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1
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Bellemare M, Bourcier L, Iglesies‐Grau J, Boulet J, O'Meara E, Bouabdallaoui N. Mechanisms of diabetic cardiomyopathy: Focus on inflammation. Diabetes Obes Metab 2025; 27:2326-2338. [PMID: 39930551 PMCID: PMC11964996 DOI: 10.1111/dom.16242] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/28/2024] [Revised: 01/23/2025] [Accepted: 01/25/2025] [Indexed: 04/04/2025]
Abstract
PURPOSE OF REVIEW Type 2 diabetes (T2D) significantly increases the risk of heart failure (HF), either through the progression of coronary artery disease (CAD) or through direct myocardial alterations, termed diabetic cardiomyopathy. This review examines key pathophysiological mechanisms underlying diabetic cardiomyopathy, focusing on the role of inflammation. It also addresses diagnostic and therapeutic approaches to mitigate myocardial damage in T2D. RECENT FINDINGS Chronic low-grade inflammation is considered as a major contributor to diabetic cardiomyopathy. T2D-related factors, including hyperglycemia and insulin resistance, activate inflammatory pathways that worsen myocardial dysfunction. Despite advances in understanding these mechanisms, no therapies specifically targeting the cardiac changes in T2D have been identified. SUMMARY While significant advances have been made in elucidating the inflammatory mechanisms contributing to diabetic cardiomyopathy, therapeutic advancements remain limited, potentially due to an incomplete understanding of regulatory pathways. A comprehensive investigation into the specific roles of immune cells and inflammatory mediators in diabetic cardiomyopathy is essential for identifying novel therapeutic targets. Expanding our knowledge of these molecular mechanisms has the potential to facilitate the development of innovative therapeutic strategies, thereby improving clinical outcomes in patients with T2D.
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Affiliation(s)
- Myriam Bellemare
- Department of MedicineMontreal Heart InstituteMontrealQCCanada
- Université de MontréalMontrealQCCanada
| | - Liane Bourcier
- Department of MedicineMontreal Heart InstituteMontrealQCCanada
- Université de MontréalMontrealQCCanada
| | - Josep Iglesies‐Grau
- Department of MedicineMontreal Heart InstituteMontrealQCCanada
- Université de MontréalMontrealQCCanada
| | - Jacinthe Boulet
- Department of MedicineMontreal Heart InstituteMontrealQCCanada
- Université de MontréalMontrealQCCanada
| | - Eileen O'Meara
- Department of MedicineMontreal Heart InstituteMontrealQCCanada
- Université de MontréalMontrealQCCanada
| | - Nadia Bouabdallaoui
- Department of MedicineMontreal Heart InstituteMontrealQCCanada
- Université de MontréalMontrealQCCanada
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2
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Kozakova M, Morizzo C, Penno G, Chiappino D, Palombo C. Diabetes-Related Changes in Carotid Wall Properties: Role of Triglycerides. J Clin Med 2024; 13:5654. [PMID: 39337141 PMCID: PMC11433327 DOI: 10.3390/jcm13185654] [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: 08/06/2024] [Revised: 09/07/2024] [Accepted: 09/19/2024] [Indexed: 09/30/2024] Open
Abstract
Background/Objectives: This study compares the power of the radiofrequency (RF) signal reflected from the media layer (media power) of the common carotid artery (CCA) and the CCA stiffness between individuals with and without type 2 diabetes mellitus (T2DM). It also evaluates the associations of CCA media power with plasma glucose and lipid levels, as well as carotid stiffness. Methods: A total of 540 individuals, 115 with and 425 without T2DM (273 males, mean age = 64 ± 8 years) were studied using RF-based tracking of the right CCA. The following parameters were measured: CCA media thickness, luminal diameter, wall tensile stress (WTS), local pulse wave velocity (PWV), and media power. Results: Compared to the non-diabetic individuals, the T2DM patients had significantly higher CCA media thickness (652 ± 122 vs. 721 ± 138 microns, p < 0.005), luminal diameter (6.12 ± 0.78 vs. 6.86 ± 0.96 mm, p < 0.0005), media power (36.1 ± 4.8 vs. 39.3 ± 4.6, p < 0.0001), and PWV (7.65 ± 1.32 vs. 8.40 ± 1.89 m/s; p < 0.01), but comparable WTS (32.7 ± 10.4 vs. 33.1 ± 10.7 kPa; p = 0.25). In the entire population, CCA media power was independently associated with male sex, pulse pressure, current smoking, and T2DM; when T2DM was not included in the model, triglycerides emerged as an independent determinant of media power. The CCA PWV was independently associated with age, pulse pressure, media power, and T2DM. Conclusions: Our findings suggest the presence of structural changes in the arterial media of T2DM patients, leading to carotid stiffening and remodeling, aiming to preserve WTS. T2DM-related changes in arterial wall composition may be driven by high plasma triglyceride levels, which have previously been associated with both arterial stiffening and the incidence of CV events.
