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Mlejnek P, Liška F, Šilhavý J, Večerková K, Šimáková M, Pravenec M, Kurtz TW. Early reduction of skin potassium without sodium accumulation in the pathogenesis of salt sensitivity in primary aldosteronism. Front Pharmacol 2025; 16:1575972. [PMID: 40365307 PMCID: PMC12069341 DOI: 10.3389/fphar.2025.1575972] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/13/2025] [Accepted: 04/10/2025] [Indexed: 05/15/2025] Open
Abstract
Introduction Primary aldosteronism is the most common form of secondary hypertension and blood pressure salt sensitivity. In the setting of hyperaldosteronism and a high-salt diet, disturbances in tissue sodium and potassium levels may contribute to salt sensitivity. This study aimed to determine whether aldosterone-dependent changes in tissue and plasma sodium and potassium concentrations occur before or after the development of salt sensitivity and hypertension in a rat model of primary aldosteronism. Previous studies in this model show that aldosterone-dependent salt sensitivity develops after 7-10 days on a high-salt diet. A secondary objective was to investigate differences in skin gene expression between aldosterone-treated rats and vehicle-treated controls. Methods Unilaterally nephrectomized male Sprague-Dawley rats received continuous infusions of aldosterone or vehicle while being fed a high-salt diet. Electrolyte concentrations in plasma, carcass, and skin were measured after 2 and 14 days of high-salt feeding. Tissue sodium and potassium concentrations were determined by atomic absorption spectroscopy and expressed as mmol/g tissue dry weight, while plasma ions (mmol/L) were measured using ion-selective electrodes. RNA sequencing (RNAseq) was used to identify differentially expressed genes in the skin, and gene set enrichment analysis (GSEA) was performed to explore biological processes associated with aldosterone treatment. Results After 2 days on the high-salt diet, aldosterone-treated rats showed significantly lower skin and plasma potassium concentrations compared to vehicle-treated controls, while sodium concentrations in the carcass, skin, and plasma did not differ significantly. At 14 days, aldosterone-treated rats continued to exhibit lower plasma potassium levels, although skin potassium differences were no longer significant. Carcass sodium concentrations were significantly higher in aldosterone-treated rats at 14 days. GSEA revealed that, at 2 days, aldosterone treatment affected biological processes related to electrolyte homeostasis and hyperosmotic responses. At 14 days, biological processes related to muscle function and calcium ion transport were significantly altered. Conclusion Aldosterone-treated rats on a high-salt diet for 2 days had lower skin and plasma potassium levels compared to salt-loaded controls, suggesting early potassium depletion precedes significant sodium accumulation and blood pressure increases. These findings raise the possibility that early potassium depletion contributes to the development of aldosterone-induced salt sensitivity. Further studies with detailed time-course analysis will be of interest to elucidate the role of early potassium depletion in increasing vascular resistance and triggering aldosterone-dependent salt sensitivity and hypertension.
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Affiliation(s)
- Petr Mlejnek
- Institute of Physiology, Czech Academy of Sciences, Prague, Czechia
| | - František Liška
- Institute of Physiology, Czech Academy of Sciences, Prague, Czechia
- Institute of Biology and Medical Genetics, First Faculty of Medicine, Charles University and General University Hospital, Prague, Czechia
| | - Jan Šilhavý
- Institute of Physiology, Czech Academy of Sciences, Prague, Czechia
| | - Kateřina Večerková
- Laboratory of Genomics and Bioinformatics, Institute of Molecular Genetics, Czech Academy of Sciences, Prague, Czechia
- Department of Informatics and Chemistry, University of Chemistry and Technology, Prague, Czechia
| | | | - Michal Pravenec
- Institute of Physiology, Czech Academy of Sciences, Prague, Czechia
- Institute of Biology and Medical Genetics, First Faculty of Medicine, Charles University and General University Hospital, Prague, Czechia
| | - Theodore W. Kurtz
- Department of Laboratory Medicine, University of California, San Francisco, San Francisco, CA, United States
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Napiórkowska-Baran K, Treichel P, Dardzińska A, Majcherczak A, Pilichowicz A, Szota M, Szymczak B, Alska E, Przybyszewska J, Bartuzi Z. Immunomodulatory Effects of Selected Non-Nutritive Bioactive Compounds and Their Role in Optimal Nutrition. Curr Issues Mol Biol 2025; 47:89. [PMID: 39996810 PMCID: PMC11854453 DOI: 10.3390/cimb47020089] [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: 12/19/2024] [Revised: 01/24/2025] [Accepted: 01/27/2025] [Indexed: 02/26/2025] Open
Abstract
The contemporary approach to nutrition increasingly considers the role of non-nutritive bioactive compounds in modulating the immune system and maintaining health. This article provides up-to-date insight into the immunomodulatory effects of selected bioactive compounds, including micro- and macronutrients, vitamins, as well as other health-promoting substances, such as omega-3 fatty acids, probiotics, prebiotics, postbiotics (including butyric acid and sodium butyrate), coenzyme Q10, lipoic acid, and plant-derived components such as phenolic acids, flavonoids, coumarins, alkaloids, polyacetylenes, saponins, carotenoids, and terpenoids. Micro- and macronutrients, such as zinc, selenium, magnesium, and iron, play a pivotal role in regulating the immune response and protecting against oxidative stress. Vitamins, especially vitamins C, D, E, and B, are vital for the optimal functioning of the immune system as they facilitate the production of cytokines, the differentiation of immunological cells, and the neutralization of free radicals, among other functions. Omega-3 fatty acids exhibit strong anti-inflammatory effects and enhance immune cell function. Probiotics, prebiotics, and postbiotics modulate the intestinal microbiota, thereby promoting the integrity of the intestinal barrier and communication between the microbiota and the immune system. Coenzyme Q10, renowned for its antioxidant attributes, participates in the protection of cells from oxidative stress and promotes energy processes essential for immune function. Sodium butyrate and lipoic acid exhibit anti-inflammatory effects and facilitate the regeneration of the intestinal epithelium, which is crucial for the maintenance of immune homeostasis. This article emphasizes the necessity of an integrative approach to optimal nutrition that considers not only nutritional but also non-nutritional bioactive compounds to provide adequate support for immune function. Without them, the immune system will never function properly, because it has been adapted to this in the course of evolution. The data presented in this article may serve as a foundation for further research into the potential applications of bioactive components in the prevention and treatment of diseases associated with immune dysfunction.
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Affiliation(s)
- Katarzyna Napiórkowska-Baran
- Department of Allergology, Clinical Immunology and Internal Diseases, Collegium Medicum Bydgoszcz, Nicolaus Copernicus University Torun, 85-067 Bydgoszcz, Poland; (M.S.); (E.A.); (Z.B.)
| | - Paweł Treichel
- Student Research Club of Clinical Immunology, Department of Allergology, Clinical Immunology and Internal Diseases, Collegium Medicum Bydgoszcz, Nicolaus Copernicus University Torun, 85-067 Bydgoszcz, Poland; (P.T.); (A.D.); (A.M.); (A.P.); (B.S.)
| | - Anita Dardzińska
- Student Research Club of Clinical Immunology, Department of Allergology, Clinical Immunology and Internal Diseases, Collegium Medicum Bydgoszcz, Nicolaus Copernicus University Torun, 85-067 Bydgoszcz, Poland; (P.T.); (A.D.); (A.M.); (A.P.); (B.S.)
| | - Agata Majcherczak
- Student Research Club of Clinical Immunology, Department of Allergology, Clinical Immunology and Internal Diseases, Collegium Medicum Bydgoszcz, Nicolaus Copernicus University Torun, 85-067 Bydgoszcz, Poland; (P.T.); (A.D.); (A.M.); (A.P.); (B.S.)
| | - Anastazja Pilichowicz
- Student Research Club of Clinical Immunology, Department of Allergology, Clinical Immunology and Internal Diseases, Collegium Medicum Bydgoszcz, Nicolaus Copernicus University Torun, 85-067 Bydgoszcz, Poland; (P.T.); (A.D.); (A.M.); (A.P.); (B.S.)
| | - Maciej Szota
- Department of Allergology, Clinical Immunology and Internal Diseases, Collegium Medicum Bydgoszcz, Nicolaus Copernicus University Torun, 85-067 Bydgoszcz, Poland; (M.S.); (E.A.); (Z.B.)
| | - Bartłomiej Szymczak
- Student Research Club of Clinical Immunology, Department of Allergology, Clinical Immunology and Internal Diseases, Collegium Medicum Bydgoszcz, Nicolaus Copernicus University Torun, 85-067 Bydgoszcz, Poland; (P.T.); (A.D.); (A.M.); (A.P.); (B.S.)
| | - Ewa Alska
- Department of Allergology, Clinical Immunology and Internal Diseases, Collegium Medicum Bydgoszcz, Nicolaus Copernicus University Torun, 85-067 Bydgoszcz, Poland; (M.S.); (E.A.); (Z.B.)
| | - Justyna Przybyszewska
- Department of Nutrition and Dietetics, Collegium Medicum Bydgoszcz, Nicolaus Copernicus University Torun, 85-067 Bydgoszcz, Poland;
| | - Zbigniew Bartuzi
- Department of Allergology, Clinical Immunology and Internal Diseases, Collegium Medicum Bydgoszcz, Nicolaus Copernicus University Torun, 85-067 Bydgoszcz, Poland; (M.S.); (E.A.); (Z.B.)
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Malta D, Esfandiari S, Goldraich LA, Allard JP, Newton GE. Postprandial Vascular Effects of a High Potassium Meal in Patients with Treated Hypertension. Nutrients 2024; 17:45. [PMID: 39796479 PMCID: PMC11723007 DOI: 10.3390/nu17010045] [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: 11/14/2024] [Revised: 12/09/2024] [Accepted: 12/18/2024] [Indexed: 01/13/2025] Open
Abstract
BACKGROUND There is compelling evidence of an inverse association between potassium intake and blood pressure (BP). A potential mechanism for this effect may be dietary potassium-mediated augmentation of endothelium-dependent relaxation. To date, studies have investigated potassium intake supplementation over several weeks in healthy volunteers with variable results on vascular function. There is no assessment of the acute vascular effects of potassium supplementation achieved by the ingestion of potassium-rich food in a hypertensive population. OBJECTIVE The purpose of this study was to investigate the effect of a high potassium meal on postprandial endothelial function as measured by flow-mediated dilatation (FMD). METHODS We performed an investigator-blinded randomized crossover trial in 33 treated hypertensive individuals. Participants consumed both a high (~2400 mg) and low (~543 mg) K+ meal, separated by a one-week washout period. The primary endpoint was endothelial function as assessed by FMD pre-meal and postprandially at 60 and 120 min. Meals were compared at each time point using the Hills-Armitage approach. RESULTS 33 individuals were included in the study (48% male, mean age 68). In the fasting state (Baseline), and at 60 min postprandial, radial artery FMD was not significantly different between the participants after consumption of either meal (baseline: high K+ 4.2 ± 2% versus Low K+ 2.6 ± 3%, p = 0.93; 60 min: high K+ 3.8 ± 4% versus Low K+ 4.1 ± 3%, p = 0.69). However, at 120 min, FMD tended to be higher in participants after the high K+ meal (5.2 ± 4.1%) than after the low K+ meal (3.9 ± 4.1%) (p = 0.07). There were no differences in participants' radial artery diameter and blood flow between meals. CONCLUSIONS This study does not support our hypothesis that a single high K+ meal improves vascular function in individuals with treated hypertension. This does not contradict the clinical evidence relating greater K+ intake with lower BP, but suggests that mechanistic investigations of increased K+ intake through diet alone and its impact on endothelial function as a mediator to reducing BP are complex and not simply due to single nutrient-mediated improvement in vascular function.
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Affiliation(s)
- Daniela Malta
- School of Nutrition, Toronto Metropolitan University, 350 Victoria St., Toronto, ON M5B 2K3, Canada
| | - Sam Esfandiari
- Institute of Medical Science, University of Toronto, 1 King’s College Circle, Toronto, ON M5S 1A8, Canada; (S.E.); (G.E.N.)
- Division of Cardiology, Department of Medicine, Sinai Health System, 600 University Avenue, Suite 427, Toronto, ON M5G 1X5, Canada
| | - Livia A. Goldraich
- Division of Cardiology, Hospital de Clinicas de Porto Alegre, Porto Alegre 90035-903, Brazil;
| | - Johane P. Allard
- Department of Nutritional Sciences, University of Toronto, Fitzgerald Building, 150 College Street, Toronto, ON M5S 3E2, Canada;
- Division of Gastroenterology, Department of Medicine, Toronto General Hospital, 9N-973, 585 University Avenue, Toronto, ON M5G 2N2, Canada
| | - Gary E. Newton
- Institute of Medical Science, University of Toronto, 1 King’s College Circle, Toronto, ON M5S 1A8, Canada; (S.E.); (G.E.N.)
- Division of Cardiology, Department of Medicine, Sinai Health System, 600 University Avenue, Suite 427, Toronto, ON M5G 1X5, Canada
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Chen B, Wang C, Li W. Genetic insights into the effect of trace elements on cardiovascular diseases: multi-omics Mendelian randomization combined with linkage disequilibrium score regression analysis. Front Immunol 2024; 15:1459465. [PMID: 39691718 PMCID: PMC11649655 DOI: 10.3389/fimmu.2024.1459465] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/04/2024] [Accepted: 11/19/2024] [Indexed: 12/19/2024] Open
Abstract
Objective Epidemiological evidence indicates that trace elements are significantly associated with cardiovascular health. However, its causality and underlying mechanisms remain unclear. Therefore, this study aimed to investigate the causal relationship between trace elements and cardiovascular disease, as well as their potential mechanism of action. Method Two-sample Mendelian randomization (MR) analyses along with mediated and multivariate MR analyses were employed. These analyses utilized 13 trace elements as exposure variables and 20 cardiovascular diseases as outcome variables, with 4907 circulating plasma proteins, 1400 serum metabolites, 731 immune cell phenotypes, and 473 intestinal flora as potential mediators. The Bayesian weighted MR method was used to validate the MR results, and linkage disequilibrium score regression (LDSC) was applied to explore the genetic correlation between trace elements and cardiovascular disease. Result Our findings indicated a positive or negative causal relationship between genetically predicted trace elements and cardiovascular disease. An analysis using the Bayesian weighted MR method demonstrated that our causal inference results were reliable. The results of the mediated MR analyses indicate that potassium may reduce the risk of ischemic heart disease by influencing the expression of the plasma proteins BDH2 and C1R. Vitamin B12 may increase the risk of coronary atherosclerosis and cardiovascular death by reducing the levels of VPS29 and PSME1 proteins, while vitamin C may mitigate the risk of cardiac arrest by inhibiting the expression of the TPST2 protein. In addition, potassium can reduce the risk of ischemic heart disease by lowering 4-methoxyphenyl sulfate levels. None of the instrumental variables exhibited pleiotropy in the MR analysis. A sensitivity analysis using the leave-one-out method further confirmed the robustness of our findings. LDSC results indicated a genetic correlation between multiple trace elements and various cardiovascular diseases. Conclusion This study uncovered the true causal relationship between trace elements and cardiovascular disease risk using genetic methods, and revealed the significant mediating role of specific plasma proteins and metabolites in this relationship.
