), nighttime diastolic blood pressure (R (2) = 0.23, β = 0.27, p = 0.007), carotid intima media thickness (cIMT) (R (2) = 0.36, β = 0.22, p = 0.008) and ACR (R (2) = 0.14, β = 0.32, p = 0.001). Our findings suggest that despite an adverse cardiovascular profile in blacks, their NO synthesis capacity profile seems favourable, and that other factors, such as NO inactivation, may prove to be more important.
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Effects of handgrip exercise or inorganic nitrate supplementation on 24-h ambulatory blood pressure and peripheral arterial function in overweight and obese middle age and older adults: A pilot RCT. Maturitas 2015; 82:228-35. [PMID: 26316026 DOI: 10.1016/j.maturitas.2015.07.028] [Citation(s) in RCA: 24] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/09/2015] [Revised: 07/29/2015] [Accepted: 07/30/2015] [Indexed: 01/31/2023]
Abstract
INTRODUCTION Hypertension is a major contributor to the global burden of cardiovascular diseases and its prevalence increases progressively with ageing. Therefore the identification of effective, age-friendly exercise and nutritional interventions which lower blood pressure (BP) is a research priority. OBJECTIVE To undertake a pilot RCT examining the efficacy of isometric handgrip exercise (IHGE) and beetroot juice (a rich source of inorganic nitrate) consumption in modifying clinic and 24-h ambulatory BP (24-h ABP), peripheral arterial function and plasma asymmetric dimethylarginine (ADMA) in older overweight and obese adults. DESIGN Thirty middle age and older adults (62±5 years) were randomised to: (a) bilateral IHGE at 50% of maximal voluntary contraction (8 min/day), (b) 140 ml/day of concentrated beetroot juice, or (c) no-intervention (control group), for 7 days. All groups followed a standardised diet to control nitrate intake. Clinic and 24-h ABP, peripheral arterial function quantified by pulse wave velocity (PWV) and arterial volume distensibility were assessed before and after intervention. SETTING Clinical ageing research unit, Newcastle University. RESULTS At baseline, there were no between-group differences in age, handgrip strength, clinic or 24-h ABP, BMI, waist circumference, fat mass, physical activity level, energy intake or urinary and plasma nitrate concentrations. After intervention, there were no significant effects on clinic systolic and diastolic BP or 24-h ABP, PWV (p=0.54), arterial volume distensibility (p=0.89), or ADMA (p=0.45). CONCLUSIONS IHGE or beetroot juice consumption for 7 days did not affect BP or peripheral arterial function in overweight and obese middle age and older adults. Ageing may reduce the effects of these interventions on vascular function and studies are needed to test this hypothesis.
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Inci U, Yildiz A, Batmaz I, Tekbas E. Assessment of serum asymmetric dimethylarginine levels and left ventricular diastolic function in patients with ankylosing spondylitis. Int J Rheum Dis 2015; 20:238-244. [PMID: 26012572 DOI: 10.1111/1756-185x.12608] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/08/2023]
Abstract
AIM To assess left ventricular diastolic functions and serum dimethylarginine (ADMA) concentrations, as well as the effect of different treatment strategies on ADMA concentrations and diastolic function parameters, in patients with ankylosing spondylitis (AS). METHOD Sixty AS patients and 40 control subjects without classical cardiovascular (CV) risk factors were included in the study. Baseline clinical and echocardiographic variables were obtained. C-reactive protein (CRP), erythrocyte sedimentation rate (ESR) and ADMA levels were measured. Spinal mobility, disease activity and functional status were assessed using Bath Ankylosing Spondylitis Metrology Index, Bath Ankylosing Spondylitis Disease Activity Index and Bath Ankylosing Spondylitis Functional Index. RESULTS CRP, ESR and ADMA levels were significantly higher in the AS group as compared to the control group. Two (5%) control subjects and six (10%) AS patients met the criteria for left ventricular diastolic dysfunction (DD) on conventional Doppler echocardiography, but the difference was not statistically significant (P = 0.36). However, using tissue Doppler imaging, 12 (20%) patients in the AS group and three (8%) subjects in the control group were diagnosed with left ventricular DD (P = 0.08). The anti-tumor necrosis factor (TNF)-α group, conventional therapy group and control group were compared in terms of ADMA, CRP, ESR levels and echocardiographic parameters. ADMA levels were significantly lower in anti-TNF-α group as compared to the conventional therapy group (P < 0.001). In the control group, ADMA levels were significantly lower than both treatment groups (P < 0.001). CONCLUSION Increased ADMA levels reveal impaired nitric oxide metabolism in a relatively young group of patients with AS, who have no classical CV risk factors. Anti-TNF-α may have beneficial effect on endothelial function in AS patients by reducing ADMA levels.