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Affiliation(s)
- Michaela Kozakova
- Department of Clinical and Experimental Medicine, University of Pisa, 56126 Pisa, Italy; (M.K.); (G.P.)
- Esaote SpA, 16153 Genova, Italy
| | - Carmela Morizzo
- School of Medicine, Department of Surgical, Medical, Molecular Pathology and Critical Care Medicine, University of Pisa, 56126 Pisa, Italy;
| | - Giuseppe Penno
- Department of Clinical and Experimental Medicine, University of Pisa, 56126 Pisa, Italy; (M.K.); (G.P.)
| | - Dante Chiappino
- Fondazione Toscana G. Monasterio, Massa-Pisa, 56124 Pisa, Italy;
| | - Carlo Palombo
- School of Medicine, Department of Surgical, Medical, Molecular Pathology and Critical Care Medicine, University of Pisa, 56126 Pisa, Italy;
- Department of Surgical, Medical, Molecular Pathology and Critical Care Medicine, University of Pisa, Via Savi 10, 56126 Pisa, Italy
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3
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Vergès B. Cardiovascular disease in type 1 diabetes, an underestimated danger: Epidemiological and pathophysiological data. Atherosclerosis 2024; 394:117158. [PMID: 37369617 DOI: 10.1016/j.atherosclerosis.2023.06.005] [Citation(s) in RCA: 6] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/24/2023] [Revised: 06/03/2023] [Accepted: 06/06/2023] [Indexed: 06/29/2023]
Abstract
Cardiovascular disease (CV) is a common complication of type 1 diabetes (T1D) and a leading cause of death. T1D patients are more likely to develop CV disease (CVD) early in life and show a reduction of life expectancy of at least 11 years. Patients with a young age of T1D onset have a substantially higher CV risk. The reasons for increased atherosclerosis in T1D patients are not entirely explained. In addition to the typical CV risk factors, long-term hyperglycemia has a significant impact by inducing oxidative stress, vascular inflammation, monocyte adhesion, arterial wall thickening and endothelial dysfunction. Additionally, CVD in T1D is also associated with nephropathy. However, CVD risk is still significantly increased in T1D patients, in good glycemic control without additional CV risk factors, indicating the involvement of supplementary potential factors. By increasing oxidative stress, vascular inflammation, and endothelial dysfunction, hypoglycemia and glucose variability may exacerbate CVD. Moreover, significant qualitative and functional abnormalities of lipoproteins are present in even well-controlled T1D patients and are likely to play a role in the development of atherosclerosis and the promotion of CVD. According to recent research, immune system dysfunction, which is typical of auto-immune T1D, may also promote CVD, likely via inflammatory pathways. In addition, T1D patients who are overweight or obese exhibit an additional CV risk due to pathophysiological mechanisms that are similar to those seen in T2D.
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Affiliation(s)
- Bruno Vergès
- Endocrinology-Diabetology Department, University-Hospital of Dijon, Dijon, France; INSERM LNC-UMR1231, Medicine University, 21000 Dijon, France; Service Endocrinologie, Diabétologie et Maladies Métaboliques, CHU-Dijon, 14 rue Gaffarel, F-21000 Dijon, France.