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Affiliation(s)
- Bohang Chen
- The First Clinical Medical College, Liaoning University of Traditional Chinese Medicine, Shenyang, Liaoning, China
| | - Chuqiao Wang
- The Department of Endocrinology, Liaoning Health Industry Group Fukuang General Hospital, Fushun, Liaoning, China
| | - Wenjie Li
- The Department of Cardiovascular Medicine, Affiliated Hospital of Liaoning University of Traditional Chinese Medicine, Shenyang, Liaoning, China
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Farapti F, Putri SA, Furqonia AW, Rejeki PS, Miftahussurur M. High Potassium Diet Rich in Spices and Herbs-Salt Substitution (HPSH-SS) for Blood Pressure Reduction in Older Adults: Protocol for Diet Concept and Randomized Controlled Trial. JMIR Res Protoc 2024; 13:e56869. [PMID: 39470696 PMCID: PMC11558212 DOI: 10.2196/56869] [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: 01/29/2024] [Revised: 04/25/2024] [Accepted: 07/24/2024] [Indexed: 10/30/2024] Open
Abstract
BACKGROUND Hypertension increases with age, often due to high sodium (Na) and low potassium (K) intake. Reducing salt and increasing K intake is challenging, especially for older adults due to taste preferences. Culinary herbs and spices, rich in K, offer a potential solution. The High Potassium Diet Rich in Spices and Herbs-Salt Substitution (HPSH-SS) diet has not yet been studied for its effectiveness in lowering blood pressure. OBJECTIVE This study aims to create an HPSH-SS diet, analyze its effects on blood pressure in older adults, and study the molecular mechanism occurring in the kidneys and blood vessels influenced by this diet. METHODS This study consists of 2 phases. The first phase involved formulating and assessing the HPSH-SS diet tailored for older adults. The intervention group (IG) received a diet of 1800 kcal/day, with 3500 mg K and 1500 mg Na, while the control group (CG) received 1500 mg K and 2000 mg Na. The diet was administered for 14 days and standardized using the NutriSurvey program and biochemistry analysis by atomic absorbance spectrophotometry (AAS). The second phase was a 14-day parallel randomized controlled trial (RCT) with the older adult participants divided into IG and CG. Primary outcomes included blood pressure; serum potassium; aldosterone; F2 isoprostane; nitric oxide plasma levels; and urine analysis of Na, K, and the Na/K ratio. Confounding variables were controlled through randomization and stratified analysis. RESULTS The menu formulation and organoleptic assessment of the HPSH-SS diet began in mid-2022 and was approved by the Ethics Committee of the Faculty of Public Health at Universitas Airlangga (78/EA/KEPK/2022) on May 11, 2022. The diet was standardized to achieve daily nutritional values of 1800 kcal energy, 3500 mg K, and 1500 mg Na. K and Na contents were analyzed using AAS from several participants' spice diet menus. Recruitment for the RCT started in March 2023, with approval from the Health Research Ethics Committee Universitas Airlangga School of Medicine, Surabaya (35/EC/KEPK/FKUA/2023). The study was registered from February 9, 2023, to February 9, 2024. Between March and June 2023, 64 participants were recruited, with 32 participants in the IG and CG. The intervention and data collection will take place over 1 year. Data management is in progress, and data analysis is yet to be performed. CONCLUSIONS This RCT protocol hypothesizes that the diet will increase serum K, plasma aldosterone, and nitric oxide levels; decrease plasma F2 isoprostane; increase urinary Na and K levels; lower the urinary Na/K ratio; and reduce systolic and diastolic blood pressure. If effective, it will offer valuable insights into dietary strategies for blood pressure regulation in older adults. INTERNATIONAL REGISTERED REPORT IDENTIFIER (IRRID) DERR1-10.2196/56869.
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Affiliation(s)
- Farapti Farapti
- Department of Nutrition, Faculty of Public Health, Universitas Airlangga, Surabaya, Indonesia
- Doctoral Program of Medical Science, Faculty of Medicine, Universitas Airlangga, Surabaya, Indonesia
| | - Sheila Amara Putri
- Department of Nutrition, Faculty of Public Health, Universitas Airlangga, Surabaya, Indonesia
| | - Annisaa Wulida Furqonia
- Department of Nutrition, Faculty of Public Health, Universitas Airlangga, Surabaya, Indonesia
- Government of Sobrah Village, Wungu District, Madiun Regency, Indonesia
| | - Purwo Sri Rejeki
- Department of Physiology, Faculty of Medicine, Universitas Airlangga, Surabaya, Indonesia
| | - Muhammad Miftahussurur
- Gastroentero-Hepatology Division, Department of Internal Medicine, Dr Soetomo Teaching Hospital, Surabaya, Indonesia
- Institute of Tropical Disease, Universitas Airlangga, Surabaya, Indonesia
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Li K, Li Y, Chen Y, Chen T, Yang Y, Li P. Ion Channels Remodeling in the Regulation of Vascular Hyporesponsiveness During Shock. Microcirculation 2024; 31:e12874. [PMID: 39011763 DOI: 10.1111/micc.12874] [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: 07/19/2023] [Revised: 04/07/2024] [Accepted: 06/16/2024] [Indexed: 07/17/2024]
Abstract
Shock is characterized with vascular hyporesponsiveness to vasoconstrictors, thereby to cause refractory hypotension, insufficient tissue perfusion, and multiple organ dysfunction. The vascular hyporeactivity persisted even though norepinephrine and fluid resuscitation were administrated, it is of critical importance to find new potential target. Ion channels are crucial in the regulation of cell membrane potential and affect vasoconstriction and vasodilation. It has been demonstrated that many types of ion channels including K+ channels, Ca2+ permeable channels, and Na+ channels exist in vascular smooth muscle cells and endothelial cells, contributing to the regulation of vascular homeostasis and vasomotor function. An increasing number of studies suggested that the structural and functional alterations of ion channels located in arteries contribute to vascular hyporesponsiveness during shock, but the underlying mechanisms remained to be fully clarified. Therefore, the expression and functional changes in ion channels in arteries associated with shock are reviewed, to pave the way for further exploring the potential of ion channel-targeted compounds in treating refractory hypotension in shock.
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Affiliation(s)
- Keqing Li
- The Key Laboratory of Medical Electrophysiology, Ministry of Education and Medical Electrophysiological Key Lab of Sichuan Province, Institute of Cardiovascular Research, Southwest Medical University, Luzhou, Sichuan, China
| | - Yuan Li
- The Key Laboratory of Medical Electrophysiology, Ministry of Education and Medical Electrophysiological Key Lab of Sichuan Province, Institute of Cardiovascular Research, Southwest Medical University, Luzhou, Sichuan, China
| | - Yinghong Chen
- The Key Laboratory of Medical Electrophysiology, Ministry of Education and Medical Electrophysiological Key Lab of Sichuan Province, Institute of Cardiovascular Research, Southwest Medical University, Luzhou, Sichuan, China
| | - Tangting Chen
- The Key Laboratory of Medical Electrophysiology, Ministry of Education and Medical Electrophysiological Key Lab of Sichuan Province, Institute of Cardiovascular Research, Southwest Medical University, Luzhou, Sichuan, China
| | - Yan Yang
- The Key Laboratory of Medical Electrophysiology, Ministry of Education and Medical Electrophysiological Key Lab of Sichuan Province, Institute of Cardiovascular Research, Southwest Medical University, Luzhou, Sichuan, China
| | - Pengyun Li
- The Key Laboratory of Medical Electrophysiology, Ministry of Education and Medical Electrophysiological Key Lab of Sichuan Province, Institute of Cardiovascular Research, Southwest Medical University, Luzhou, Sichuan, China
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Abstract
Excessive salt intake raises blood pressure, but the implications of this observation for human health have remained contentious. It has also been recognized for many years that potassium intake may mitigate the effects of salt intake on blood pressure and possibly on outcomes such as stroke. Recent large randomized intervention trials have provided strong support for the benefits of replacing salt (NaCl) with salt substitute (75% NaCl, 25% KCl) on hard outcomes, including stroke. During the same period of time, major advances have been made in understanding how the body senses and tastes salt, and how these sensations drive intake. Additionally, new insights into the complex interactions between systems that control sodium and potassium excretion by the kidneys, and the brain have highlighted the existence of a potassium switch in the kidney distal nephron. This switch seems to contribute importantly to the blood pressure-lowering effects of potassium intake. In recognition of these evolving data, the United States Food and Drug Administration is moving to permit potassium-containing salt substitutes in food manufacturing. Given that previous attempts to reduce salt consumption have not been successful, this new approach has a chance of improving health and ending the 'Salt Wars'.
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Affiliation(s)
- Robert Little
- Department of Biomedicine, Aarhus University, Aarhus, Denmark
- LeDucq Transatlantic Network of Excellence
| | - David H. Ellison
- Division of Nephrology and Hypertension, Department of Medicine, Oregon Health and Science University, Portland, Oregon, USA
- Oregon Clinical & Translational Research Institute, Oregon Health & Science University, Portland, Oregon, USA
- LeDucq Transatlantic Network of Excellence
- VA Portland Health Care System, Portland, OR
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Abstract
Salt (sodium chloride) is an essential nutrient required to maintain physiological functions. However, for most people, daily salt intake far exceeds their physiological need and is habitually greater than recommended upper thresholds. Excess salt intake leads to elevation in blood pressure which drives cardiovascular morbidity and mortality. Indeed, excessive salt intake is estimated to be responsible for ≈5 million deaths per year globally. For approximately one-third of otherwise healthy individuals (and >50% of those with hypertension), the effect of salt intake on blood pressure elevation is exaggerated; such people are categorized as salt sensitive and salt sensitivity of blood pressure is considered an independent risk factor for cardiovascular disease and death. The prevalence of salt sensitivity is higher in women than in men and, in both, increases with age. This narrative review considers the foundational concepts of salt sensitivity and the underlying effector systems that cause salt sensitivity. We also consider recent updates in preclinical and clinical research that are revealing new modifying factors that determine the blood pressure response to high salt intake.
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Affiliation(s)
- Matthew A Bailey
- Edinburgh Kidney, University/BHF Centre for Cardiovascular Science, The Queen's Medical Research Institute, University of Edinburgh, United Kingdom (M.A.B., N.D.)
| | - Neeraj Dhaun
- Edinburgh Kidney, University/BHF Centre for Cardiovascular Science, The Queen's Medical Research Institute, University of Edinburgh, United Kingdom (M.A.B., N.D.)
- Department of Renal Medicine, Royal Infirmary of Edinburgh, United Kingdom (N.D.)
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Deng CY, Ke XP, Guo XG. Dietary calcium, phosphorus, and potassium intake associated with erectile dysfunction in the National Health and Nutrition Examination Survey (NHANES) 2001 to 2004. PLoS One 2024; 19:e0297129. [PMID: 38381721 PMCID: PMC10880986 DOI: 10.1371/journal.pone.0297129] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/30/2023] [Accepted: 12/28/2023] [Indexed: 02/23/2024] Open
Abstract
BACKGROUND Erectile dysfunction is now a common disorder of sexual function, and its relationship to dietary calcium, phosphorus, and potassium has not been well studied. We set out to determine if dietary intakes of calcium, phosphorus, and potassium are related to erectile dysfunction in U.S. men. METHODS For this cross-sectional investigation, we used data from NHANES 2001-2004. To investigate the connection of dietary calcium, phosphorus, and potassium intake with erectile dysfunction, we employed multivariate logistic regression, smoothed curve fitting, and subgroup analysis. RESULTS This cross-sectional study comprised 3,556 eligible male subjects in total, with a weighted mean age of 49.93±18.13 years. After controlling for race and age, the greatest tertile of calcium consumption was found to have a 34% lower risk of erectile dysfunction than the lowest tertile (OR = 0.66; 95% CI = 0.52-0.84; p = 0.0006). The risk of erectile dysfunction was found to be reduced by 33% (OR = 0.67; 95% CI = 0.52-0.87; p = 0.0024) for the highest tertile of phosphorus intake compared to the lowest tertile of phosphorus intake and by 35% (OR = 0.65; 95% CI = 0.50-0.83; p = 0.0006) for the highest tertile of potassium intake compared to the lowest tertile of potassium intake in the fully adjusted model. CONCLUSION Erectile dysfunction and dietary consumption of calcium, phosphorus, and potassium are inversely associated with the U.S. population. To confirm the accuracy of our findings, additional prospective studies are necessary. Furthermore, it is imperative to do further fundamental research at the molecular level to gain a deeper understanding of the underlying mechanisms.
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Affiliation(s)
- Chen-Yuan Deng
- Department of Clinical Laboratory Medicine, Guangdong Provincial Key Laboratory of Major Obstetric Diseases, Guangdong Provincial Clinical Research Center for Obstetrics and Gynecology, The Third Affiliated Hospital of Guangzhou Medical University, Guangzhou, China
- Department of Clinical Medicine, The Third Clinical School of Guangzhou Medical University, Guangzhou, China
| | - Xin-Peng Ke
- Department of Clinical Medicine, The Third Clinical School of Guangzhou Medical University, Guangzhou, China
| | - Xu-Guang Guo
- Department of Clinical Laboratory Medicine, Guangdong Provincial Key Laboratory of Major Obstetric Diseases, Guangdong Provincial Clinical Research Center for Obstetrics and Gynecology, The Third Affiliated Hospital of Guangzhou Medical University, Guangzhou, China
- Department of Clinical Medicine, The Third Clinical School of Guangzhou Medical University, Guangzhou, China
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Sala C, Rescaldani M, Gherbesi E, Bolla G, Cuspidi C, Ruscica M, Carugo S. Platelet Cyclic GMP Levels Are Reduced in Patients with Primary Aldosteronism. J Clin Med 2023; 12:7081. [PMID: 38002693 PMCID: PMC10672647 DOI: 10.3390/jcm12227081] [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: 08/29/2023] [Revised: 10/26/2023] [Accepted: 11/10/2023] [Indexed: 11/26/2023] Open
Abstract
BACKGROUND AND AIM Nitric oxide inhibits platelet aggregation by increasing the second messenger cyclic guanosine-3',5'-monophosphate (cGMP) through the activation of soluble guanylyl cyclase in target cells. Within this context, the oxidative stress associated with the aldosterone excess impairs the nitric oxide availability. Thus, the aim of the present study was to assess the impact of chronic aldosterone excess on the platelet nitric oxide/cGMP pathway in humans. METHODS The levels of cGMP were evaluated in platelets of male patients, 12 with primary aldosteronism (PA) and 32 with uncomplicated essential hypertension (EH), matched for age and blood pressure (BP) values. RESULTS PA and EH patients were 52.8 ± 3 years old and 51.6 ± 1.6 years old, respectively. Systolic and diastolic BP were 158 ± 5.0 mmHg and 105.9 ± 2.3 mmHg in PA and did not differ compared to EH patients (156.6 ± 2.4 mmHg and 104.7 ± 1.2 mmHg). Mean aldosterone levels were significantly higher in PA (25.5 ± 8.8 ng/dL) compared toEH (8.11 ± 0.73 ng/dL), whereas potassium was significantly lower in PA (3.52 ± 0.18 mEq/L) compared to EH (4.08 ± 0.04 mEq/L). Aldosterone and potassium were inversely related (r = -0.49, p = 0.0006) in the whole study population (n = 44). Platelet cGMP was significantly lower in PA (5.1 ± 0.36 pM/109 cells) than in EH (7.1 ± 0.53 pM/109 cells), and in the entire study cohort, it was directly related to plasma potassium (r = 0.43, p = 0.0321). CONCLUSIONS These results show an impairment of nitric oxide/cGMP signaling in platelets of PA patients. This effect is likely related to the potassium-depleting effect of chronic aldosterone excess. Future studies are needed to understand whether the platelet nitric oxide/cGMP system is involved in the atherothrombotic events in these patients.