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Affiliation(s)
- Umit Inci
- Department of Cardiology, Dicle University School of Medicine, Diyarbakir, Turkey
| | - Abdulkadir Yildiz
- Department of Cardiology, Dicle University School of Medicine, Diyarbakir, Turkey
| | - Ibrahim Batmaz
- Department of Physical Medicine and Rehabilitation, Dicle University School of Medicine, Diyarbakir, Turkey
| | - Ebru Tekbas
- Department of Cardiology, Dicle University School of Medicine, Diyarbakir, Turkey
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Schultz CD, Rangneker G, Lim HS, Fraudeau A, Young G, Roberts-Thomson K, John B, Worthley M, Sanders P, Willoughby SR. Characterization of thrombogenic, endothelial and inflammatory markers in supraventricular tachycardia: a study in patients with structurally normal hearts. Clin Exp Pharmacol Physiol 2015; 41:551-7. [PMID: 24827644 DOI: 10.1111/1440-1681.12256] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/12/2013] [Revised: 05/01/2014] [Accepted: 05/05/2014] [Indexed: 11/28/2022]
Abstract
Patients with atrial fibrillation (AF) are at an increased risk of thromboembolism and stroke primarily from the development of thrombi within the left atrium. Pathological changes in blood constituents and atrial endothelial damage promote left atrial thrombus formation. It is not known whether factors predisposing to left atrial thrombus formation in AF are disease specific or also evident within the normal heart. The present study examined whether there are differences in platelet reactivity, endothelial function and inflammation in blood samples obtained from intracardiac and peripheral sites in subjects within structurally normal hearts. Sixteen patients with diagnosed left-sided supraventricular tachycardia (SVT) undergoing a routine elective electrophysiological study and ablation were investigated. Blood samples were taken simultaneously from the femoral vein, right atrium and left atrium, immediately following trans-septal puncture and prior to heparin bolus administration. Between peripheral and atrial sample sites, patients with SVT showed no change in platelet reactivity or aggregation (P-selectin (CD62P) P = 0.91; platelet-derived soluble CD40 ligand P = 0.9), thrombus formation (thrombin-antithrombin complex; P = 0.55), endothelial function (von Willebrand factor P = 0.75; asymmetric dimethylarginine (ADMA) P = 0.97; nitric oxide P = 0.61), or inflammation (vascular cell adhesion molecule-1 P = 0.59; intercellular adhesion molecule-1 (ICAM-1) P = 0.69). However, SVT patients had lower ADMA and ICAM-1 levels than AF patients. The present study demonstrates, for the first time, that SVT subjects with structurally normal hearts have consistent haemostatic function between atrial and peripheral sites. These results suggest that the atria of SVT patients do not contain predisposing thrombogenic, endothelial or inflammatory factors that promote and/or initiate thrombus formation.