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4
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Elrashidy RA, Mohamed HE, Abdel Aal SM, Mohamed SR, Tolba SM, Mahmoud YK. Oleuropein attenuates the nephrotoxic effect of sunitinib in rats: Unraveling the potential role of SIRT6/Notch-1/NLRP-3/IL-1β axis. Arch Biochem Biophys 2024; 755:109986. [PMID: 38582273 DOI: 10.1016/j.abb.2024.109986] [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: 02/11/2024] [Revised: 04/01/2024] [Accepted: 04/03/2024] [Indexed: 04/08/2024]
Abstract
Sunitinib (SUN) is a chemotherapeutic agent clinically approved for treatment of metastatic renal carcinoma. Despite its remarkable benefits, various renal toxicities have been reported that limit its clinical uses. Oleuropein (OLE) is the main polyphenolic constituent of olive tree and mediates the majority of its valuable pharmacological activities. The current study examined the probable renoprotective effects of OLE against SUN-induced nephrotoxicity. Adult male albino rats were co-treated by SUN (25 mg/kg, 3 times/week, PO) with either a drug vehicle or OLE (60 mg/kg/day, daily, PO) for four weeks. A control group comprising of age-matched rats was used. Four weeks later, blood specimens were collected to assess kidney functions. Kidneys were harvested for biochemical and histopathological analyses. Administration of SUN induced kidney dysfunction, along with marked rises in endothelin-1 (ET-1) and monocyte chemotactic protein-1 (MCP-1) levels in renal tissues. Histological abnormalities were also detected in kidneys of SUN-treated rats including glomerular and tubular interstitial congestion along with interstitial fibrosis. On molecular levels, there was a decline in renal SIRT6 expression along with significant up-regulation of Notch-1, NLRP-3, interleukin -1β (IL-1β) and cleaved caspsase-3. All these changes were almost alleviated by OLE co-treatment. These findings suggest the implication of SIRT6/Notch-1/NLRP3/IL-1β axis in the pathogenesis of SUN-induced nephrotoxicity and highlight OLE as a prospective renoprotective agent during SUN chemotherapy to halt its renal toxicity likely through promotion of SIRT6 and suppression of Notch-1/NLRP3/IL-1β signaling pathway.
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Affiliation(s)
- Rania A Elrashidy
- Biochemistry Department, Faculty of Pharmacy, Zagazig University, Zagazig, 44519, Egypt.
| | - Hoda E Mohamed
- Biochemistry Department, Faculty of Pharmacy, Zagazig University, Zagazig, 44519, Egypt
| | - Sara M Abdel Aal
- Histology & Cell Biology Department, Faculty of Medicine, Zagazig University, Zagazig, 44519, Egypt
| | - Samar R Mohamed
- Histology & Cell Biology Department, Faculty of Medicine, Zagazig University, Zagazig, 44519, Egypt
| | - Sara M Tolba
- Biochemistry Department, Faculty of Pharmacy, Zagazig University, Zagazig, 44519, Egypt
| | - Yasmin K Mahmoud
- Biochemistry Department, Faculty of Pharmacy, Zagazig University, Zagazig, 44519, Egypt
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5
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Uceda AB, Mariño L, Casasnovas R, Adrover M. An overview on glycation: molecular mechanisms, impact on proteins, pathogenesis, and inhibition. Biophys Rev 2024; 16:189-218. [PMID: 38737201 PMCID: PMC11078917 DOI: 10.1007/s12551-024-01188-4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 03/21/2024] [Indexed: 05/14/2024] Open
Abstract
The formation of a heterogeneous set of advanced glycation end products (AGEs) is the final outcome of a non-enzymatic process that occurs in vivo on long-life biomolecules. This process, known as glycation, starts with the reaction between reducing sugars, or their autoxidation products, with the amino groups of proteins, DNA, or lipids, thus gaining relevance under hyperglycemic conditions. Once AGEs are formed, they might affect the biological function of the biomacromolecule and, therefore, induce the development of pathophysiological events. In fact, the accumulation of AGEs has been pointed as a triggering factor of obesity, diabetes-related diseases, coronary artery disease, neurological disorders, or chronic renal failure, among others. Given the deleterious consequences of glycation, evolution has designed endogenous mechanisms to undo glycation or to prevent it. In addition, many exogenous molecules have also emerged as powerful glycation inhibitors. This review aims to provide an overview on what glycation is. It starts by explaining the similarities and differences between glycation and glycosylation. Then, it describes in detail the molecular mechanism underlying glycation reactions, and the bio-molecular targets with higher propensity to be glycated. Next, it discusses the precise effects of glycation on protein structure, function, and aggregation, and how computational chemistry has provided insights on these aspects. Finally, it reports the most prevalent diseases induced by glycation, and the endogenous mechanisms and the current therapeutic interventions against it.