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Affiliation(s)
- Carla Sala
- Department of Cardio-Thoracic-Vascular Diseases, Foundation IRCCS Ca’ Granda Ospedale Maggiore Policlinico, 20122 Milan, Italy (G.B.); (S.C.)
- Department of Clinical Sciences and Community Health, University of Milan, 20122 Milan, Italy
| | - Marta Rescaldani
- Cardiovascular Department, Association Socio Sanitary Territorial Santi Paolo e Carlo, 20153 Milan, Italy;
| | - Elisa Gherbesi
- Department of Cardio-Thoracic-Vascular Diseases, Foundation IRCCS Ca’ Granda Ospedale Maggiore Policlinico, 20122 Milan, Italy (G.B.); (S.C.)
| | - Gianni Bolla
- Department of Cardio-Thoracic-Vascular Diseases, Foundation IRCCS Ca’ Granda Ospedale Maggiore Policlinico, 20122 Milan, Italy (G.B.); (S.C.)
- Department of Clinical Sciences and Community Health, University of Milan, 20122 Milan, Italy
| | - Cesare Cuspidi
- Department of Medicine and Surgery, University of Milano-Bicocca, 20126 Milan, Italy;
| | - Massimiliano Ruscica
- Department of Cardio-Thoracic-Vascular Diseases, Foundation IRCCS Ca’ Granda Ospedale Maggiore Policlinico, 20122 Milan, Italy (G.B.); (S.C.)
- Department of Pharmacological and Biomolecular Sciences “Rodolfo Paoletti”, University of Milan, 20122 Milan, Italy
| | - Stefano Carugo
- Department of Cardio-Thoracic-Vascular Diseases, Foundation IRCCS Ca’ Granda Ospedale Maggiore Policlinico, 20122 Milan, Italy (G.B.); (S.C.)
- Department of Clinical Sciences and Community Health, University of Milan, 20122 Milan, Italy
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11
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Afsar B, Afsar RE. The role of glycosaminoglycans in blood pressure regulation. Microcirculation 2023; 30:e12832. [PMID: 37794746 DOI: 10.1111/micc.12832] [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: 02/01/2023] [Revised: 05/06/2023] [Accepted: 09/23/2023] [Indexed: 10/06/2023]
Abstract
Essential hypertension (HT) is the global health problem and is a major risk factor for the development of cardiovascular and kidney disease. High salt intake has been associated with HT and impaired kidney sodium excretion is considered to be a major mechanism for the development of HT. Although kidney has a very important role in regulation of BP, this traditional view of BP regulation was challenged by recent findings suggesting that nonosmotic tissue sodium deposition is very important for BP regulation. This new paradigm indicates that sodium can be stored and deposited nonosmotically in the interstitium without water retention and without increased BP. One of the major determinants of this deposition is glycosaminoglycans (GAGs). By binding to GAGs found in the endothelial surface layer (ESL) which contains glycocalyx, sodium is osmotically inactivated and not induce concurrent water retention. Thus, GAGs has important function for homeostatic BP and sodium regulation. In the current review, we summarized the role of GAGs in ESL and BP regulation.
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Affiliation(s)
- Baris Afsar
- School of Medicine, Department of Nephrology, Suleyman Demirel University, Isparta, Turkey
| | - Rengin Elsurer Afsar
- School of Medicine, Department of Nephrology, Suleyman Demirel University, Isparta, Turkey
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12
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Kettritz R, Loffing J. Potassium homeostasis - Physiology and pharmacology in a clinical context. Pharmacol Ther 2023; 249:108489. [PMID: 37454737 DOI: 10.1016/j.pharmthera.2023.108489] [Citation(s) in RCA: 14] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/15/2023] [Revised: 07/03/2023] [Accepted: 07/06/2023] [Indexed: 07/18/2023]
Abstract
Membrane voltage controls the function of excitable cells and is mainly a consequence of the ratio between the extra- and intracellular potassium concentration. Potassium homeostasis is safeguarded by balancing the extra-/intracellular distribution and systemic elimination of potassium to the dietary potassium intake. These processes adjust the plasma potassium concentration between 3.5 and 4.5 mmol/L. Several genetic and acquired diseases but also pharmacological interventions cause dyskalemias that are associated with increased morbidity and mortality. The thresholds at which serum K+ not only associates but also causes increased mortality are hotly debated. We discuss physiologic, pathophysiologic, and pharmacologic aspects of potassium regulation and provide informative case vignettes. Our aim is to help clinicians, epidemiologists, and pharmacologists to understand the complexity of the potassium homeostasis in health and disease and to initiate appropriate treatment strategies in dyskalemic patients.
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Affiliation(s)
- Ralph Kettritz
- Department of Nephrology and Medical Intensive Care, Charité - Universitätsmedizin Berlin, Freie Universität Berlin and Humboldt-Universität zu Berlin, Berlin, Germany; Experimental and Clinical Research Center, Max Delbrück Center for Molecular Medicine in the Helmholtz Association and Charité Universitätsmedizin Berlin, Germany.
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13
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Kim JY, Lee S, Jang S, Kim CW, Gu BH, Kim M, Kim I. T helper cell polarity determines salt sensitivity and hypertension development. Hypertens Res 2023; 46:2168-2178. [PMID: 37463980 DOI: 10.1038/s41440-023-01365-0] [Citation(s) in RCA: 7] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/02/2023] [Revised: 06/11/2023] [Accepted: 06/15/2023] [Indexed: 07/20/2023]
Abstract
High-salt intake is known to induce pathogenic T helper (Th) 17 cells and hypertension, but contrary to what is known, causes hypertension only in salt-sensitive (SS) individuals. Thus, we hypothesized that Th cell polarity determines salt sensitivity and hypertension development. Cultured splenic T cells from Dahl SS and salt-resistant (SR) rats subjected to hypertonic salt solutions were evaluated via ELISA, flow cytometry, immunocytochemistry and RT-qPCR. Seven-week-old SS and SR rats were fed a chow (CD) or high-salt diet (HSD) for 4 weeks, with weekly measurements of systolic blood pressure. The relaxation response of the aorta rings to the cumulative addition of acetylcholine was measured ex vivo. In these experimental animals, the Th cell polarity (Th17 and T regulatory [Treg]), the expression of Th17- or Treg-related genes, and the enrichment of the transcription factors RORγt and FOXP3 on the target gene promoter regions were determined via flow cytometry, RT-qPCR, and chromatin immunoprecipitation. Hypertonic salt solution induced Th17 and Treg cell differentiation in cultured splenic T cells isolated from SS and SR rats, respectively. HSD induced hypertension, endothelial dysfunction and proinflammatory Th17 cell differentiation only in SS rats. The enrichment of RORγt on the promoter regions of Il17a and Il23r increased their expression only in SS rats. Regardless of HSD, SR rats remained normotensive with Treg polarity, causing high Treg-related gene expressions (Il10, Cd25 and Foxp3). This study demonstrated that Th cell polarity determines salt sensitivity and drives hypertension development. SR rats were protected from HSD-associated hypertension via anti-inflammatory Treg polarity.
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Affiliation(s)
- Jee Young Kim
- Department of Pharmacology, Kyungpook National University, Daegu, 41944, Republic of Korea
- Cardiovascular Research Institute, Kyungpook National University, Daegu, 41944, Republic of Korea
- BK21 Plus KNU Biomedical Convergence Program, Kyungpook National University, Daegu, 41944, Republic of Korea
- Department of Biomedical Science, School of Medicine, Kyungpook National University, Daegu, 41944, Republic of Korea
| | - Soyung Lee
- Department of Pharmacology, Kyungpook National University, Daegu, 41944, Republic of Korea
- Cardiovascular Research Institute, Kyungpook National University, Daegu, 41944, Republic of Korea
- BK21 Plus KNU Biomedical Convergence Program, Kyungpook National University, Daegu, 41944, Republic of Korea
- Department of Biomedical Science, School of Medicine, Kyungpook National University, Daegu, 41944, Republic of Korea
| | - Sungmin Jang
- Department of Pharmacology, Kyungpook National University, Daegu, 41944, Republic of Korea
- Cardiovascular Research Institute, Kyungpook National University, Daegu, 41944, Republic of Korea
- BK21 Plus KNU Biomedical Convergence Program, Kyungpook National University, Daegu, 41944, Republic of Korea
- Department of Biomedical Science, School of Medicine, Kyungpook National University, Daegu, 41944, Republic of Korea
| | - Cheong-Wun Kim
- Department of Pharmacology, Kyungpook National University, Daegu, 41944, Republic of Korea
- Cardiovascular Research Institute, Kyungpook National University, Daegu, 41944, Republic of Korea
- BK21 Plus KNU Biomedical Convergence Program, Kyungpook National University, Daegu, 41944, Republic of Korea
- Department of Biomedical Science, School of Medicine, Kyungpook National University, Daegu, 41944, Republic of Korea
| | - Bon-Hee Gu
- Department of Animal Science, College of Natural Resources & Live Science, Pusan National University, Miryang, 50463, Republic of Korea
- Life and Industry Convergence Research Institute, Pusan National University, Miryang, 50463, Republic of Korea
| | - Myunghoo Kim
- Department of Animal Science, College of Natural Resources & Live Science, Pusan National University, Miryang, 50463, Republic of Korea
- Life and Industry Convergence Research Institute, Pusan National University, Miryang, 50463, Republic of Korea
| | - Inkyeom Kim
- Department of Pharmacology, Kyungpook National University, Daegu, 41944, Republic of Korea.
- Cardiovascular Research Institute, Kyungpook National University, Daegu, 41944, Republic of Korea.
- BK21 Plus KNU Biomedical Convergence Program, Kyungpook National University, Daegu, 41944, Republic of Korea.
- Department of Biomedical Science, School of Medicine, Kyungpook National University, Daegu, 41944, Republic of Korea.
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14
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Xie Y, Mossavar-Rahmani Y, Chen Y, Abramowitz MK, Chen W. Association of Dietary Potassium Intake With Abdominal Aortic Calcification and Pulse Pressure in US Adults. J Ren Nutr 2023; 33:657-665. [PMID: 37302720 PMCID: PMC10528025 DOI: 10.1053/j.jrn.2023.06.003] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/01/2022] [Revised: 05/29/2023] [Accepted: 06/04/2023] [Indexed: 06/13/2023] Open
Abstract
OBJECTIVES Arterial calcification contributes to cardiovascular mortality. Based on a recent animal study, we hypothesized that higher dietary potassium intake was associated with less abdominal aortic calcification (AAC) and lower arterial stiffness among adults in the United States. METHODS Cross-sectional analyses were performed on participants over 40 years old from the National Health and Nutrition Examination Survey 2013-2014. Dietary potassium intake was categorized into quartiles (Q1: <1911, Q2: 1911-2461, Q3: 2462-3119, and Q4: >3119 mg/d). Primary outcome AAC was quantified using the Kauppila scoring system. AAC scores were categorized into no AAC (AAC = 0, reference group), mild/moderate (AAC >0 to ≤ 6), and severe AAC (AAC >6). Pulse pressure was used as a surrogate for arterial stiffness and examined as a secondary outcome. RESULTS Among 2,418 participants, there was not a linear association between dietary potassium intake and AAC. Higher dietary potassium intake was associated with less severe AAC when comparing dietary potassium intake in Q2 with Q1 (odds ratio 0.55; 95% confidence interval: 0.34 to 0.92; P = .03). Higher dietary potassium intake was significantly associated with lower pulse pressure (P = .007): per 1000 mg/d higher dietary potassium intake, pulse pressure was 1.47 mmHg lower in the fully adjusted model. Compared to participants with dietary potassium intake in Q1, pulse pressure was 2.84 mmHg lower in Q4 (P = .04). CONCLUSIONS We did not find a linear association between dietary potassium intake and AAC. Dietary potassium intake was negatively associated with pulse pressure.
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Affiliation(s)
- Yuping Xie
- Division of Pediatric Nephrology, Children's Hospital at Montefiore/Albert Einstein College of Medicine, Bronx, New York; Department of Pediatrics, SUNY Downstate Medical Center, Brooklyn, New York
| | - Yasmin Mossavar-Rahmani
- Department of Epidemiology &Population Health, Albert Einstein College of Medicine, Bronx, New York
| | - Yabing Chen
- Department of Pathology, University of Alabama at Birmingham, Birmingham, Alabama; Research Department, Birmingham Veterans Affairs Medical Center, Birmingham, Alabama
| | - Matthew K Abramowitz
- Department of Medicine, Albert Einstein College of Medicine, Bronx, New York; Institute for Aging Research, Albert Einstein College of Medicine, Bronx, New York; Diabetes Research Center, Albert Einstein College of Medicine, Bronx, New York; Fleischer Institute for Diabetes and Metabolism, Albert Einstein College of Medicine, Bronx, New York
| | - Wei Chen
- Department of Medicine, Albert Einstein College of Medicine, Bronx, New York; Department of Medicine, University of Rochester School of Medicine and Dentistry, Rochester, New York; Department of Developmental and Molecular Biology, Albert Einstein College of Medine, Bronx, New York.
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15
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Nissaisorakarn V, Ormseth G, Earle W, Morales-Alvarez MC, Hiremath S, Juraschek SP. Less sodium, more potassium, or both: population-wide strategies to prevent hypertension. Am J Physiol Renal Physiol 2023; 325:F99-F104. [PMID: 37262087 PMCID: PMC11905867 DOI: 10.1152/ajprenal.00007.2023] [Citation(s) in RCA: 7] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/17/2023] [Revised: 05/24/2023] [Accepted: 05/25/2023] [Indexed: 06/03/2023] Open
Abstract
Hypertension is among the most prevalent medical conditions globally and a major contributor to chronic kidney disease, cardiovascular disease, and death. Prevention through nonpharmacological, population-level interventions is critically needed to halt this worldwide epidemic. However, there are ongoing disagreements as to where public policy efforts should focus. Recently the Salt Substitute and Stroke Study demonstrated the efficacy of substituting table salt with potassium salt to reduce the risk of stroke, major cardiovascular events, and death. However, this sparked debate over whether sodium or potassium should be prioritized in countries where table salt substitution was less feasible. In this commentary, we summarize arguments in favor of either strategy: reduced sodium or increased potassium intake. Moreover, we discuss evidence and policy approaches related to either or combined approaches relevant to cultural context. Ultimately, there is an urgent need for policies that both reduce sodium and increase potassium intake; however, identifying a strategy that fits cultural context will be key to improve population-wide blood pressures.