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Affiliation(s)
- Carlee D Schultz
- Centre for Heart Rhythm Disorders, University of Adelaide and Cardiovascular Investigation Unit, Royal Adelaide Hospital, Adelaide, SA, Australia
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Rroji M, Eloot S, Dhondt A, Van Biesen W, Glorieux G, Neirynck N, Vandennoortgate N, Liabeuf S, Massy Z, Vanholder R. Association of advanced age with concentrations of uraemic toxins in CKD. J Nephrol 2015; 29:81-91. [DOI: 10.1007/s40620-015-0195-z] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/01/2014] [Accepted: 03/27/2015] [Indexed: 11/28/2022]
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Use of Dual-Source Computed Tomography to Evaluate Renal Cortical Perfusion in Patients With Essential Hypertension Without Diabetes: Preliminary Results. J Comput Assist Tomogr 2015; 39:473-8. [PMID: 25756803 DOI: 10.1097/rct.0000000000000230] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/25/2022]
Abstract
OBJECTIVES To assess renal cortical perfusion parameter changes using computed tomography (CT) renal perfusion examination in patients with essential hypertension (EH), especially those with EH-related target organ damage (TOD), and to correlate renal perfusion parameters with clinical and laboratory data. METHODS Consecutive patients with EH (without exclusion criteria) and healthy controls underwent 128-slice dual-source CT perfusion imaging. Quantitative perfusion analysis of renal cortex parameters [blood flow (BF), blood volume, time to peak, and mean transit time] was performed. RESULTS Ninety-one participants (60 patients with EH, 31 healthy controls) underwent renal perfusion CT imaging, and 84 participants (92.3%) were eligible for perfusion analysis. The BF values were lower in patients with EH than that in controls. Blood flow was correlated with age (P < 0.01), duration of hypertension (P < 0.01), estimated glomerular filtration rate (eGFR; P < 0.01), pulse pressure (P < 0.05), and body mass index (BMI; P < 0.05). Duration of hypertension, eGFR, and BMI were independently associated with BF. No parameter differed between control subjects and those with EH but not. Blood flow was lower in patients with TOD than in control subjects (P < 0.01), but no other parameter differed. Blood flow was lower (P < 0.01) and mean transit time and time to peak were higher (P < 0.05) in the TOD than that in the non-TOD group. CONCLUSIONS Essential hypertension, especially EH-related TOD, alters renal cortical perfusion parameters, especially BF. Four-dimensional spiral CT renal perfusion examination showed that duration of hypertension, eGFR, and BMI were independently associated with decreased BF.
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The aging kidney: increased susceptibility to nephrotoxicity. Int J Mol Sci 2014; 15:15358-76. [PMID: 25257519 PMCID: PMC4200815 DOI: 10.3390/ijms150915358] [Citation(s) in RCA: 89] [Impact Index Per Article: 8.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/25/2014] [Revised: 08/12/2014] [Accepted: 08/18/2014] [Indexed: 12/13/2022] Open
Abstract
Three decades have passed since a series of studies indicated that the aging kidney was characterized by increased susceptibility to nephrotoxic injury. Data from these experimental models is strengthened by clinical data demonstrating that the aging population has an increased incidence and severity of acute kidney injury (AKI). Since then a number of studies have focused on age-dependent alterations in pathways that predispose the kidney to acute insult. This review will focus on the mechanisms that are altered by aging in the kidney that may increase susceptibility to injury, including hemodynamics, oxidative stress, apoptosis, autophagy, inflammation and decreased repair.
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Giovannini C, Piaggi S, Federico G, Scarpato R. High levels of γ-H2AX foci and cell membrane oxidation in adolescents with type 1 diabetes. Mutat Res 2014; 770:128-35. [PMID: 25771879 DOI: 10.1016/j.mrfmmm.2014.08.005] [Citation(s) in RCA: 20] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/12/2014] [Revised: 06/12/2014] [Accepted: 08/20/2014] [Indexed: 12/24/2022]
Abstract
Oxidative stress caused by an excess of free radicals is implicated in the pathogenesis and development of type 1 diabetes mellitus (T1DM) and, in turn, it can lead to genome damage, especially in the form of DNA double-strand break (DSB). The DNA DSB is a potentially carcinogenic lesion for human cells. Thus, we aimed to evaluate whether the level of oxidative stress was increased in peripheral blood lymphocytes of a group of affected adolescents. In 35 T1DM adolescents and 19 healthy controls we assessed: (1) spontaneous and H2O2-induced oxidation of cell membrane using a fluorescence lipid probe; (2) spontaneous and LPS-induced expression of iNOS protein and indirect NO determination via cytofluorimetric analysis of O2(-); (3) immunofluorescent detection of the basal level of histone H2AX phosphorylation (γ-H2AX foci), a well-validated marker of DNA DSB. In T1DM, the frequencies of oxidized cells, both spontaneous and H2O2-induced (47.13±0.02) were significantly higher than in controls (35.90±0.03). Patients showed, in general, both a reduced iNOS expression and production of NO. Furthermore, the level of spontaneous nuclear damage, quantified as γ-H2AX foci, was markedly increased in T1DM adolescents (6.15±1.08% of γ-H2AX(+) cells; 8.72±2.14 γ-H2AXF/n; 9.26±2.37 γ-H2AXF/np), especially in females. In the present study, we confirmed the role that oxidative stress plays in the disease damaging lipids of cell membrane and, most importantly, causing genomic damage in circulating white blood cells of affected adolescents. This also indicates that oxidative stress can affect several tissues in the body. However, although the observed DNA damage is a clear indication that the proper DNA repair mechanisms are activated, the risk for young T1DM subjects of developing not only cardiovascular complications but also some type of cancer cannot be ruled out. In this view, females, probably due to hormonal imbalance typical of adolescence, might represent a more susceptible population.