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Affiliation(s)
- Ana Belén Uceda
- Departament de Química, Universitat de Les Illes Balears, Health Research Institute of the Balearic Islands (IdISBa), Ctra. Valldemossa Km 7.5, 07122 Palma, Spain
| | - Laura Mariño
- Departament de Química, Universitat de Les Illes Balears, Health Research Institute of the Balearic Islands (IdISBa), Ctra. Valldemossa Km 7.5, 07122 Palma, Spain
| | - Rodrigo Casasnovas
- Departament de Química, Universitat de Les Illes Balears, Health Research Institute of the Balearic Islands (IdISBa), Ctra. Valldemossa Km 7.5, 07122 Palma, Spain
| | - Miquel Adrover
- Departament de Química, Universitat de Les Illes Balears, Health Research Institute of the Balearic Islands (IdISBa), Ctra. Valldemossa Km 7.5, 07122 Palma, Spain
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6
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Bronowicka-Szydełko A, Gostomska-Pampuch K, Kuzan A, Pietkiewicz J, Krzystek-Korpacka M, Gamian A. Effect of advanced glycation end-products in a wide range of medical problems including COVID-19. Adv Med Sci 2024; 69:36-50. [PMID: 38335908 DOI: 10.1016/j.advms.2024.01.003] [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: 06/07/2023] [Revised: 09/07/2023] [Accepted: 01/19/2024] [Indexed: 02/12/2024]
Abstract
Glycation is a physiological process that determines the aging of the organism, while in states of metabolic disorders it is significantly intensified. High concentrations of compounds such as reducing sugars or reactive aldehydes derived from lipid oxidation, occurring for example in diabetes, atherosclerosis, dyslipidemia, obesity or metabolic syndrome, lead to increased glycation of proteins, lipids and nucleic acids. The level of advanced glycation end-products (AGEs) in the body depends on rapidity of their production and the rate of their removal by the urinary system. AGEs, accumulated in the extracellular matrix of the blood vessels and other organs, cause irreversible changes in the biochemical and biomechanical properties of tissues. As a consequence, micro- and macroangiopathies appear in the system, and may contribute to the organ failure, like kidneys and heart. Elevated levels of AGEs also increase the risk of Alzheimer's disease and various cancers. In this paper, we propose a new classification due to modified amino acid residues: arginyl-AGEs, monolysyl-AGEs and lysyl-arginyl-AGEs and dilysyl-AGEs. Furthermore, we describe in detail the effect of AGEs on the pathogenesis of metabolic and old age diseases, such as diabetic complications, atherosclerosis and neurodegenerative diseases. We summarize the currently available data on the diagnostic value of AGEs and present the AGEs as a therapeutic goal in a wide range of medical problems, including SARS-CoV-2 infection and so-called long COVID.
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Affiliation(s)
| | | | - Aleksandra Kuzan
- Department of Medical Biochemistry, Wroclaw Medical University, Wroclaw, Poland.
| | - Jadwiga Pietkiewicz
- Department of Medical Biochemistry, Wroclaw Medical University, Wroclaw, Poland
| | | | - Andrzej Gamian
- Department of Immunology of Infectious Diseases, Hirszfeld Institute of Immunology and Experimental Therapy, Polish Academy of Sciences, Wroclaw, Poland
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7
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Huang Y, Ding Y, Wang B, Ji Q, Peng C, Tan Q. Neutrophils extracellular traps and ferroptosis in diabetic wounds. Int Wound J 2023; 20:3840-3854. [PMID: 37199077 PMCID: PMC10588347 DOI: 10.1111/iwj.14231] [Citation(s) in RCA: 10] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/25/2023] [Revised: 05/02/2023] [Accepted: 05/02/2023] [Indexed: 05/19/2023] Open
Abstract
Wound healing is an extremely complex process involving multiple levels of cells and tissues. It is mainly completed through four stages: haemostasis, inflammation, proliferation, and remodelling. When any one of these stages is impaired, it may lead to delayed healing or even transformation into chronic refractory wounds. Diabetes is a kind of common metabolic disease that affects approximately 500 million people worldwide, 25% of whom develop skin ulcers that break down repeatedly and are difficult to heal, making it a growing public health problem. Neutrophils extracellular traps and ferroptosis are new types of programmed cell death identified in recent years and have been found to interact with diabetic wounds. In this paper, the normal wound healing and interfering factors of the diabetic refractory wound were outlined. The mechanism of two kinds of programmed cell death was also described, and the interaction mechanism between different types of programmed cell death and diabetic refractory wounds was discussed.