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Affiliation(s)
- Voravech Nissaisorakarn
- Division of Nephrology, Department of Medicine, Beth Israel Deaconess Medical Center/Harvard Medical School, Boston, Massachusetts, United States
| | - George Ormseth
- Division of General Medicine, Department of Medicine, Beth Israel Deaconess Medical Center/Harvard Medical School, Boston, Massachusetts, United States
| | - William Earle
- Division of General Medicine, Department of Medicine, Beth Israel Deaconess Medical Center/Harvard Medical School, Boston, Massachusetts, United States
| | - Martha Catalina Morales-Alvarez
- Division of Nephrology, Department of Medicine, Beth Israel Deaconess Medical Center/Harvard Medical School, Boston, Massachusetts, United States
| | - Swapnil Hiremath
- Division of Nephrology, Department of Medicine, University of Ottawa and the Ottawa Hospital, Ottawa, Ontario, Canada
| | - Stephen P Juraschek
- Division of General Medicine, Department of Medicine, Beth Israel Deaconess Medical Center/Harvard Medical School, Boston, Massachusetts, United States
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16
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da Silva DVT, Baião DDS, Almeida CC, Paschoalin VMF. A Critical Review on Vasoactive Nutrients for the Management of Endothelial Dysfunction and Arterial Stiffness in Individuals under Cardiovascular Risk. Nutrients 2023; 15:nu15112618. [PMID: 37299579 DOI: 10.3390/nu15112618] [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: 04/23/2023] [Revised: 05/30/2023] [Accepted: 06/01/2023] [Indexed: 06/12/2023] Open
Abstract
Pathophysiological conditions such as endothelial dysfunction and arterial stiffness, characterized by low nitric oxide bioavailability, deficient endothelium-dependent vasodilation and heart effort, predispose individuals to atherosclerotic lesions and cardiac events. Nitrate (NO3-), L-arginine, L-citrulline and potassium (K+) can mitigate arterial dysfunction and stiffness by intensifying NO bioavailability. Dietary compounds such as L-arginine, L-citrulline, NO3- and K+ exert vasoactive effects as demonstrated in clinical interventions by noninvasive flow-mediated vasodilation (FMD) and pulse-wave velocity (PWV) prognostic techniques. Daily L-arginine intakes ranging from 4.5 to 21 g lead to increased FMD and reduced PWV responses. Isolated L-citrulline intake of at least 5.6 g has a better effect compared to watermelon extract, which is only effective on endothelial function when supplemented for longer than 6 weeks and contains at least 6 g of L-citrulline. NO3- supplementation employing beetroot at doses greater than 370 mg promotes hemodynamic effects through the NO3--NO2-/NO pathway, a well-documented effect. A potassium intake of 1.5 g/day can restore endothelial function and arterial mobility, where decreased vascular tone takes place via ATPase pump/hyperpolarization and natriuresis, leading to muscle relaxation and NO release. These dietary interventions, alone or synergically, can ameliorate endothelial dysfunction and should be considered as adjuvant therapies in cardiovascular diseases.
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Affiliation(s)
- Davi Vieira Teixeira da Silva
- Instituto de Química, Programa de Pós-Graduação em Ciência de Alimentos e Programa de Pós-Graduação em Química, Universidade Federal do Rio de Janeiro, Av. Athos da Silveira Ramos 149, sala 545, Cidade Universitária, Rio de Janeiro 21941-909, RJ, Brazil
| | - Diego Dos Santos Baião
- Instituto de Química, Programa de Pós-Graduação em Ciência de Alimentos e Programa de Pós-Graduação em Química, Universidade Federal do Rio de Janeiro, Av. Athos da Silveira Ramos 149, sala 545, Cidade Universitária, Rio de Janeiro 21941-909, RJ, Brazil
| | - Cristine Couto Almeida
- Instituto de Química, Programa de Pós-Graduação em Ciência de Alimentos e Programa de Pós-Graduação em Química, Universidade Federal do Rio de Janeiro, Av. Athos da Silveira Ramos 149, sala 545, Cidade Universitária, Rio de Janeiro 21941-909, RJ, Brazil
| | - Vania Margaret Flosi Paschoalin
- Instituto de Química, Programa de Pós-Graduação em Ciência de Alimentos e Programa de Pós-Graduação em Química, Universidade Federal do Rio de Janeiro, Av. Athos da Silveira Ramos 149, sala 545, Cidade Universitária, Rio de Janeiro 21941-909, RJ, Brazil
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17
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Vahldieck C, Cianflone E, Fels B, Löning S, Depelmann P, Sabatino J, Salerno N, Karsten CM, Torella D, Weil J, Sun D, Goligorsky MS, Kusche-Vihrog K. Endothelial Glycocalyx and Cardiomyocyte Damage Is Prevented by Recombinant Syndecan-1 in Acute Myocardial Infarction. THE AMERICAN JOURNAL OF PATHOLOGY 2023; 193:474-492. [PMID: 36669683 PMCID: PMC10123521 DOI: 10.1016/j.ajpath.2022.12.009] [Citation(s) in RCA: 10] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 05/31/2022] [Revised: 11/24/2022] [Accepted: 12/20/2022] [Indexed: 01/19/2023]
Abstract
The outer layer of endothelial cells (ECs), consisting of the endothelial glycocalyx (eGC) and the cortex (CTX), provides a protective barrier against vascular diseases. Structural and functional impairments of their mechanical properties are recognized as hallmarks of endothelial dysfunction and can lead to cardiovascular events, such as acute myocardial infarction (AMI). This study investigated the effects of AMI on endothelial nanomechanics and function and the use of exogenous recombinant syndecan-1 (rSyn-1), a major component of the eGC, as recovering agent. ECs were exposed in vitro to serum samples collected from patients with AMI. In addition, in situ ECs of ex vivo aorta preparations derived from a mouse model for AMI were employed. Effects were quantified by using atomic force microscopy-based nanoindentation measurements, fluorescence staining, and histologic examination of the mouse hearts. AMI serum samples damaged eGC/CTX and augmented monocyte adhesion to the endothelial surface. In particular, the anaphylatoxins C3a and C5a played an important role in these processes. The impairment of endothelial function could be prevented by rSyn-1 treatment. In the mouse model of myocardial infarction, pretreatment with rSyn-1 alleviated eGC/CTX deterioration and reduced cardiomyocyte damage in histologic analyses. However, echocardiographic measurements did not indicate a functional benefit. These results provide new insights into the underlying mechanisms of AMI-induced endothelial dysfunction and perspectives for future studies on the benefit of rSyn-1 in post-AMI treatment.
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Affiliation(s)
- Carl Vahldieck
- Institute of Physiology, University of Luebeck, Luebeck, Germany; Department of Anesthesiology and Intensive Care Medicine, University Medical Centre Schleswig-Holstein Campus Luebeck, University of Luebeck, Luebeck, Germany.
| | - Eleonora Cianflone
- Department of Medical and Surgical Sciences, University Magna Græcia of Catanzaro, Catanzaro, Italy
| | - Benedikt Fels
- Institute of Physiology, University of Luebeck, Luebeck, Germany; DZHK (German Research Centre for Cardiovascular Research), Partner Site Hamburg/Luebeck/Kiel, Luebeck, Germany
| | - Samuel Löning
- Institute of Physiology, University of Luebeck, Luebeck, Germany
| | - Patrik Depelmann
- Institute of Physiology, University of Luebeck, Luebeck, Germany
| | - Jolanda Sabatino
- Department of Medical and Surgical Sciences, University Magna Græcia of Catanzaro, Catanzaro, Italy; Division of Pediatric Cardiology, Department of Women's and Children's Health, University Hospital Padua, Padua, Italy; Pediatric Research Institute "Città della Speranza", Padua, Italy
| | - Nadia Salerno
- Department of Medical and Surgical Sciences, University Magna Græcia of Catanzaro, Catanzaro, Italy
| | - Christian M Karsten
- Institute for Systemic Inflammation Research, University of Luebeck, Luebeck, Germany
| | - Daniele Torella
- Department of Experimental and Clinical Medicine, University Magna Græcia of Catanzaro, Catanzaro, Italy
| | - Joachim Weil
- Medizinische Klinik II, Sana Kliniken Luebeck, Luebeck, Germany
| | - Dong Sun
- Renal Research Institute and Departments of Medicine, Pharmacology and Physiology, New York Medical College, Valhalla, New York
| | - Michael S Goligorsky
- Renal Research Institute and Departments of Medicine, Pharmacology and Physiology, New York Medical College, Valhalla, New York
| | - Kristina Kusche-Vihrog
- Institute of Physiology, University of Luebeck, Luebeck, Germany; DZHK (German Research Centre for Cardiovascular Research), Partner Site Hamburg/Luebeck/Kiel, Luebeck, Germany
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18
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D’Elia L, Cappuccio FP, Masulli M, La Fata E, Rendina D, Galletti F. Effect of Potassium Supplementation on Endothelial Function: A Systematic Review and Meta-Analysis of Intervention Studies. Nutrients 2023; 15:853. [PMID: 36839211 PMCID: PMC9961878 DOI: 10.3390/nu15040853] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/03/2023] [Revised: 02/03/2023] [Accepted: 02/06/2023] [Indexed: 02/11/2023] Open
Abstract
(1) Background: Endothelial dysfunction is an early predictor of cardiovascular diseases. Although a large body of evidence shows an inverse association between potassium intake and cardiovascular risk, the studies on endothelial function provided contrasting results. Thus, we carried out a systematic review and a meta-analysis of the available intervention studies of the potassium supplementation on endothelial function. (2) Methods: A systematic search of the online databases available (up to December 2022) was conducted including the intervention trials that reported flow-mediated dilation (FMD) changes-a non-invasive method of assessing endothelial function-after two different potassium intake regimens. For each study, the mean difference (MD) and 95% confidence intervals were pooled using a random effect model. (3) Results: Five studies met the pre-defined inclusion criteria and provided eight cohorts with 332 participants. In the pooled analysis, potassium supplementation was associated with a significant increase in FMD (MD: 0.74%), with a higher effect for a urinary potassium excretion higher than 90 mmol/day. There was a moderate heterogeneity among studies (I2 = 59%), explained by the different amount of potassium supplementation. (4) Conclusions: The results of our meta-analysis indicate that dietary potassium supplement improves endothelial function. This effect is directly associated with the amount of potassium supplement. The findings support the campaigns in favour of an increase in dietary potassium intake to reduce cardiovascular risk.
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Affiliation(s)
- Lanfranco D’Elia
- Department of Clinical Medicine and Surgery, “Federico II” University of Naples Medical School, 80138 Naples, Italy
| | - Francesco P. Cappuccio
- World Health Organization Collaborating Centre for Nutrition, Warwick Medical School, University of Warwick, Coventry CV4 7AL, UK
- Department of Medicine, University Hospital Coventry and Warwickshire NHS Trust, Coventry CV2 2DX, UK
| | - Maria Masulli
- Department of Clinical Medicine and Surgery, “Federico II” University of Naples Medical School, 80138 Naples, Italy
| | - Ersilia La Fata
- UOC Cure Domiciliari, ASL Napoli 2 Nord, 80078 Frattaminore, Italy
| | - Domenico Rendina
- Department of Clinical Medicine and Surgery, “Federico II” University of Naples Medical School, 80138 Naples, Italy
| | - Ferruccio Galletti
- Department of Clinical Medicine and Surgery, “Federico II” University of Naples Medical School, 80138 Naples, Italy
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19
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Radoslavova S, Fels B, Pethö Z, Gruner M, Ruck T, Meuth SG, Folcher A, Prevarskaya N, Schwab A, Ouadid-Ahidouch H. TRPC1 channels regulate the activation of pancreatic stellate cells through ERK1/2 and SMAD2 pathways and perpetuate their pressure-mediated activation. Cell Calcium 2022; 106:102621. [PMID: 35905654 DOI: 10.1016/j.ceca.2022.102621] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/25/2022] [Revised: 07/04/2022] [Accepted: 07/05/2022] [Indexed: 11/02/2022]
Abstract
Pancreatic stellate cell (PSC) activation is a major event occurring during pancreatic ductal adenocarcinoma (PDAC) development. Up to now mechanisms underlying their activation by mechanical cues such as the elevated tissue pressure in PDAC remain poorly understood. Here we investigate the role of one potential mechano-transducer, TRPC1 ion channel, in PSC activation. Using pre-activated human siTRPC1 and murine TRPC1-KO PSCs, we show that TRPC1 promotes αSMA (α-smooth muscle actin) expression, the main activation marker, in cooperation with the phosphorylated SMAD2, under normal and elevated pressure. Functional studies following TRPC1 silencing demonstrate the dual role of TRPC1 in the modulation of PSC proliferation and IL-6 secretion through the activation of ERK1/2 and SMAD2 pathways. Moreover, pressurization changes the mechanical behavior of PSCs by increasing their cellular stiffness and emitted traction forces in a TRPC1-dependent manner. In summary, these results point to a role of TRPC1 channels in sensing and transducing the characteristic mechanical properties of the PDAC microenvironment in PSCs.
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Affiliation(s)
- Silviya Radoslavova
- Laboratory of Cellular and Molecular Physiology, UR-UPJV 4667, University of Picardie Jules Verne, 80039 Amiens, France; University of Lille, Inserm U1003 - PHYCEL - Cellular Physiology, F-59000 Lille, France
| | - Benedikt Fels
- Institute of Physiology, University Lübeck, Lübeck, Germany; DZHK (German Research Centre for Cardiovascular Research), Partner Site Hamburg/Lübeck/Kiel, Lübeck, Germany
| | - Zoltan Pethö
- Institute of Physiology II, University Münster, Münster, Germany
| | - Matthias Gruner
- Institute of Physiology II, University Münster, Münster, Germany
| | - Tobias Ruck
- Klinik für Neurologie, Medical Faculty, Universitätsklinikum Düsseldorf, Düsseldorf, Germany
| | - Sven G Meuth
- Klinik für Neurologie, Medical Faculty, Universitätsklinikum Düsseldorf, Düsseldorf, Germany
| | - Antoine Folcher
- University of Lille, Inserm U1003 - PHYCEL - Cellular Physiology, F-59000 Lille, France
| | - Natalia Prevarskaya
- University of Lille, Inserm U1003 - PHYCEL - Cellular Physiology, F-59000 Lille, France.
| | - Albrecht Schwab
- Institute of Physiology II, University Münster, Münster, Germany.
| | - Halima Ouadid-Ahidouch
- Laboratory of Cellular and Molecular Physiology, UR-UPJV 4667, University of Picardie Jules Verne, 80039 Amiens, France.
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20
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Xie L, Sun Z, Brown NJ, Glinskii OV, Meininger GA, Glinsky VV. Changes in dynamics of tumor/endothelial cell adhesive interactions depending on endothelial cell growth state and elastic properties. PLoS One 2022; 17:e0269552. [PMID: 35666755 PMCID: PMC9170101 DOI: 10.1371/journal.pone.0269552] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/11/2022] [Accepted: 05/23/2022] [Indexed: 11/18/2022] Open
Abstract
Cancer cell adhesion to the endothelium is a crucial process in hematogenous metastasis, but how the integrity of the endothelial barrier and endothelial cell (EC) mechanical properties influence the adhesion between metastatic cancer cells and the endothelium remain unclear. In the present study, we have measured the adhesion between single cancer cells and two types of ECs at various growth states and their mechanical properties (elasticity) using atomic force microscopy single cell force spectroscopy. We demonstrated that the EC stiffness increased and adhesion with cancer cells decreased, as ECs grew from a single cell to a confluent state and developed cell-cell contacts, but this was reversed when confluent cells returned to a single state in a scratch assay. Our results suggest that the integrity of the endothelial barrier is an important factor in reducing the ability of the metastatic tumor cells to adhere to the vascular endothelium, extravasate and lodge in the vasculature of a distant organ where secondary metastatic tumors would develop.