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Affiliation(s)
| | - Simona Piaggi
- Sezione di Patologia Sperimentale, Dipartimento di Ricerca Traslazionale e delle Nuove Tecnologie in Medicina e Chirurgia, Pisa University, Pisa, Italy
| | - Giovanni Federico
- Unità di Endocrinologia Pediatrica e Diabete, Dipartimento di Medicina Clinica e Sperimentale Pisa University, Pisa, Italy
| | - Roberto Scarpato
- Unità di Genetica, Dipartimento di Biologia, Pisa University, Pisa, Italy.
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Mordi I, Tzemos N. Is reversal of endothelial dysfunction still an attractive target in modern cardiology? World J Cardiol 2014; 6:824-835. [PMID: 25228961 PMCID: PMC4163711 DOI: 10.4330/wjc.v6.i8.824] [Citation(s) in RCA: 18] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/03/2013] [Revised: 04/17/2014] [Accepted: 05/29/2014] [Indexed: 02/06/2023] Open
Abstract
Although the endothelium has a number of important functions, the term endothelial dysfunction is commonly used to describe impairment in its vasodilatory capacity. There have been numerous studies evaluating the relationship between endothelial dysfunction and cardiovascular disease, however assessment of endothelial function is perhaps still primarily thought of as a research tool and has not reached widespread clinical acceptance. In this review we explore the relationship between endothelial dysfunction and cardiovascular disease, its prognostic significance, methods of pharmacological reversal of endothelial dysfunction, and ask the question, is reversal of endothelial dysfunction still an attractive target in modern cardiology?
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Abstract
Background Impaired generation and signaling of nitric oxide (NO) contribute substantially to cardiovascular (CV) risk (CVR) associated with hypertension, hyperlipidemia, and diabetes mellitus. In our rapidly aging society, advanced age is, in itself, a consistent and independent CVR factor. Many processes involved in aging are modulated by NO. We therefore postulated that aging might be independently associated with impaired NO signaling. Methods and Results In a prospective cohort study of 204 subjects (mean age 63±6 at study entry), we evaluated the effects of 4 years of aging on parameters of NO generation and effect, including platelet aggregability and responsiveness to NO, and plasma concentrations of the NO synthase inhibitor, asymmetric dimethylarginine (ADMA). Clinical history, lipid profile, high‐sensitivity C‐reactive protein, routine biochemistry, and 25‐hydroxyvitamin D levels were obtained at study entry and after 4 years of follow‐up. Aging was associated with marked deterioration of responsiveness of platelets to NO (P<0.0001) and increases in plasma ADMA concentrations (P<0.0001). There was a significant correlation between changes in these parameters over time (r=0.2; P=0.013). On multivariable analyses, the independent correlates of deterioration of responsiveness of platelets to NO were female gender (β=0.17; P=0.034) and low vitamin D concentrations (β=0.16; P=0.04), whereas increases in ADMA were associated with presence of diabetes (β=0.16; P=0.03) and impaired renal function (β=0.2; P=0.004). Conclusions Aging is associated with marked impairment of determinants of NO generation and effect, to an extent which is commensurate with adverse impact on CV outcomes. This deterioration represents a potential target for therapeutic interventions.