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Affiliation(s)
- Yumeng Huang
- Department of Burns and Plastic SurgeryNanjing Drum Tower Hospital Clinical College of Jiangsu UniversityNanjingChina
| | - Youjun Ding
- Department of Burns and Plastic SurgeryNanjing Drum Tower Hospital Clinical College of Jiangsu UniversityNanjingChina
- Department of Emergency SurgeryThe Fourth Affiliated Hospital of Jiangsu University (Zhenjiang Fourth People's Hospital)ZhenjiangChina
| | - Beizhi Wang
- Department of Burns and Plastic SurgeryNanjing Drum Tower Hospital Clinical College of Nanjing University of Chinese MedicineNanjingChina
| | - Qian Ji
- Department of OncologyAffiliated Hospital of Jiangsu UniversityZhenjiangChina
| | - Chen Peng
- Department of OncologyAffiliated Hospital of Jiangsu UniversityZhenjiangChina
| | - Qian Tan
- Department of Burns and Plastic SurgeryNanjing Drum Tower Hospital Clinical College of Jiangsu UniversityNanjingChina
- Department of Burns and Plastic Surgery, Nanjing Drum Tower HospitalThe Affiliated Hospital of Nanjing University Medical SchoolNanjingChina
- Department of Burns and Plastic SurgeryAnqing Shihua Hospital of Nanjing Drum Tower Hospital GroupAnqingChina
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8
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Urbano F, Farella I, Brunetti G, Faienza MF. Pediatric Type 1 Diabetes: Mechanisms and Impact of Technologies on Comorbidities and Life Expectancy. Int J Mol Sci 2023; 24:11980. [PMID: 37569354 PMCID: PMC10418611 DOI: 10.3390/ijms241511980] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/29/2023] [Revised: 07/20/2023] [Accepted: 07/24/2023] [Indexed: 08/13/2023] Open
Abstract
Type 1 diabetes (T1D) is one of the most common chronic diseases in childhood, with a progressively increasing incidence. T1D management requires lifelong insulin treatment and ongoing health care support. The main goal of treatment is to maintain blood glucose levels as close to the physiological range as possible, particularly to avoid blood glucose fluctuations, which have been linked to morbidity and mortality in patients with T1D. Indeed, the guidelines of the International Society for Pediatric and Adolescent Diabetes (ISPAD) recommend a glycated hemoglobin (HbA1c) level < 53 mmol/mol (<7.0%) for young people with T1D to avoid comorbidities. Moreover, diabetic disease strongly influences the quality of life of young patients who must undergo continuous monitoring of glycemic values and the administration of subcutaneous insulin. In recent decades, the development of automated insulin delivery (AID) systems improved the metabolic control and the quality of life of T1D patients. Continuous subcutaneous insulin infusion (CSII) combined with continuous glucose monitoring (CGM) devices connected to smartphones represent a good therapeutic option, especially in young children. In this literature review, we revised the mechanisms of the currently available technologies for T1D in pediatric age and explored their effect on short- and long-term diabetes-related comorbidities, quality of life, and life expectation.
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Affiliation(s)
- Flavia Urbano
- Giovanni XXIII Pediatric Hospital, 70126 Bari, Italy;
| | - Ilaria Farella
- Clinica Medica “A. Murri”, University of Bari “Aldo Moro”, 70124 Bari, Italy;
| | - Giacomina Brunetti
- Department of Biosciences, Biotechnologies, and Environment, University of Bari “Aldo Moro”, 70125 Bari, Italy
| | - Maria Felicia Faienza
- Department of Precision and Regenerative Medicine and Ionian Area, University of Bari “Aldo Moro”, 70124 Bari, Italy;
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9
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Infante B, Conserva F, Pontrelli P, Leo S, Stasi A, Fiorentino M, Troise D, dello Strologo A, Alfieri C, Gesualdo L, Castellano G, Stallone G. Recent advances in molecular mechanisms of acute kidney injury in patients with diabetes mellitus. Front Endocrinol (Lausanne) 2023; 13:903970. [PMID: 36686462 PMCID: PMC9849571 DOI: 10.3389/fendo.2022.903970] [Citation(s) in RCA: 9] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/24/2022] [Accepted: 12/14/2022] [Indexed: 01/06/2023] Open
Abstract
Several insults can lead to acute kidney injury (AKI) in native kidney and transplant patients, with diabetes critically contributing as pivotal risk factor. High glucose per se can disrupt several signaling pathways within the kidney that, if not restored, can favor the instauration of mechanisms of maladaptive repair, altering kidney homeostasis and proper function. Diabetic kidneys frequently show reduced oxygenation, vascular damage and enhanced inflammatory response, features that increase the kidney vulnerability to hypoxia. Importantly, epidemiologic data shows that previous episodes of AKI increase susceptibility to diabetic kidney disease (DKD), and that patients with DKD and history of AKI have a generally worse prognosis compared to DKD patients without AKI; it is therefore crucial to monitor diabetic patients for AKI. In the present review, we will describe the causes that contribute to increased susceptibility to AKI in diabetes, with focus on the molecular mechanisms that occur during hyperglycemia and how these mechanisms expose the different types of resident renal cells to be more vulnerable to maladaptive repair during AKI (contrast- and drug-induced AKI). Finally, we will review the list of the existing candidate biomarkers of diagnosis and prognosis of AKI in patients with diabetes.