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Affiliation(s)
- Leike Xie
- Dalton Cardiovascular Research Center, University of Missouri, Columbia, Missouri, United States of America
- Department of Pathology and Anatomical Sciences, University of Missouri, Columbia, Missouri, United States of America
| | - Zhe Sun
- Dalton Cardiovascular Research Center, University of Missouri, Columbia, Missouri, United States of America
| | - Nicola J. Brown
- Microcirculation Research Group, Department of Oncology and Metabolism, Faculty of Medicine, Dentistry and Health, University of Sheffield, Sheffield, United Kingdom
| | - Olga V. Glinskii
- Dalton Cardiovascular Research Center, University of Missouri, Columbia, Missouri, United States of America
- Department of Medical Pharmacology and Physiology, University of Missouri, Columbia, Missouri, United States of America
- Research Service, Harry S. Truman Memorial Veterans Hospital, Columbia, Missouri, United States of America
| | - Gerald A. Meininger
- Dalton Cardiovascular Research Center, University of Missouri, Columbia, Missouri, United States of America
- Department of Medical Pharmacology and Physiology, University of Missouri, Columbia, Missouri, United States of America
| | - Vladislav V. Glinsky
- Dalton Cardiovascular Research Center, University of Missouri, Columbia, Missouri, United States of America
- Department of Pathology and Anatomical Sciences, University of Missouri, Columbia, Missouri, United States of America
- Research Service, Harry S. Truman Memorial Veterans Hospital, Columbia, Missouri, United States of America
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21
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Fedorov DA, Sidorenko SV, Yusipovich AI, Bukach OV, Gorbunov AM, Lopina OD, Klimanova EA. Increased Extracellular Sodium Concentration as a Factor Regulating Gene Expression in Endothelium. BIOCHEMISTRY. BIOKHIMIIA 2022; 87:489-499. [PMID: 35790409 DOI: 10.1134/s0006297922060013] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 02/17/2022] [Revised: 04/26/2022] [Accepted: 04/26/2022] [Indexed: 06/15/2023]
Abstract
Hyperosmotic stimulation of endothelial cells often leads to its dysfunction accompanied, among other things, by proinflammatory response. The mechanisms of this phenomenon are not fully understood. It may arise due to increase in the plasma Na+ concentration, due to increase in the extracellular osmolarity, increase in the intracellular Na+i/K+i ratio, and/or change in the cell stiffness. In the present study we investigated the effects of short-term increase in osmolarity of extracellular medium on the mRNA content of some genes important for endothelial function (including Na+i/K+i-sensitive ones) and the equivalent elasticity constant of human umbilical vein endothelial cells membranes. Hyperosmotic stimulation of these cells with NaCl but not mannitol resulted in accumulation of Na+ ions inside the cells despite the Na,K-ATPase activation, and was also accompanied by the decrease in their equivalent elasticity constant. The amount of IL1α mRNA decreased with increasing osmolarity of the extracellular medium, whereas the amount of ATF3, PAR2, and PTGS2 mRNAs increased only in response to the increasing NaCl concentration. At the same time, under the conditions of our experiments, we did not detect changes in the expression of the osmoprotective transcription factor NFAT5. The obtained data indicate that the increase of extracellular Na+ concentration in the physiological range is an independent factor that affects intracellular Na+i/K+i ratio and regulates expression of some genes (in particular, ATF3, PAR2, PTGS2) in endothelial cells.
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Affiliation(s)
- Dmitry A Fedorov
- Faculty of Biology, Lomonosov Moscow State University, Moscow, 119234, Russia.
| | | | | | - Olesya V Bukach
- Faculty of Biology, Lomonosov Moscow State University, Moscow, 119234, Russia.
| | - Andrey M Gorbunov
- Faculty of Biology, Lomonosov Moscow State University, Moscow, 119234, Russia.
| | - Olga D Lopina
- Faculty of Biology, Lomonosov Moscow State University, Moscow, 119234, Russia.
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22
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Kurtz T, Pravenec M, DiCarlo S. Mechanism-based strategies to prevent salt sensitivity and salt-induced hypertension. Clin Sci (Lond) 2022; 136:599-620. [PMID: 35452099 PMCID: PMC9069470 DOI: 10.1042/cs20210566] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/06/2022] [Revised: 03/21/2022] [Accepted: 03/30/2022] [Indexed: 12/15/2022]
Abstract
High-salt diets are a major cause of hypertension and cardiovascular (CV) disease. Many governments are interested in using food salt reduction programs to reduce the risk for salt-induced increases in blood pressure and CV events. It is assumed that reducing the salt concentration of processed foods will substantially reduce mean salt intake in the general population. However, contrary to expectations, reducing the sodium density of nearly all foods consumed in England by 21% had little or no effect on salt intake in the general population. This may be due to the fact that in England, as in other countries including the U.S.A., mean salt intake is already close to the lower normal physiologic limit for mean salt intake of free-living populations. Thus, mechanism-based strategies for preventing salt-induced increases in blood pressure that do not solely depend on reducing salt intake merit attention. It is now recognized that the initiation of salt-induced increases in blood pressure often involves a combination of normal increases in sodium balance, blood volume and cardiac output together with abnormal vascular resistance responses to increased salt intake. Therefore, preventing either the normal increases in sodium balance and cardiac output, or the abnormal vascular resistance responses to salt, can prevent salt-induced increases in blood pressure. Suboptimal nutrient intake is a common cause of the hemodynamic disturbances mediating salt-induced hypertension. Accordingly, efforts to identify and correct the nutrient deficiencies that promote salt sensitivity hold promise for decreasing population risk of salt-induced hypertension without requiring reductions in salt intake.
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Affiliation(s)
- Theodore W. Kurtz
- Department of Laboratory Medicine, University of California, San Francisco, San Francisco, CA 94017-0134, U.S.A
| | - Michal Pravenec
- Institute of Physiology, Czech Academy of Sciences, Prague 14220, Czech Republic
| | - Stephen E. DiCarlo
- Department of Physiology, College of Osteopathic Medicine, Michigan State University, East Lansing, MI 48824, U.S.A
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23
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Gruber S, Stasi E, Steiner R, Reincke M, Bornstein S, Beuschlein F. Incidence of Primary Aldosteronism in Patients with Hypokalemia (IPAHK+): Study Design and Baseline Characteristics. Horm Metab Res 2021; 53:787-793. [PMID: 34891208 DOI: 10.1055/a-1685-0583] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 10/19/2022]
Abstract
Hypokalemia plays a central role for case finding, course, treatment decision, and prognosis of patients with primary aldosteronism. However, to date there is a lack of high-level evidence about the incidence of primary aldosteronism in hypokalemic patients. The IPAHK+study is an epidemiological, cross-sectional, monocentric study to provide evidence on the incidence of PA in a hypokalemic population. The aim of the current analysis was to describe the baseline characteristics of the first 100 patients eligible for study inclusion. The recruitment of patients with hypokalemia (≤3 mmol/l) is carried out continuously on a referral-basis by the central laboratory of the University Hospital Zurich through an automated suitability testing and data delivery system. The careful evaluation of the first 100 reported patients was based on the available reporting system. Out of 28 140 screened patients, 222 (0.79%) were identified with a serum potassium value of≤3 mmol/l (mean 2.89±0.02 mmol/l). Mean potassium levels were slightly lower in non-hypertensive subjects compared to hypertensive subjects (mean difference 0.07 mmol/l, p=0.033), while no significant difference was found between the sexes and patients with and without the diagnosis of primary aldosteronism, atrial fibrillation, or the use of diuretics. The incidence of PA was 4% in the total population studied and 7.5% in the subgroup of hypertensive patients. In conclusion, the continuous enrollment of patients from the IPHAK+hypokalemia registry into the IPAHK+trial will provide evidence about the actual incidence of primary aldosteronism in a hypokalemic outpatient population.
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Affiliation(s)
- Sven Gruber
- Department of Endocrinology, Diabetology and Clinical Nutrition, University Hospital Zurich and University of Zurich, Zurich, Switzerland
| | - Evangelia Stasi
- Department of Endocrinology, Diabetology and Clinical Nutrition, University Hospital Zurich and University of Zurich, Zurich, Switzerland
| | - Regula Steiner
- Institute for Clinical Chemistry, University Hospital Zurich and University of Zurich, Zurich, Switzerland
| | - Martin Reincke
- Medizinische Klinik und Poliklinik IV, Klinikum der Universität München, Munich, Germany
| | - Stefan Bornstein
- Department of Internal Medicine III, University Hospital Carl Gustav Carus, Technische Universität Dresden, Dresden, Germany
| | - Felix Beuschlein
- Department of Endocrinology, Diabetology and Clinical Nutrition, University Hospital Zurich and University of Zurich, Zurich, Switzerland
- Medizinische Klinik und Poliklinik IV, Klinikum der Universität München, Munich, Germany
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24
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Oberleithner H. Quantifying salt sensitivity. Biol Chem 2021; 402:1597-1602. [PMID: 34505462 DOI: 10.1515/hsz-2021-0206] [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: 03/28/2021] [Accepted: 07/03/2021] [Indexed: 11/15/2022]
Abstract
Inner surfaces of blood vessels and outer surfaces of erythrocytes are coated with a negatively charged protective film of proteoglycans, which serves as an effective buffer system for the positively charged sodium ions. If this protective coating is poorly developed or impaired, it loses its buffering capacity. As a consequence, the organism becomes increasingly sensitive to sodium, which in the long run leads to organ damage, especially if daily salt consumption is high. Recently, it has become possible to quantify salt sensitivity using a technically simple method - the salt blood test (SBT). Aim of this mini-review is to explain the physiological concept underlying the SBT and its potential practical relevance in the prevention of cardiovascular disease.
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Affiliation(s)
- Hans Oberleithner
- Institute of Physiology II, Medical Faculty, University of Münster, 48149 Münster, Germany
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25
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Affiliation(s)
- David H Ellison
- From the Oregon Clinical and Translational Research Institute, Oregon Health and Science University (D.H.E) and the VA Portland Health Care System (D.H.E.) - both in Portland; and LeDucq Transatlantic Network of Excellence (D.H.E., P.W.) and the Departments of Medicine and Physiology, Johns Hopkins University (P.W.) - both in Baltimore
| | - Paul Welling
- From the Oregon Clinical and Translational Research Institute, Oregon Health and Science University (D.H.E) and the VA Portland Health Care System (D.H.E.) - both in Portland; and LeDucq Transatlantic Network of Excellence (D.H.E., P.W.) and the Departments of Medicine and Physiology, Johns Hopkins University (P.W.) - both in Baltimore
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26
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Na + i/K + i imbalance contributes to gene expression in endothelial cells exposed to elevated NaCl. Heliyon 2021; 7:e08088. [PMID: 34632152 PMCID: PMC8488490 DOI: 10.1016/j.heliyon.2021.e08088] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/04/2021] [Revised: 08/27/2021] [Accepted: 09/26/2021] [Indexed: 12/16/2022] Open
Abstract
High-salt consumption contributes to the development of hypertension and is considered an independent risk factor for vascular remodelling, cardiac hypertrophy and stroke incidence. Alterations in NO production, inflammation and endothelial cell stiffening are considered now as plausible mediators of cardiovascular dysfunction. We studied early responses of endothelial cells (HUVEC) caused by a moderate increase in extracellular sodium concentration. Exposure of HUVEC to elevated sodium within the physiological range up to 24 h is accompanied by changes in monovalent cations fluxes and Na,K-ATPase activation, and, in turn, results in a significant decrease in the content of PTGS2, IL6 and IL1LR1 mRNAs. The expression of NOS3 and FOS genes, as well as the abundance of cytosolic and nuclear NFAT5 protein, remained unchanged. We assessed the mechanical properties of endothelial cells by estimating Young's modulus and equivalent elastic constant using atomic force and interference microscopy, respectively. These parameters were unaffected by elevated-salt exposure for 24 h. The data obtained suggest that even small and short-term elevations of extracellular sodium concentration affect the expression of genes involved in the control of endothelial function through the Na+i/K+i-dependent mechanism(s).
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27
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Aryal SR, Siddiqui M, Sharifov OF, Coffin MD, Zhang B, Gaddam KK, Gupta H, Denney TS, Dell'Italia LJ, Oparil S, Calhoun DA, Lloyd SG. Spironolactone Reduces Aortic Stiffness in Patients With Resistant Hypertension Independent of Blood Pressure Change. J Am Heart Assoc 2021; 10:e019434. [PMID: 34459249 PMCID: PMC8649301 DOI: 10.1161/jaha.120.019434] [Citation(s) in RCA: 14] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/30/2022]
Abstract
Background Aortic stiffness is an independent predictor of cardiovascular events in patients with arterial hypertension. Resistant hypertension is often linked to hyperaldosteronism and associated with adverse outcomes. Spironolactone, a mineralocorticoid receptor antagonist, has been shown to reduce both the arterial blood pressure (BP) and aortic stiffness in resistant hypertension. However, the mechanism of aortic stiffness reduction by spironolactone is not well understood. We hypothesized that spironolactone reduces aortic stiffness in resistant hypertension independently of BP change. Methods and Results Patients with uncontrolled BP (≥140/90 mm Hg) despite use of ≥3 antihypertensive medications (including diuretics) were prospectively recruited. Participants were started on spironolactone at 25 mg/d, and increased to 50 mg/d at 4 weeks while other antihypertensive medications were withdrawn to maintain constant mean BP. Phase‐contrast cardiac magnetic resonance imaging of the ascending aorta was performed in 30 participants at baseline and after 6 months of spironolactone treatment to measure aortic pulsatility, distensibility, and pulse wave velocity. Pulse wave velocity decreased (6.3±2.3 m/s to 4.5±1.8 m/s, P<0.001) and pulsatility and distensibility increased (15.9%±5.3% to 22.1%±7.9%, P<0.001; and 0.28%±0.10%/mm Hg to 0.40%±0.14%/mm Hg, P<0.001, respectively) following 6 months of spironolactone. Conclusions Our results suggest that spironolactone improves aortic properties in resistant hypertension independently of BP, which may support the hypothesis of an effect of aldosterone on the arterial wall. A larger prospective study is needed to confirm our findings.