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Affiliation(s)
- Aaron L Sverdlov
- University of Adelaide, The Queen Elizabeth Hospital, Adelaide, Australia (A.L.S., D.T.N., W.P.C., Y.Y.C., J.D.H.)
| | - Doan T M Ngo
- University of Adelaide, The Queen Elizabeth Hospital, Adelaide, Australia (A.L.S., D.T.N., W.P.C., Y.Y.C., J.D.H.)
| | - Wai P A Chan
- University of Adelaide, The Queen Elizabeth Hospital, Adelaide, Australia (A.L.S., D.T.N., W.P.C., Y.Y.C., J.D.H.)
| | - Yuliy Y Chirkov
- University of Adelaide, The Queen Elizabeth Hospital, Adelaide, Australia (A.L.S., D.T.N., W.P.C., Y.Y.C., J.D.H.)
| | - John D Horowitz
- University of Adelaide, The Queen Elizabeth Hospital, Adelaide, Australia (A.L.S., D.T.N., W.P.C., Y.Y.C., J.D.H.)
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Molnar T, Pusch G, Papp V, Feher G, Szapary L, Biri B, Nagy L, Keki S, Illes Z. The L-arginine pathway in acute ischemic stroke and severe carotid stenosis: temporal profiles and association with biomarkers and outcome. J Stroke Cerebrovasc Dis 2014; 23:2206-2214. [PMID: 25018114 DOI: 10.1016/j.jstrokecerebrovasdis.2014.05.002] [Citation(s) in RCA: 20] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/10/2014] [Revised: 04/29/2014] [Accepted: 05/05/2014] [Indexed: 11/17/2022] Open
Abstract
BACKGROUND Endothelial dysfunction is associated with increased levels of asymmetric dimethylarginine (ADMA) and symmetric dimethylarginine (SDMA) resulting in a decreased production of nitric oxide, which regulates the vascular tone. METHODS Patients with acute ischemic stroke (AIS, n = 55) and asymptomatic significant carotid stenosis (AsCS, n = 44) were prospectively investigated. L-arginine, ADMA, SDMA, S100 B, and high-sensitivity C-reactive protein (hsCRP) were serially measured within 6 hours after the onset of stroke, at 24 and 72 poststroke hours. All markers were compared with healthy subjects (n = 45). The severity of AIS was daily assessed by National Institute of Health Stroke Scale scoring. RESULTS Even within 6 hours after the onset of stroke, L-arginine, ADMA, and SDMA were significantly higher in patients with AIS compared with both AsCS and healthy subjects. S100 B reflecting infarct size, positively correlated with the level of SDMA at 72 poststroke hours; changes in concentration of S100 B positively correlated with changes in the concentration of ADMA by 72 hours. Change in concentration of both ADMA and SDMA correlated with the change in concentration of hsCRP. Concentrations of L-arginine and hsCRP at 72 poststroke hours, respectively, were independent predictors of poststroke infection. S100 B level measured within 6 hours after the onset of AIS and hsCRP at 72 poststroke hours were independent predictors of death. CONCLUSIONS Metabolites of the L-arginine pathway were elevated in the very acute phase of ischemic stroke indicating a more pronounced endothelial dysfunction compared with AsCS. An increased basal L-arginine level in patients with AIS might be an adaptive mechanism; such transient elevation of the L-arginine/ADMA ratio at 24 poststroke hours may suggest that a temporary increase of L-arginine along with decrease of ADMA might be related to the protective role of L-arginine. Changes in the L-arginine pathway are predictive of poststroke infections.