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Affiliation(s)
- Barbara Infante
- Department of Medical and Surgical Sciences, University of Foggia, Foggia, Italy
| | - Francesca Conserva
- Department of Emergency and Organ Transplantation, University of Bari Aldo Moro, Bari, Italy
| | - Paola Pontrelli
- Department of Emergency and Organ Transplantation, University of Bari Aldo Moro, Bari, Italy
| | - Serena Leo
- Department of Medical and Surgical Sciences, University of Foggia, Foggia, Italy
| | - Alessandra Stasi
- Department of Emergency and Organ Transplantation, University of Bari Aldo Moro, Bari, Italy
| | - Marco Fiorentino
- Department of Emergency and Organ Transplantation, University of Bari Aldo Moro, Bari, Italy
| | - Dario Troise
- Department of Medical and Surgical Sciences, University of Foggia, Foggia, Italy
| | | | - Carlo Alfieri
- Nephrology, Dialysis and Renal Transplant Unit, Department of Clinical Sciences and Community Health, University of Milan, Fondazione IRCCS Cà Granda Ospedale Maggiore Policlinico, Milan, Italy
| | - Loreto Gesualdo
- Department of Emergency and Organ Transplantation, University of Bari Aldo Moro, Bari, Italy
| | - Giuseppe Castellano
- Nephrology, Dialysis and Renal Transplant Unit, Department of Clinical Sciences and Community Health, University of Milan, Fondazione IRCCS Cà Granda Ospedale Maggiore Policlinico, Milan, Italy
| | - Giovanni Stallone
- Department of Medical and Surgical Sciences, University of Foggia, Foggia, Italy
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10
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Hadzi-Petrushev N, Angelovski M, Mladenov M. Advanced Glycation End Products and Diabetes. CONTEMPORARY ENDOCRINOLOGY 2023:99-127. [DOI: 10.1007/978-3-031-39721-9_5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/03/2025]
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11
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Prasad K. Involvement of AGE and Its Receptors in the Pathogenesis of Hypertension in Elderly People and Its Treatment. Int J Angiol 2022; 31:213-221. [PMID: 36588874 PMCID: PMC9803554 DOI: 10.1055/s-0042-1756175] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/04/2023] Open
Abstract
Both systolic and diastolic blood pressures increase with age up to 50 to 60 years of age. After 60 years of age systolic pressure rises to 84 years of age but diastolic pressure remains stable or even decreases. In the oldest age group (85-99 years), the systolic blood pressure (SBP) is high and diastolic pressure (DBP) is the lowest. Seventy percent of people older than 65 years are hypertensive. This paper deals with the role of advanced glycation end products (AGE) and its cell receptor (RAGE) and soluble receptor (sRAGE) in the development of hypertension in the elderly population. Plasma/serum levels of AGE are higher in older people as compared with younger people. Serum levels of AGE are positively correlated with age, arterial stiffness, and hypertension. Low serum levels of sRAGE are associated with arterial stiffness and hypertension. Levels of sRAGE are negatively correlated with age and blood pressure. Levels of sRAGE are lower in patients with arterial stiffness and hypertension than patients with high levels of sRAGE. AGE could induce hypertension through numerous mechanisms including, cross-linking with collagen, reduction of nitric oxide, increased expression of endothelin-1, and transforming growth factor-β (TGF-β). Interaction of AGE with RAGE could produce hypertension through the generation of reactive oxygen species, increased sympathetic activity, activation of nuclear factor-kB, and increased expression of cytokines, cell adhesion molecules, and TGF- β. In conclusion, the AGE-RAGE axis could be involved in hypertension in elderly people. Treatment for hypertension in elderly people should be targeted at reduction of AGE levels in the body, prevention of AGE formation, degradation of AGE in vivo, downregulation of RAGE expression, blockade of AGE-RAGE interaction, upregulation of sRAGE expression, and use of antioxidants.