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Affiliation(s)
- Sudeep R Aryal
- Division of Cardiovascular Disease University of Alabama at Birmingham Birmingham AL
| | - Mohammed Siddiqui
- Vascular Biology and Hypertension Program University of Alabama at Birmingham Birmingham AL
| | - Oleg F Sharifov
- Division of Cardiovascular Disease University of Alabama at Birmingham Birmingham AL
| | - Megan D Coffin
- School of Medicine University of Alabama at Birmingham Birmingham AL
| | - Bin Zhang
- Division of Biostatistics and Epidemiology Cincinnati Children's Hospital Medical Center Cincinnati OH.,Department of Pediatrics University of Cincinnati College of Medicine Cincinnati OH
| | - Krishna K Gaddam
- Division of Cardiovascular Disease University of Alabama at Birmingham Birmingham AL
| | | | - Thomas S Denney
- Department of Electrical and Computer Engineering Auburn University Auburn AL
| | - Louis J Dell'Italia
- Division of Cardiovascular Disease University of Alabama at Birmingham Birmingham AL.,VA Medical Center Birmingham AL
| | - Suzanne Oparil
- Division of Cardiovascular Disease University of Alabama at Birmingham Birmingham AL.,Vascular Biology and Hypertension Program University of Alabama at Birmingham Birmingham AL
| | - David A Calhoun
- Vascular Biology and Hypertension Program University of Alabama at Birmingham Birmingham AL
| | - Steven G Lloyd
- Division of Cardiovascular Disease University of Alabama at Birmingham Birmingham AL.,VA Medical Center Birmingham AL
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28
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Ritter M, Bresgen N, Kerschbaum HH. From Pinocytosis to Methuosis-Fluid Consumption as a Risk Factor for Cell Death. Front Cell Dev Biol 2021; 9:651982. [PMID: 34249909 PMCID: PMC8261248 DOI: 10.3389/fcell.2021.651982] [Citation(s) in RCA: 30] [Impact Index Per Article: 7.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/11/2021] [Accepted: 04/29/2021] [Indexed: 12/11/2022] Open
Abstract
The volumes of a cell [cell volume (CV)] and its organelles are adjusted by osmoregulatory processes. During pinocytosis, extracellular fluid volume equivalent to its CV is incorporated within an hour and membrane area equivalent to the cell's surface within 30 min. Since neither fluid uptake nor membrane consumption leads to swelling or shrinkage, cells must be equipped with potent volume regulatory mechanisms. Normally, cells respond to outwardly or inwardly directed osmotic gradients by a volume decrease and increase, respectively, i.e., they shrink or swell but then try to recover their CV. However, when a cell death (CD) pathway is triggered, CV persistently decreases in isotonic conditions in apoptosis and it increases in necrosis. One type of CD associated with cell swelling is due to a dysfunctional pinocytosis. Methuosis, a non-apoptotic CD phenotype, occurs when cells accumulate too much fluid by macropinocytosis. In contrast to functional pinocytosis, in methuosis, macropinosomes neither recycle nor fuse with lysosomes but with each other to form giant vacuoles, which finally cause rupture of the plasma membrane (PM). Understanding methuosis longs for the understanding of the ionic mechanisms of cell volume regulation (CVR) and vesicular volume regulation (VVR). In nascent macropinosomes, ion channels and transporters are derived from the PM. Along trafficking from the PM to the perinuclear area, the equipment of channels and transporters of the vesicle membrane changes by retrieval, addition, and recycling from and back to the PM, causing profound changes in vesicular ion concentrations, acidification, and-most importantly-shrinkage of the macropinosome, which is indispensable for its proper targeting and cargo processing. In this review, we discuss ion and water transport mechanisms with respect to CVR and VVR and with special emphasis on pinocytosis and methuosis. We describe various aspects of the complex mutual interplay between extracellular and intracellular ions and ion gradients, the PM and vesicular membrane, phosphoinositides, monomeric G proteins and their targets, as well as the submembranous cytoskeleton. Our aim is to highlight important cellular mechanisms, components, and processes that may lead to methuotic CD upon their derangement.
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Affiliation(s)
- Markus Ritter
- Center for Physiology, Pathophysiology and Biophysics, Institute for Physiology and Pathophysiology, Paracelsus Medical University, Salzburg, Austria
- Institute for Physiology and Pathophysiology, Paracelsus Medical University, Nuremberg, Germany
- Gastein Research Institute, Paracelsus Medical University, Salzburg, Austria
- Ludwig Boltzmann Institute for Arthritis und Rehabilitation, Salzburg, Austria
- Kathmandu University School of Medical Sciences, Dhulikhel, Nepal
| | - Nikolaus Bresgen
- Department of Biosciences, University of Salzburg, Salzburg, Austria
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29
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Dotson BL, Heiston EM, Miller SL, Malin SK. Insulin stimulation reduces aortic wave reflection in adults with metabolic syndrome. Am J Physiol Heart Circ Physiol 2021; 320:H2305-H2312. [PMID: 33861146 DOI: 10.1152/ajpheart.00975.2020] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/22/2022]
Abstract
Adults with metabolic syndrome (MetS) have increased fasting arterial stiffness and altered central hemodynamics that contribute, partly, to increased cardiovascular disease (CVD) risk. Although insulin affects aortic wave reflections in healthy adults, the effects in individuals with MetS are unclear. We hypothesized that insulin stimulation would reduce measures of pressure waveforms and hemodynamics in people with MetS. Thirty-five adults with obesity (27 women; 54.2 ± 6.0 yr; 37.1 ± 4.8 kg/m2) were selected for MetS (ATP III criteria) following an overnight fast. Pulse wave analysis was assessed using applanation tonometry before and after a 2-h euglycemic-hyperinsulinemic clamp (90 mg/dL, 40 mU/m2/min). Deconvolution analysis was used to decompose the aortic waveform [augmentation index corrected to heart rate of 75 beats/min (AIx@75); augmentation pressure (AP)] into backward and forward pressure components. Aerobic fitness (V̇o2max), body composition (DXA), and blood biochemistries were also assessed. Insulin significantly reduced augmentation index (AIx@75, 28.0 ± 9.6 vs. 23.0 ± 9.9%, P < 0.01), augmentation pressure (14.8 ± 6.4 vs. 12.0 ± 5.7 mmHg, P < 0.01), pulse pressure amplification (1.26 ± 0.01 vs. 0.03 ± 0.01, P = 0.01), and inflammation [high-sensitivity C-reactive protein (hsCRP): P = 0.02; matrix metallopeptidase 7 (MMP-7): P = 0.03] compared to fasting. In subgroup analyses to understand HTN influence, there were no insulin stimulation differences on any outcome. V̇o2max, visceral fat, and blood potassium correlated with fasting AIx@75 (r = -0.39, P = 0.02; r = 0.41, P = 0.03; r = -0.53, P = 0.002). Potassium levels were also associated with insulin-mediated reductions in AP (r = 0.52, P = 0.002). Our results suggest insulin stimulation improves indices of aortic reflection in adults with MetS.NEW & NOTEWORTHY This study is one of the first to investigate the effects of insulin on central and peripheral hemodynamics in adults with metabolic syndrome. We provide evidence that insulin infusion reduces aortic wave reflection, potentially through a reduction in inflammation and/or via a potassium-mediated vascular response.
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Affiliation(s)
- Brielle L Dotson
- Department of Kinesiology, University of Virginia, Charlottesville, Virginia
| | - Emily M Heiston
- Department of Kinesiology, University of Virginia, Charlottesville, Virginia.,Division of Cardiology, Pauley Heart Center, Virginia Commonwealth University, Richmond, Virginia
| | - Stephanie L Miller
- Department of Kinesiology, University of Virginia, Charlottesville, Virginia
| | - Steven K Malin
- Department of Kinesiology, University of Virginia, Charlottesville, Virginia.,Department of Kinesiology and Health, Rutgers University, New Brunswick, New Jersey.,Division of Endocrinology, Metabolism and Nutrition; Rutgers University, New Brunswick, New Jersey.,New Jersey Institute for Food, Nutrition and Health, Rutgers University, New Brunswick, New Jersey.,Institute of Translational Medicine and Science, Rutgers University, New Brunswick, New Jersey
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30
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Kurtz TW, DiCarlo SE, Pravenec M, Morris RC. No evidence of racial disparities in blood pressure salt sensitivity when potassium intake exceeds levels recommended in the US dietary guidelines. Am J Physiol Heart Circ Physiol 2021; 320:H1903-H1918. [PMID: 33797275 DOI: 10.1152/ajpheart.00980.2020] [Citation(s) in RCA: 16] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/26/2023]
Abstract
On average, black individuals are widely believed to be more sensitive than white individuals to blood pressure (BP) effects of changes in salt intake. However, few studies have directly compared the BP effects of changing salt intake in black versus white individuals. In this narrative review, we analyze those studies and note that when potassium intake substantially exceeds the recently recommended US dietary goal of 87 mmol/day, black adults do not appear more sensitive than white adults to BP effects of short-term or long-term increases in salt intake (from an intake ≤50 mmol/day up to 150 mmol/day or more). However, with lower potassium intakes, racial differences in salt sensitivity are observed. Mechanistic studies suggest that racial differences in salt sensitivity are related to differences in vascular resistance responses to changes in salt intake mediated by vasodilator and vasoconstrictor pathways. With respect to cause and prevention of racial disparities in salt sensitivity, it is noteworthy that 1) on average, black individuals consume less potassium than white individuals and 2) consuming supplemental potassium bicarbonate, or potassium rich foods can prevent racial disparities in salt sensitivity. However, the new US dietary guidelines reduced the dietary potassium goal well below the amount associated with preventing racial disparities in salt sensitivity. These observations should motivate research on the impact of the new dietary potassium guidelines on racial disparities in salt sensitivity, the risks and benefits of potassium-containing salt substitutes or supplements, and methods for increasing consumption of foods rich in nutrients that protect against salt-induced hypertension.
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Affiliation(s)
- Theodore W Kurtz
- Department of Laboratory Medicine, University of California, San Francisco, California
| | - Stephen E DiCarlo
- Department of Physiology, College of Osteopathic Medicine, Michigan State University, East Lansing, Michigan
| | - Michal Pravenec
- Institute of Physiology, Czech Academy of Sciences, Prague, Czech Republic
| | - R Curtis Morris
- Department of Medicine, University of California, San Francisco, California
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Mechanisms of Dietary Sodium-Induced Impairments in Endothelial Function and Potential Countermeasures. Nutrients 2021; 13:nu13010270. [PMID: 33477837 PMCID: PMC7832854 DOI: 10.3390/nu13010270] [Citation(s) in RCA: 28] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/19/2020] [Revised: 01/13/2021] [Accepted: 01/16/2021] [Indexed: 01/11/2023] Open
Abstract
Despite decades of efforts to reduce sodium intake, excess dietary sodium remains commonplace, and contributes to increased cardiovascular morbidity and mortality independent of its effects on blood pressure. An increasing amount of research suggests that high-sodium diets lead to reduced nitric oxide-mediated endothelial function, even in the absence of a change in blood pressure. As endothelial dysfunction is an early step in the progression of cardiovascular diseases, the endothelium presents a target for interventions aimed at reducing the impact of excess dietary sodium. In this review, we briefly define endothelial function and present the literature demonstrating that excess dietary sodium results in impaired endothelial function. We then discuss the mechanisms through which sodium impairs the endothelium, including increased reactive oxygen species, decreased intrinsic antioxidant defenses, endothelial cell stiffening, and damage to the endothelial glycocalyx. Finally, we present selected research findings suggesting that aerobic exercise or increased intake of dietary potassium may counteract the deleterious vascular effects of a high-sodium diet.
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Higher Intakes of Potassium and Magnesium, but Not Lower Sodium, Reduce Cardiovascular Risk in the Framingham Offspring Study. Nutrients 2021; 13:nu13010269. [PMID: 33477824 PMCID: PMC7832857 DOI: 10.3390/nu13010269] [Citation(s) in RCA: 16] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/10/2020] [Revised: 01/14/2021] [Accepted: 01/16/2021] [Indexed: 11/30/2022] Open
Abstract
We explored the dose-response relations of sodium, potassium, magnesium and calcium with cardiovascular disease (CVD) risk in the Framingham Offspring Study, as well as the combined effects of these minerals. Analyses included 2362 30–64 year-old men and women free of CVD at baseline. Cox proportional-hazards models were used estimate adjusted hazard ratios (HR) and 95% confidence intervals (CIs) for mineral intakes and incident CVD. Cox models with restricted cubic spline functions were used to examine dose-response relations, adjusting for confounding by age, sex, body mass index, dietary fiber intake, and time-varying occurrence of hypertension. Lower sodium intake (<2500 vs. ≥3500 mg/d) was not associated with a lower risk of CVD. In contrast, potassium intake ≥3000 (vs. <2500) mg/d was associated with a 25% lower risk (95% CI: 0.59, 0.95), while magnesium intake ≥320 (vs. <240) mg/d led to a 34% lower risk (95% CI: 0.51, 0.87) of CVD. Calcium intake ≥700 (vs. <500) mg/d was associated with a non-statistically significant 19% lower risk. Restricted cubic spline curves showed inverse dose-response relations of potassium and magnesium with CVD risk, but no such associations were observed for sodium or calcium. These results highlight the importance of potassium and magnesium to cardiovascular health.
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33
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Stimulation of Epithelial Sodium Channels in Endothelial Cells by Bone Morphogenetic Protein-4 Contributes to Salt-Sensitive Hypertension in Rats. OXIDATIVE MEDICINE AND CELLULAR LONGEVITY 2020; 2020:3921897. [PMID: 33194000 PMCID: PMC7641672 DOI: 10.1155/2020/3921897] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 03/18/2020] [Revised: 07/05/2020] [Accepted: 07/16/2020] [Indexed: 01/03/2023]
Abstract
Previous studies have shown that high salt induces artery stiffness by causing endothelial dysfunction via increased sodium influx. We used our unique split-open artery technique combined with protein biochemistry and in vitro measurement of vascular tone to test a hypothesis that bone morphogenetic protein 4 (BMP4) mediates high salt-induced loss of vascular relaxation by stimulating the epithelial sodium channel (ENaC) in endothelial cells. The data show that high salt intake increased BMP4 both in endothelial cells and in the serum and that exogenous BMP4 stimulated ENaC in endothelial cells. The data also show that the stimulation is mediated by p38 mitogen-activated protein kinases (p38 MAPK) and serum and glucocorticoid-regulated kinase 1 (Sgk1)/neural precursor cell expressed developmentally downregulated gene 4-2 (Nedd4-2) (Sgk1/Nedd4-2). Furthermore, BMP4 decreased mesenteric artery relaxation in a benzamil-sensitive manner. These results suggest that high salt intake stimulates endothelial cells to express and release BMP4 and that the released BMP4 reduces artery relaxation by stimulating ENaC in endothelial cells. Therefore, stimulation of ENaC in endothelial cells by BMP4 may serve as another pathway to participate in the complex mechanism of salt-sensitive (SS) hypertension.
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34
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Jaques DA, Pruijm M, Ackermann D, Vogt B, Guessous I, Burnier M, Pechere-Bertschi A, Bochud M, Ponte B. Sodium Intake Is Associated With Renal Resistive Index in an Adult Population-Based Study. Hypertension 2020; 76:1898-1905. [PMID: 33012201 DOI: 10.1161/hypertensionaha.120.15932] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022]
Abstract
Renal resistive index (RRI) has been associated with adverse renal and cardiovascular outcomes. Although traditionally considered a marker of intrinsic renal damage, RRI could also reflect systemic vascular dysfunction. As sodium intake was linked to alterations in vascular properties, we wished to characterize the association of salt consumption with RRI in the general adult population. Participants were recruited in a population-based study in Switzerland. RRI was measured by ultrasound in 3 segmental arteries. Sodium intake (UNa; mmol/24 h) was estimated on 24-hour urine samples. Carotido-femoral pulse wave velocity was obtained by applanation tonometry. Mixed multivariate regression models were used with RRI or pulse wave velocity as independent variables and UNa as dependent variable, adjusting for possible confounders. We included 1002 patients in the analyses with 528 (52.7%) women and mean age of 47.2±17.4. Mean values of UNa and RRI were 141.8±61.1 mmol/24 h and 63.8±5.5%, respectively. In multivariate analysis, UNa was positively associated with RRI (P=0.002) but not with pulse wave velocity (P=0.344). Plasma renin activity and aldosterone did not modify the relationship between UNa and RRI (P=0.087 for interaction). UNa/urinary potassium ratio was positively associated with pulse wave velocity ≥12 m/s (P=0.033). Our results suggest that dietary salt consumption has a direct impact on renal hemodynamic in the adult general population. Alterations in vascular properties likely explain those findings, but inadequate renal vaso-motor response is also possible. Sodium intake could thus potentially be linked to underlying structural systemic damages affecting this population.