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Affiliation(s)
- Tihamer Molnar
- Department of Anesthesiology and Intensive Care, University of Pecs, Pecs, Hungary.
| | | | - Viktoria Papp
- Department of Neurology, University of Pecs, Pecs, Hungary
| | - Gergely Feher
- Department of Neurology, University of Pecs, Pecs, Hungary
| | - Laszlo Szapary
- Department of Neurology, University of Pecs, Pecs, Hungary
| | - Bernadett Biri
- Department of Applied Chemistry, University of Debrecen, Debrecen, Hungary
| | - Lajos Nagy
- Department of Applied Chemistry, University of Debrecen, Debrecen, Hungary
| | - Sandor Keki
- Department of Applied Chemistry, University of Debrecen, Debrecen, Hungary
| | - Zsolt Illes
- Department of Neurology, Odense University Hospital, Odense, Denmark; Institute of Clinical Research, University of Southern Denmark, Odense, Denmark
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Tanahashi K, Akazawa N, Miyaki A, Choi Y, Ra SG, Matsubara T, Kumagai H, Oikawa S, Miyauchi T, Maeda S. Plasma ADMA concentrations associate with aerobic fitness in postmenopausal women. Life Sci 2014; 108:30-3. [DOI: 10.1016/j.lfs.2014.05.003] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/02/2013] [Revised: 03/21/2014] [Accepted: 05/02/2014] [Indexed: 11/17/2022]
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Watarai R, Suzuki K, Ichino N, Osakabe K, Sugimoto K, Yamada H, Hamajima T, Hamajima N, Inoue T. Association between serum levels of carotenoids and serum asymmetric dimethylarginine levels in Japanese subjects. J Epidemiol 2014; 24:250-7. [PMID: 24727752 PMCID: PMC4000773 DOI: 10.2188/jea.je20130137] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/23/2023] Open
Abstract
Background Asymmetric dimethylarginine (ADMA) is an endogenous inhibitor of endothelium nitric oxide synthase (NOS). ADMA binds to a substrate-binding site of NOS and then inhibits nitric oxide production from vascular endothelial cells. Elevated ADMA levels are a risk factor for cardiovascular disease. Recently, it was reported that plasma ADMA levels were negatively correlated with vegetable and fruit consumption. The purpose of this study was to examine the association between serum levels of carotenoids and serum ADMA levels in Japanese subjects. Methods We conducted a cross-sectional study of 470 subjects (203 men and 267 women) who attended a health examination in August 2011. Serum levels of several carotenoids were separately measured by high-performance liquid chromatography. Serum ADMA levels were determined by using an enzyme-linked immunosorbent assay kit. Results In women, the multivariate-adjusted odds ratios (ORs) of elevated serum ADMA levels were significantly decreased in the highest tertile for β-cryptoxanthin (OR 0.47, 95% CI 0.23–0.95), α-carotene (OR 0.39, 95% CI 0.18–0.79), and β-carotene (OR 0.36, 95% CI 0.17–0.73) compared to the lowest tertile. In men, significantly decreased ORs were observed in the highest tertiles of serum zeaxanthin/lutein (OR 0.23, 95% CI 0.06–0.69) and α-carotene (OR 0.26, 95% CI 0.07–0.82), and in the middle and the highest tertiles of serum β-carotene (OR 0.27, 95% CI 0.09–0.74 and OR 0.20, 95% CI 0.03–0.88, respectively) when the tertile cutoff points of women were extrapolated to men. Conclusions Higher serum levels of carotenoids, such as α-carotene and β-carotene, may help to prevent elevated serum ADMA levels in Japanese subjects.
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Affiliation(s)
- Rika Watarai
- Clinical Laboratory Medicine, Fujita Health University Graduate School of Health Sciences
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The aging kidney revisited: a systematic review. Ageing Res Rev 2014; 14:65-80. [PMID: 24548926 DOI: 10.1016/j.arr.2014.02.003] [Citation(s) in RCA: 172] [Impact Index Per Article: 15.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/09/2013] [Revised: 02/05/2014] [Accepted: 02/06/2014] [Indexed: 01/10/2023]
Abstract
As for the whole human body, the kidney undergoes age-related changes which translate in an inexorable and progressive decline in renal function. Renal aging is a multifactorial process where gender, race and genetic background and several key-mediators such as chronic inflammation, oxidative stress, the renin-angiotensin-aldosterone (RAAS) system, impairment in kidney repair capacities and background cardiovascular disease play a significant role. Features of the aging kidney include macroscopic and microscopic changes and important functional adaptations, none of which is pathognomonic of aging. The assessment of renal function in the framework of aging is problematic and the question whether renal aging should be considered as a physiological or pathological process remains a much debated issue. Although promising dietary and pharmacological approaches have been tested to retard aging processes or renal function decline in the elderly, proper lifestyle modifications, as those applicable to the general population, currently represent the most plausible approach to maintain kidney health.