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Affiliation(s)
- Kailash Prasad
- Department of Physiology (APP), College of Medicine, University of Saskatchewan, Saskatoon, SK, Canada
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12
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Said MA. Vitamin D attenuates endothelial dysfunction in streptozotocin induced diabetic rats by reducing oxidative stress. Arch Physiol Biochem 2022; 128:959-963. [PMID: 32233807 DOI: 10.1080/13813455.2020.1741645] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
Diabetes mellitus (DM) is associated with micro- and macrovascular complications and increased cardiovascular risk. Vitamin D deficiency is the most common nutrient deficiency in the world. This study aimed to examine the effects of diabetes on the endothelial function and the role of vitamin D supplementation. Male Wistar rats (n = 30) were randomly assigned to three groups; control untreated, diabetic untreated, and diabetic groups treated with vitamin D at a dose of 12.5 μg/kg body weight, dissolved in 0.3 ml olive oil orally for 10 weeks. Compared to the control group, the serum glucose, serum asymmetric dimethylarginine (ADMA), aortic malondialdehyde (MDA) levels, endothelin-1 (ET-1) level, inducible nitric oxide synthase (iNOS) activity in diabetic rats were increased, whereas aortic superoxide dismutase (SOD) activity, nitric oxide (NO) levels, and constitutive NOS (cNOS) activity were decreased. Administration of vitamin D to diabetic rats resulted in a decrease of serum glucose, serum ADMA, a decrease of aortic MDA levels, ET-1 and iNOS activity, an increase of aortic SOD activity, NO levels, and cNOS activity. Vitamin D administration attenuated diabetic induced endothelial dysfunction by reducing oxidative stress. These results indicate that chronic vitamin D treatment might be useful in preventing diabetic vascular complications associated with endothelial dysfunction.
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Affiliation(s)
- Mona A Said
- Department of Physiology, Faculty of Medicine, Benha University, Benha, Egypt
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13
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Yuste RA, Muenkel M, Axarlis K, Gómez Benito MJ, Reuss A, Blacker G, Tal MC, Kraiczy P, Bastounis EE. Borrelia burgdorferi modulates the physical forces and immunity signaling in endothelial cells. iScience 2022; 25:104793. [PMID: 35992087 PMCID: PMC9389243 DOI: 10.1016/j.isci.2022.104793] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/31/2022] [Revised: 06/09/2022] [Accepted: 07/13/2022] [Indexed: 12/04/2022] Open
Abstract
Borrelia burgdorferi (Bb), a vector-borne bacterial pathogen and the causative agent of Lyme disease, can spread to distant tissues in the human host by traveling in and through monolayers of endothelial cells (ECs) lining the vasculature. To examine whether Bb alters the physical forces of ECs to promote its dissemination, we exposed ECs to Bb and observed a sharp and transient increase in EC traction and intercellular forces, followed by a prolonged decrease in EC motility and physical forces. All variables returned to baseline at 24 h after exposure. RNA sequencing analysis revealed an upregulation of innate immune signaling pathways during early but not late Bb exposure. Exposure of ECs to heat-inactivated Bb recapitulated only the early weakening of EC mechanotransduction. The differential responses to live versus heat-inactivated Bb indicate a tight interplay between innate immune signaling and physical forces in host ECs and suggest their active modulation by Bb.
Early exposure to Borrelia decreases endothelial cell motility and physical forces Early exposure to Borrelia also upregulates the host’s innate immune signaling pathways Host cell mechanics and signaling return to steady state at late exposure times Exposure to dead bacteria steadily reduces motility and physical forces of host cells
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14
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Huang Y, Yue L, Qiu J, Gao M, Liu S, Wang J. Endothelial Dysfunction and Platelet Hyperactivation in Diabetic Complications Induced by Glycemic Variability. Horm Metab Res 2022; 54:419-428. [PMID: 35835141 PMCID: PMC9282943 DOI: 10.1055/a-1880-0978] [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] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/24/2022]
Abstract
The development and progression of the complications of chronic diabetes mellitus are attributed not only to increased blood glucose levels but also to glycemic variability. Therefore, a deeper understanding of the role of glycemic variability in the development of diabetic complications may provide more insight into targeted clinical treatment strategies in the future. Previously, the mechanisms implicated in glycemic variability-induced diabetic complications have been comprehensively discussed. However, endothelial dysfunction and platelet hyperactivation, which are two newly recognized critical pathogenic factors, have not been fully elucidated yet. In this review, we first evaluate the assessment of glycemic variability and then summarise the roles of endothelial dysfunction and platelet hyperactivation in glycemic variability-induced complications of diabetes, highlighting the molecular mechanisms involved and their interconnections.