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Affiliation(s)
- David A Jaques
- From the Division of Nephrology and Hypertension (D.A.J., A.P.-B., B.P.), Geneva University Hospitals, Switzerland
| | - Menno Pruijm
- Division of Nephrology and Hypertension, Lausanne University Hospitals, Switzerland (M.P., M.B.)
| | - Daniel Ackermann
- Division of Nephrology and Hypertension, Bern University Hospitals, Switzerland (D.A., B.V.)
| | - Bruno Vogt
- Division of Nephrology and Hypertension, Bern University Hospitals, Switzerland (D.A., B.V.)
| | - Idris Guessous
- Division of Primary Care Medicine (I.G.), Geneva University Hospitals, Switzerland
| | - Michel Burnier
- Division of Nephrology and Hypertension, Lausanne University Hospitals, Switzerland (M.P., M.B.).,University Centre for General Medicine and Public Health, Lausanne, Switzerland (M.B.)
| | - Antoinette Pechere-Bertschi
- From the Division of Nephrology and Hypertension (D.A.J., A.P.-B., B.P.), Geneva University Hospitals, Switzerland
| | | | - Belen Ponte
- From the Division of Nephrology and Hypertension (D.A.J., A.P.-B., B.P.), Geneva University Hospitals, Switzerland
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35
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Goyal A, Lo KB, Chatterjee K, Mathew RO, McCullough PA, Bangalore S, Rangaswami J. Acute coronary syndromes in the peri‐operative period after kidney transplantation in United States. Clin Transplant 2020; 34:e14083. [DOI: 10.1111/ctr.14083] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/17/2020] [Revised: 08/07/2020] [Accepted: 09/03/2020] [Indexed: 12/21/2022]
Affiliation(s)
- Abhinav Goyal
- Department of Digestive Diseases and Transplantation Einstein Medical Center Philadelphia PA USA
| | - Kevin Bryan Lo
- Department of Internal Medicine Einstein Medical Center Philadelphia PA USA
| | | | - Roy O. Mathew
- Division of Nephrology Columbia VA Health Care System Columbia SC USA
| | - Peter A. McCullough
- Baylor University Medical Center Dallas TX USA
- Baylor Jack and Jane Hamilton Heart and Vascular Hospital Baylor Heart and Vascular Institute Dallas TX USA
| | | | - Janani Rangaswami
- Division of Nephrology Department of Medicine Einstein Medical Center Philadelphia PA USA
- Sidney Kimmel College of Thomas Jefferson University Philadelphia PA USA
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36
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Wei KY, Gritter M, Vogt L, de Borst MH, Rotmans JI, Hoorn EJ. Dietary potassium and the kidney: lifesaving physiology. Clin Kidney J 2020; 13:952-968. [PMID: 33391739 PMCID: PMC7769543 DOI: 10.1093/ckj/sfaa157] [Citation(s) in RCA: 30] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/29/2020] [Indexed: 02/07/2023] Open
Abstract
Potassium often has a negative connotation in Nephrology as patients with chronic kidney disease (CKD) are prone to develop hyperkalaemia. Approaches to the management of chronic hyperkalaemia include a low potassium diet or potassium binders. Yet, emerging data indicate that dietary potassium may be beneficial for patients with CKD. Epidemiological studies have shown that a higher urinary potassium excretion (as proxy for higher dietary potassium intake) is associated with lower blood pressure (BP) and lower cardiovascular risk, as well as better kidney outcomes. Considering that the composition of our current diet is characterized by a high sodium and low potassium content, increasing dietary potassium may be equally important as reducing sodium. Recent studies have revealed that dietary potassium modulates the activity of the thiazide-sensitive sodium-chloride cotransporter in the distal convoluted tubule (DCT). The DCT acts as a potassium sensor to control the delivery of sodium to the collecting duct, the potassium-secreting portion of the kidney. Physiologically, this allows immediate kaliuresis after a potassium load, and conservation of potassium during potassium deficiency. Clinically, it provides a novel explanation for the inverse relationship between dietary potassium and BP. Moreover, increasing dietary potassium intake can exert BP-independent effects on the kidney by relieving the deleterious effects of a low potassium diet (inflammation, oxidative stress and fibrosis). The aim of this comprehensive review is to link physiology with clinical medicine by proposing that the same mechanisms that allow us to excrete an acute potassium load also protect us from hypertension, cardiovascular disease and CKD.
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Affiliation(s)
- Kuang-Yu Wei
- Department of Internal Medicine, Division of Nephrology and Transplantation, Erasmus MC, University Medical Center Rotterdam, Rotterdam, The Netherlands.,Department of Internal Medicine, Division of Nephrology, Tri-Service General Hospital, National Defense Medical Center, Taipei, Taiwan
| | - Martin Gritter
- Department of Internal Medicine, Division of Nephrology and Transplantation, Erasmus MC, University Medical Center Rotterdam, Rotterdam, The Netherlands
| | - Liffert Vogt
- Department of Internal Medicine, Division of Nephrology, Amsterdam University Medical Center, Amsterdam, The Netherlands
| | - Martin H de Borst
- Department of Internal Medicine, Division of Nephrology, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands
| | - Joris I Rotmans
- Department of Internal Medicine, Division of Nephrology, Leiden University Medical Center, Leiden, The Netherlands
| | - Ewout J Hoorn
- Department of Internal Medicine, Division of Nephrology and Transplantation, Erasmus MC, University Medical Center Rotterdam, Rotterdam, The Netherlands
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37
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Abstract
Hypokalemia is closely linked with the pathophysiology of primary aldosteronism (PA). Although hypokalemic PA is less common than the normokalemic course of the disease, hypokalemia is of particular importance for the manifestation and development of comorbidities. Specifically, a growing body of evidence demonstrates that hypokalemia in PA patients is associated with a more severe disease course regarding cardiovascular and metabolic morbidity and mortality. It is also well appreciated that low potassium levels per se can promote or exacerbate hypertension. The spectrum of hypokalemia-related symptoms ranges from asymptomatic courses to life-threatening conditions. Hypokalemia is found in 9-37% of all cases of PA with a predominance in patients with aldosterone producing adenoma. Conversely, hypokalemia resolves in almost 100% of cases after both, specific medical or surgical treatment of the disease. However, to date, high-level evidence about the prevalence of primary aldosteronism in a hypokalemic population is missing. Epidemiological data are expected from the recently launched IPAHK+study ("Incidence of Primary Aldosteronism in Patients with Hypokalemia").
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Affiliation(s)
- Sven Gruber
- Klinik für Endokrinologie, Diabetologie und Klinische Ernährung, UniversitätsSpital Zürich, Zurich, Switzerland
| | - Felix Beuschlein
- Klinik für Endokrinologie, Diabetologie und Klinische Ernährung, UniversitätsSpital Zürich, Zurich, Switzerland
- Medizinische Klinik und Poliklinik IV, Klinikum der Universität München, Munich, Germany
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38
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Danilov KA, Vassilieva SG, Polikarpova AV, Starikova AV, Shmidt AA, Galkin II, Tsitrina AA, Egorova TV, Orlov SN, Kotelevtsev YV. In vitro assay for the efficacy assessment of AAV vectors expressing microdystrophin. Exp Cell Res 2020; 392:112033. [PMID: 32360435 DOI: 10.1016/j.yexcr.2020.112033] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/28/2019] [Revised: 03/23/2020] [Accepted: 04/21/2020] [Indexed: 12/26/2022]
Abstract
AAV-delivered microdystrophin genes hold great promise for Duchenne muscular dystrophy (DMD) treatment. It is anticipated that the optimization of engineered dystrophin genes will be required to increase the efficacy and reduce the immunogenicity of transgenic proteins. An in vitro system is required for the efficacy testing of genetically engineered dystrophin genes. We report here on the proof of concept for an in vitro assay based on the assessment of sarcolemma damage after repetitively applied electrical stimuli. The primary cell culture of myoblasts was established from wild-type C57BL/10ScSnJ and dystrophin-deficient mdx mice. The preparation parameters and the differentiation of contractile myotubes were optimized. DAPI and TO-PRO-3 dyes were used to assess myotubular membrane permeability in response to electrical pulse stimulation (EPS). Myotubes derived from mdx mice exhibited a greater increase in membrane damage, as assessed by TO-PRO-3-measured permeability after EPS, than was exhibited by the healthy control myotubes. AAV-DJ particles carrying the microdystrophin gene were used to transduce mdx-derived differentiated myotubes. Microdystrophin delivery ameliorated the disease phenotype and reduced the EPS-induced membrane damage to a level comparable to that of the healthy controls. Thus, the in vitro system was shown to be capable of supporting studies on DMD gene therapy.
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Affiliation(s)
- Kirill A Danilov
- Center of Life Sciences, Skolkovo Institute of Science and Technology, Moscow, 121205, Russia; Atlas Biomed Group Limited, Tintagel House, 92 Albert Embankment, Lambeth, SE1 7TY, London, United Kingdom.
| | - Svetlana G Vassilieva
- Laboratory of Modeling and Gene Therapy of Hereditary Diseases, Institute of Gene Biology, Russian Academy of Sciences, Moscow, 119334, Russia; Marlin Biotech LLC, Moscow, 143026, Russia.
| | - Anna V Polikarpova
- Laboratory of Modeling and Gene Therapy of Hereditary Diseases, Institute of Gene Biology, Russian Academy of Sciences, Moscow, 119334, Russia; Marlin Biotech LLC, Moscow, 143026, Russia.
| | - Anna V Starikova
- Laboratory of Modeling and Gene Therapy of Hereditary Diseases, Institute of Gene Biology, Russian Academy of Sciences, Moscow, 119334, Russia; Marlin Biotech LLC, Moscow, 143026, Russia.
| | - Anna A Shmidt
- Laboratory of Modeling and Gene Therapy of Hereditary Diseases, Institute of Gene Biology, Russian Academy of Sciences, Moscow, 119334, Russia; Marlin Biotech LLC, Moscow, 143026, Russia; Center for Precision Genome Editing and Genetic Technologies for Biomedicine, Institute of Gene Biology, Russian Academy of Sciences, Moscow, 119334, Russia.
| | - Ivan I Galkin
- Marlin Biotech LLC, Moscow, 143026, Russia; A.N. Belozersky Institute of Physico-Chemical Biology, Lomonosov Moscow State University, 119992, Moscow, Russia.
| | - Alexandra A Tsitrina
- Institute of Developmental Biology, Russian Academy of Sciences, Moscow, 119334, Russia.
| | - Tatiana V Egorova
- Laboratory of Modeling and Gene Therapy of Hereditary Diseases, Institute of Gene Biology, Russian Academy of Sciences, Moscow, 119334, Russia; Marlin Biotech LLC, Moscow, 143026, Russia.
| | - Sergei N Orlov
- M.V. Lomonosov Moscow State University, Moscow, 119234, Russia; National Research Tomsk State University, Tomsk, 634050, Russia.
| | - Yuri V Kotelevtsev
- Center for Neurobiology and Brain Restoration, Skolkovo Institute of Science and Technology, Moscow, 121205, Russia.
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39
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Cosgun ZC, Fels B, Kusche-Vihrog K. Nanomechanics of the Endothelial Glycocalyx. THE AMERICAN JOURNAL OF PATHOLOGY 2020; 190:732-741. [DOI: 10.1016/j.ajpath.2019.07.021] [Citation(s) in RCA: 42] [Impact Index Per Article: 8.4] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Received: 05/04/2019] [Revised: 07/10/2019] [Accepted: 07/30/2019] [Indexed: 12/12/2022]
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40
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It takes more than two to tango: mechanosignaling of the endothelial surface. Pflugers Arch 2020; 472:419-433. [PMID: 32239285 PMCID: PMC7165135 DOI: 10.1007/s00424-020-02369-2] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/20/2019] [Revised: 03/13/2020] [Accepted: 03/18/2020] [Indexed: 02/07/2023]
Abstract
The endothelial surface is a highly flexible signaling hub which is able to sense the hemodynamic forces of the streaming blood. The subsequent mechanosignaling is basically mediated by specific structures, like the endothelial glycocalyx building the top surface layer of endothelial cells as well as mechanosensitive ion channels within the endothelial plasma membrane. The mechanical properties of the endothelial cell surface are characterized by the dynamics of cytoskeletal proteins and play a key role in the process of signal transmission from the outside (lumen of the blood vessel) to the interior of the cell. Thus, the cell mechanics directly interact with the function of mechanosensitive structures and ion channels. To precisely maintain the vascular tone, a coordinated functional interdependency between endothelial cells and vascular smooth muscle cells is necessary. This is given by the fact that mechanosensitive ion channels are expressed in both cell types and that signals are transmitted via autocrine/paracrine mechanisms from layer to layer. Thus, the outer layer of the endothelial cells can be seen as important functional mechanosensitive and reactive cellular compartment. This review aims to describe the known mechanosensitive structures of the vessel building a bridge between the important role of physiological mechanosignaling and the proper vascular function. Since mutations and dysfunction of mechanosensitive proteins are linked to vascular pathologies such as hypertension, they play a potent role in the field of channelopathies and mechanomedicine.
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41
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Bui VC, Nguyen TH. Direct monitoring of drug-induced mechanical response of individual cells by atomic force microscopy. J Mol Recognit 2020; 33:e2847. [PMID: 32212218 DOI: 10.1002/jmr.2847] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/20/2019] [Revised: 03/08/2020] [Accepted: 03/10/2020] [Indexed: 01/12/2023]
Abstract
Mechanical characteristics of individual cells play a vital role in many biological processes and are considered as indicators of the cells' states. Disturbances including methyl-β-cyclodextrin (MβCD) and cytochalasin D (cytoD) are known to significantly affect the state of cells, but little is known about the real-time response of single cells to these drugs in their physiological condition. Here, nanoindentation-based atomic force microscopy (AFM) was used to measure the elasticity of human embryonic kidney cells in the presence and absence of these pharmaceuticals. The results showed that depletion of cholesterol in the plasma membrane with MβCD resulted in cell stiffening whereas depolymerization of the actin cytoskeleton by cytoD resulted in cell softening. Using AFM for real-time measurements, we observed that cells mechanically responded right after these drugs were added. In more detail, the cell´s elasticity suddenly increased with increasing instability upon cholesterol extraction while it is rapidly decreased without changing cellular stability upon depolymerizing actin cytoskeleton. These results demonstrated that actin cytoskeleton and cholesterol contributed differently to the cell mechanical characteristics.
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Affiliation(s)
- Van-Chien Bui
- Institute for Immunology and Transfusion Medicine, University Medicine Greifswald, Greifswald, Germany.,ZIK HIKE, University of Greifswald, Greifswald, Germany
| | - Thi-Huong Nguyen
- Institute for Immunology and Transfusion Medicine, University Medicine Greifswald, Greifswald, Germany.,Institute for Bioprocessing and Analytical Measurement Techniques, Heilbad Heiligenstadt, Germany
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42
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Jannatbabaei A, Tafazzoli‐Shadpour M, Seyedjafari E. Effects of substrate mechanics on angiogenic capacity and nitric oxide release in human endothelial cells. Ann N Y Acad Sci 2020; 1470:31-43. [DOI: 10.1111/nyas.14326] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/07/2019] [Revised: 12/15/2019] [Accepted: 02/13/2020] [Indexed: 01/06/2023]
Affiliation(s)
- Atefeh Jannatbabaei
- Department of Biomedical EngineeringAmirkabir University of Technology Tehran Iran
| | | | - Ehsan Seyedjafari
- Department of Biotechnology, College of ScienceUniversity of Tehran Tehran Iran
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43
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Effects of Actin Cytoskeleton Disruption on Electroporation In Vitro. Appl Biochem Biotechnol 2020; 191:1545-1561. [PMID: 32157625 DOI: 10.1007/s12010-020-03271-4] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/23/2019] [Accepted: 02/13/2020] [Indexed: 01/26/2023]
Abstract
The role of actin fibers in cellular responses to external electric pulses is not clear yet. In this study, we utilized the blocker of actin polymerization, cytochalasin D (cytoD), and investigated its effects on the electropore generation. Eight 100 μs electric pulses of sub-kilovolt per centimeter voltage with 100 ms intervals were applied to adhered cells in vitro, and the membrane permeability was quantified using membrane-impermeable propidium iodide (PI) dye. With cytoD application, the transfer of PI dye decreased significantly in all the applied voltages. At the same time, the roughness of cells increased, the membrane stiffness decreased, and the transmembrane resting potential decreased. Our result supports that actin fibers have clear effects on electroporation through modulating membrane properties including transmembrane resting potential.