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Nishiyama Y, Otsuka T, Ueda M, Inagaki H, Muraga K, Abe A, Kawada T, Katayama Y. Asymmetric dimethylarginine is related to the predicted stroke risk in middle-aged Japanese men. J Neurol Sci 2014; 338:87-91. [DOI: 10.1016/j.jns.2013.12.021] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/13/2013] [Revised: 12/11/2013] [Accepted: 12/11/2013] [Indexed: 09/30/2022]
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Alonso-Bouzón C, Carcaillon L, García-García FJ, Amor-Andrés MS, El Assar M, Rodríguez-Mañas L. Association between endothelial dysfunction and frailty: the Toledo Study for Healthy Aging. AGE (DORDRECHT, NETHERLANDS) 2014; 36:495-505. [PMID: 23959520 PMCID: PMC3889911 DOI: 10.1007/s11357-013-9576-1] [Citation(s) in RCA: 63] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 11/14/2012] [Accepted: 07/31/2013] [Indexed: 06/02/2023]
Abstract
Cardiovascular disease (CVD), both clinical and subclinical, has been proposed as one of the mechanisms underlying frailty. However, there is no evidence addressing the relationship between the earliest stage of CVD (endothelial dysfunction) and frailty. The goal of the study was to analyze the association between endothelial dysfunction, evaluated by asymmetric dimethylarginine (ADMA) levels, and frailty. We used data from the Toledo Study for Healthy Aging, a prospective Spanish cohort study. Biological samples were obtained and ADMA levels were determined using an enzyme immunoassay method. Logistic regression was used to estimate the odds ratio (OR) and 95 % confidence intervals of frailty associated with ADMA. Adjustments were made for age, gender, cardiovascular risk factors, and presence of atherosclerotic disease (assessed by ankle–brachial index; ABI). One thousand two hundred eighty-seven community-dwelling elderly were included. One hundred seven (8.3 %) were identified as frail, 542 (42.1 %) as pre-frail, and 638 (49.6 %) as non-frail. ADMAvalues were higher in frail subjects than in non-frail ones. In addition, an interaction between the presence of atherosclerotic disease and ADMA on the odds of frailty (p=0.045) was detected. After adjustments for age, classical cardiovascular risk factors, and ABI, the risk of frailty was associated with increasing levels of ADMA in subjects without atherosclerotic disease [OR for 1 standard deviation increase in ADMA=1.14 (1.01–1.28), p=0.032] but not in those with atherosclerotic disease. In our study, endothelial dysfunction, assessed by ADMA levels, is associated with frailty. These findings provide additional support for a relevant role of vascular system since its earliest stage in frailty.
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Affiliation(s)
- Cristina Alonso-Bouzón
- />Geriatric Department, Hospital Universitario de Getafe, Carretera de Toledo, Km, 12.500, 28905 Getafe, Madrid Spain
| | - Laure Carcaillon
- />Inserm, CESP Centre for Research in Epidemiology and Population Health, U1018, Hormones and Cardiovascular Disease Team, 94807 Villejuif, France
| | | | - María S. Amor-Andrés
- />Geriatric Department, Hospital Virgen del Valle, Complejo Hospitalario de Toledo, Toledo, Spain
| | - Mariam El Assar
- />Fundación para la Investigación Biomédica del Hospital Universitario de Getafe, Madrid, Spain
| | - Leocadio Rodríguez-Mañas
- />Geriatric Department, Hospital Universitario de Getafe, Carretera de Toledo, Km, 12.500, 28905 Getafe, Madrid Spain
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