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44
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Chambers L, Dorrance AM. Regulation of ion channels in the microcirculation by mineralocorticoid receptor activation. CURRENT TOPICS IN MEMBRANES 2020; 85:151-185. [PMID: 32402638 DOI: 10.1016/bs.ctm.2020.02.001] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/17/2022]
Abstract
The mineralocorticoid receptor (MR) has classically been studied in the renal epithelium for its role in regulating sodium and water balance and, subsequently, blood pressure. However, the MR also plays a critical role in the microvasculature by regulating ion channel expression and function. Activation of the MR by its endogenous agonist aldosterone results in translocation of the MR into the nucleus, where it can act as a transcription factor. Although most of the actions of the aldosterone can be attributed to its genomic activity though MR activation, it can also act by nongenomic mechanisms. Activation of this ubiquitous receptor increases the expression of epithelial sodium channels (ENaC) in both the endothelium and smooth muscle cells of peripheral and cerebral vessels. MR activation also regulates activity of calcium channels, calcium-activated potassium channels, and various transient receptor potential (TRP) channels. Modification of these ion channels results in a myriad of negative consequences, including impaired endothelium-dependent vasodilation, alterations in generation of myogenic tone, and increased inflammation and oxidative stress. Taken together, these studies demonstrate the importance of studying the impact of the MR on ion channel function in the vasculature. While research in this area has made advances in recent years, there are still many large gaps in knowledge that need to be filled. Crucial future directions of study include defining the molecular mechanisms involved in this interaction, as well as elucidating the potential sex differences that may exist, as these areas of understanding are currently lacking.
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Affiliation(s)
- Laura Chambers
- Department of Pharmacology and Toxicology, Michigan State University, East Lansing, MI, United States
| | - Anne M Dorrance
- Department of Pharmacology and Toxicology, Michigan State University, East Lansing, MI, United States.
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45
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Mandriota N, Friedsam C, Jones-Molina JA, Tatem KV, Ingber DE, Sahin O. Cellular nanoscale stiffness patterns governed by intracellular forces. NATURE MATERIALS 2019; 18:1071-1077. [PMID: 31209386 PMCID: PMC6754298 DOI: 10.1038/s41563-019-0391-7] [Citation(s) in RCA: 50] [Impact Index Per Article: 8.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 06/23/2016] [Accepted: 04/30/2019] [Indexed: 05/24/2023]
Abstract
Cell stiffness measurements have led to insights into various physiological and pathological processes1,2. Although many cellular behaviours are influenced by intracellular mechanical forces3-6 that also alter the material properties of the cell, the precise mechanistic relationship between intracellular forces and cell stiffness remains unclear. Here we develop a cell mechanical imaging platform with high spatial resolution that reveals the existence of nanoscale stiffness patterns governed by intracellular forces. On the basis of these findings, we develop and validate a cellular mechanical model that quantitatively relates cell stiffness to intracellular forces. This allows us to determine the magnitude of tension within actin bundles, cell cortex and plasma membrane from the cell stiffness patterns across individual cells. These results expand our knowledge on the mechanical interaction between cells and their environments, and offer an alternative approach to determine physiologically relevant intracellular forces from high-resolution cell stiffness images.
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Affiliation(s)
- Nicola Mandriota
- Department of Biological Sciences, Columbia University, New York, NY, USA
| | - Claudia Friedsam
- Wyss Institute for Biologically Inspired Engineering, Harvard University, Boston, MA, USA
| | | | - Kathleen V Tatem
- Department of Biological Sciences, Columbia University, New York, NY, USA
- Department of Physics, Columbia University, New York, NY, USA
| | - Donald E Ingber
- Wyss Institute for Biologically Inspired Engineering, Harvard University, Boston, MA, USA
- Harvard John A. Paulson School of Engineering and Applied Sciences, Harvard University, Cambridge, MA, USA
- Vascular Biology Program and Departments of Surgery, Boston Children's Hospital and Harvard Medical School, Boston, MA, USA
| | - Ozgur Sahin
- Department of Biological Sciences, Columbia University, New York, NY, USA.
- Department of Physics, Columbia University, New York, NY, USA.
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46
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Estimated 24-h urinary sodium and sodium-to-potassium ratio are predictors of kidney function decline in a population-based study. J Hypertens 2019; 37:1853-1860. [DOI: 10.1097/hjh.0000000000002098] [Citation(s) in RCA: 18] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/31/2022]
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47
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Rusaczonek M, Zapotoczny B, Szymonski M, Konior J. Application of a layered model for determination of the elasticity of biological systems. Micron 2019; 124:102705. [PMID: 31252332 DOI: 10.1016/j.micron.2019.102705] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/28/2018] [Revised: 06/13/2019] [Accepted: 06/14/2019] [Indexed: 01/22/2023]
Abstract
Elasticity of biological systems is considered to be an important property that might be related to functional or pathological changes. Therefore, careful study and detailed understanding of cell and tissue elasticity is crucial for correct description of their functioning. Atomic Force Microscopy (AFM) is a powerful technique, which allows for determination of the physical properties, such as elasticity, of soft-matter systems in nano-scale. An important step in AFM elasticity studies is a proper interpretation of experimental data. Two most frequently used theoretical schemes applied to determine elasticity are due to Hertz and Sneddon, which are effectively one-parameter models. In this work, we go beyond this approach. Firstly, as elasticity is a local property, we extract from the slope of experimental force-indentation curve an elasticity parameter, which varies with indentation depth. Then secondly, we find best approximation of this parameter by applying the two-layer model with four effective parameters, as proposed by Kovalev. This method is employed to the experimental data taken on murine liver sinusoidal endothelial cells in non-alcoholic fatty liver disease model. The obtained results show additional effects, not seen within the traditional, simplified scheme. Namely, the elasticity of the first layer does not change its value in the model of non-alcoholic fatty liver disease, but the increase of stiffness is noticed in second layer. The second goal of this article is to reveal and discuss the differences between traditional approaches and the one being presented. The deviations from the original assumptions are analysed and the corresponding restrictions on utility of theoretical models are presented.
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Affiliation(s)
- M Rusaczonek
- Marian Smoluchowski Institute of Physics, Department of Physics, Astronomy, and Applied Computer Science, Jagiellonian University, 30-059 Kraków, Poland.
| | - B Zapotoczny
- Marian Smoluchowski Institute of Physics, Department of Physics, Astronomy, and Applied Computer Science, Jagiellonian University, 30-059 Kraków, Poland
| | - M Szymonski
- Marian Smoluchowski Institute of Physics, Department of Physics, Astronomy, and Applied Computer Science, Jagiellonian University, 30-059 Kraków, Poland
| | - J Konior
- Marian Smoluchowski Institute of Physics, Department of Physics, Astronomy, and Applied Computer Science, Jagiellonian University, 30-059 Kraków, Poland
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Gandola AE, Dainelli L, Zimmermann D, Dahlui M, Detzel P. Milk Powder Fortified with Potassium and Phytosterols to Decrease the Risk of Cardiovascular Events among the Adult Population in Malaysia: A Cost-Effectiveness Analysis. Nutrients 2019; 11:E1235. [PMID: 31151244 PMCID: PMC6627836 DOI: 10.3390/nu11061235] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/17/2019] [Revised: 05/17/2019] [Accepted: 05/27/2019] [Indexed: 11/17/2022] Open
Abstract
This study evaluated the cost-effectiveness of the consumption of a milk powder product fortified with potassium (+1050.28 mg/day) and phytosterols (+1200 mg/day) to lower systolic blood pressure and low-density lipoprotein cholesterol, respectively, and, therefore, the risk of myocardial infarction (MI) and stroke among the 35-75-year-old population in Malaysia. A Markov model was created against a do-nothing option, from a governmental perspective, and with a time horizon of 40 years. Different data sources, encompassing clinical studies, practice guidelines, grey literature, and statistical yearbooks, were used. Sensitivity analyses were performed to evaluate the impact of uncertainty on the base case estimates. With an incremental cost-effectiveness ratio equal to international dollars (int$) 22,518.03 per quality-adjusted life-years gained, the intervention can be classified as very cost-effective. If adopted nationwide, it would help prevent at least 13,400 MIs, 30,500 strokes, and more than 10,600 and 17,100 MI- and stroke-related deaths. The discounted cost savings generated for the health care system by those who consume the fortified milk powder would amount to int$8.1 per person, corresponding to 0.7% of the total yearly health expenditure per capita. Sensitivity analyses confirmed the robustness of the results. Together with other preventive interventions, the consumption of milk powder fortified with potassium and phytosterols represents a cost-effective strategy to attenuate the rapid increase in cardiovascular burden in Malaysia.
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Affiliation(s)
- Anita E Gandola
- Nestlé Research Center, 1000 Lausanne, Switzerland.
- Università della Svizzera Italiana, 6900 Lugano, Switzerland.
| | | | | | - Maznah Dahlui
- Centre of Population Health, Faculty of Medicine, University of Malaya, Kuala Lumpur 50603, Malaysia.
- Faculty of Public Health, Universitas Airlangga, Surabaya 60115, Indonesia.
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Fels J, Kusche-Vihrog K. Endothelial Nanomechanics in the Context of Endothelial (Dys)function and Inflammation. Antioxid Redox Signal 2019; 30:945-959. [PMID: 29433330 PMCID: PMC6354603 DOI: 10.1089/ars.2017.7327] [Citation(s) in RCA: 24] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/21/2017] [Accepted: 08/31/2017] [Indexed: 12/31/2022]
Abstract
SIGNIFICANCE Stiffness of endothelial cells is closely linked to the function of the vasculature as it regulates the release of vasoactive substances such as nitric oxide (NO) and reactive oxygen species. The outer layer of endothelial cells, consisting of the glycocalyx above and the cortical zone beneath the plasma membrane, is a vulnerable compartment able to adapt its nanomechanical properties to any changes of forces exerted by the adjacent blood stream. Sustained stiffening of this layer contributes to the development of endothelial dysfunction and vascular pathologies. Recent Advances: The development of specific techniques to quantify the mechanical properties of cells enables the detailed investigation of the mechanistic link between structure and function of cells. CRITICAL ISSUES Challenging the mechanical stiffness of cells, for instance, by inflammatory mediators can lead to the development of endothelial dysfunction. Prevention of sustained stiffening of the outer layer of endothelial cells in turn improves endothelial function. FUTURE DIRECTIONS The mechanical properties of cells can be used as critical marker and test system for the proper function of the vascular system. Pharmacological substances, which are able to improve endothelial nanomechanics and function, could take a new importance in the prevention and treatment of vascular diseases. Thus, detailed knowledge acquisition about the structure/function relationship of endothelial cells and the underlying signaling pathways should be promoted.
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Affiliation(s)
- Johannes Fels
- Institute of Cell Dynamics and Imaging, University of Münster, Münster, Germany
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Maase M, Rygula A, Pacia MZ, Proniewski B, Mateuszuk L, Sternak M, Kaczor A, Chlopicki S, Kusche-Vihrog K. Combined Raman- and AFM-based detection of biochemical and nanomechanical features of endothelial dysfunction in aorta isolated from ApoE/LDLR-/- mice. NANOMEDICINE-NANOTECHNOLOGY BIOLOGY AND MEDICINE 2018; 16:97-105. [PMID: 30550804 DOI: 10.1016/j.nano.2018.11.014] [Citation(s) in RCA: 18] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 08/20/2018] [Revised: 11/09/2018] [Accepted: 11/20/2018] [Indexed: 01/08/2023]
Abstract
Endothelial dysfunction is recognized as a critical condition in the development of cardiovascular disorders. This multifactorial process involves changes in the biochemical and mechanical properties of endothelial cells leading to disturbed release of vasoprotective mediators. Hypercholesterolemia and increased stiffness of the endothelial cortex are independently shown to result in reduced release of nitric oxide and thus endothelial dysfunction. However, direct evidence linking these parameters to each other is missing. Here, a novel method combining Raman spectroscopy for biochemical analysis and Atomic Force Microscopy (AFM) for analyzing the endothelial nanomechanics was established. Using this dual approach, the same areas of native ex vivo aortas were investigated, either derived from mice with endothelial dysfunction (ApoE/LDLR-/-) or wild type mice. In particular an increased intracellular lipid content and elevated cortical stiffness/elasticity were shown in ApoE/LDLR-/- aortas, demonstrating a direct link between endothelial dysfunction, the biochemical composition and the nanomechanical properties of endothelial cells.
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Affiliation(s)
- Martina Maase
- Institute of Physiology II, University of Münster, Robert-Koch Str. 27b, 48149 Münster, Germany
| | - Anna Rygula
- Jagiellonian Centre for Experimental Therapeutics (JCET), Jagiellonian University, Bobrzynskiego 14, 30-348 Krakow, Poland
| | - Marta Z Pacia
- Jagiellonian Centre for Experimental Therapeutics (JCET), Jagiellonian University, Bobrzynskiego 14, 30-348 Krakow, Poland; Faculty of Chemistry, Jagiellonian University, Gronostajowa 2, 30-387 Krakow, Poland
| | - Bartosz Proniewski
- Jagiellonian Centre for Experimental Therapeutics (JCET), Jagiellonian University, Bobrzynskiego 14, 30-348 Krakow, Poland
| | - Lukasz Mateuszuk
- Jagiellonian Centre for Experimental Therapeutics (JCET), Jagiellonian University, Bobrzynskiego 14, 30-348 Krakow, Poland
| | - Magdalena Sternak
- Jagiellonian Centre for Experimental Therapeutics (JCET), Jagiellonian University, Bobrzynskiego 14, 30-348 Krakow, Poland
| | - Agnieszka Kaczor
- Jagiellonian Centre for Experimental Therapeutics (JCET), Jagiellonian University, Bobrzynskiego 14, 30-348 Krakow, Poland; Faculty of Chemistry, Jagiellonian University, Gronostajowa 2, 30-387 Krakow, Poland
| | - Stefan Chlopicki
- Jagiellonian Centre for Experimental Therapeutics (JCET), Jagiellonian University, Bobrzynskiego 14, 30-348 Krakow, Poland; Chair of Pharmacology, Jagiellonian University, Grzegorzecka 16, 31-531 Krakow, Poland.
| | - Kristina Kusche-Vihrog
- Institute of Physiology II, University of Münster, Robert-Koch Str. 27b, 48149 Münster, Germany; Institute of Physiology, University of Lübeck, Ratzeburger Allee 160, 23562 Lübeck, Germany.
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