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Affiliation(s)
- Ye Huang
- Emergency Department, China Academy of Chinese Medical Sciences Xiyuan
Hospital, Beijing, China
| | - Long Yue
- Emergency Department, China Academy of Chinese Medical Sciences Xiyuan
Hospital, Beijing, China
| | - Jiahuang Qiu
- Research Center for Eco-Environmental Sciences, Chinese Academy of
Sciences, Beijing, China
| | - Ming Gao
- Research Center for Eco-Environmental Sciences, Chinese Academy of
Sciences, Beijing, China
| | - Sijin Liu
- Research Center for Eco-Environmental Sciences, Chinese Academy of
Sciences, Beijing, China
| | - Jingshang Wang
- Department of Traditional Chinese Medicine, Capital Medical University
Beijing Obstetrics and Gynecology Hospital, Beijing, China
- Correspondence Prof. Jingshang
Wang Capital Medical University Beijing Obstetrics and
Gynecology HospitalDepartment of Traditional Chinese
MedicineBeijingChina 18811213525
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15
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Advanced Glycations End Products in the Skin as Biomarkers of Cardiovascular Risk in Type 2 Diabetes. Int J Mol Sci 2022; 23:ijms23116234. [PMID: 35682915 PMCID: PMC9181586 DOI: 10.3390/ijms23116234] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/16/2022] [Revised: 05/31/2022] [Accepted: 05/31/2022] [Indexed: 02/01/2023] Open
Abstract
The incidence and prevalence of diabetes are increasing worldwide, and cardiovascular disease (CVD) is the leading cause of death among subjects with type 2 diabetes (T2D). The assessment and stratification of cardiovascular risk in subjects with T2D is a challenge. Advanced glycation end products are heterogeneous molecules produced by non-enzymatic glycation of proteins, lipids, or nucleic acids. Accumulation of advanced glycation end products is increased in subjects with T2D and is considered to be one of the major pathogenic mechanism in developing complications in diabetes. Skin AGEs could be assessed by skin autofluorescence. This method has been validated and related to the presence of micro and macroangiopathy in individuals with type 2 diabetes. In this context, the aim of this review is to critically summarize current knowledge and scientific evidence on the relationship between skin AGEs and CVD in subjects with type 2 diabetes, with a brief reference to other diabetes-related complications.
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16
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Molecular Signature of Neuroinflammation Induced in Cytokine-Stimulated Human Cortical Spheroids. Biomedicines 2022; 10:biomedicines10051025. [PMID: 35625761 PMCID: PMC9138619 DOI: 10.3390/biomedicines10051025] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/24/2022] [Revised: 04/22/2022] [Accepted: 04/25/2022] [Indexed: 12/04/2022] Open
Abstract
Crucial in the pathogenesis of neurodegenerative diseases is the process of neuroinflammation that is often linked to the pro-inflammatory cytokines Tumor necrosis factor alpha (TNFα) and Interleukin-1beta (IL-1β). Human cortical spheroids (hCSs) constitute a valuable tool to study the molecular mechanisms underlying neurological diseases in a complex three-dimensional context. We recently designed a protocol to generate hCSs comprising all major brain cell types. Here we stimulate these hCSs for three time periods with TNFα and with IL-1β. Transcriptomic analysis reveals that the main process induced in the TNFα- as well as in the IL-1β-stimulated hCSs is neuroinflammation. Central in the neuroinflammatory response are endothelial cells, microglia and astrocytes, and dysregulated genes encoding cytokines, chemokines and their receptors, and downstream NFκB- and STAT-pathway components. Furthermore, we observe sets of neuroinflammation-related genes that are specifically modulated in the TNFα-stimulated and in the IL-1β-stimulated hCSs. Together, our results help to molecularly understand human neuroinflammation and thus a key mechanism of neurodegeneration.
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17
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Abu Helal R, Muturi HT, Lee AD, Li W, Ghadieh HE, Najjar SM. Aortic Fibrosis in Insulin-Sensitive Mice with Endothelial Cell-Specific Deletion of Ceacam1 Gene. Int J Mol Sci 2022; 23:4335. [PMID: 35457157 PMCID: PMC9027102 DOI: 10.3390/ijms23084335] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/18/2022] [Revised: 04/07/2022] [Accepted: 04/10/2022] [Indexed: 12/24/2022] Open
Abstract
(1) Background: Mice with global Ceacam1 deletion developed plaque-like aortic lesions even on C57BL/6J background in the presence of increased endothelial cell permeability and insulin resistance. Loss of endothelial Ceacam1 gene caused endothelial dysfunction and reduced vascular integrity without affecting systemic insulin sensitivity. Because endothelial cell injury precedes atherosclerosis, we herein investigated whether the loss of endothelial Ceacam1 initiates atheroma formation in the absence of insulin resistance. (2) Methods: Endothelial cell-specific Ceacam1 null mice on C57BL/6J.Ldlr-/- background (Ldlr-/-VECadCre+Cc1fl/fl) were fed an atherogenic diet for 3-5 months before metabolic, histopathological, and en-face analysis of aortae were compared to their control littermates. Sirius Red stain was also performed on liver sections to analyze hepatic fibrosis. (3) Results: These mice displayed insulin sensitivity without significant fat deposition on aortic walls despite hypercholesterolemia. They also displayed increased inflammation and fibrosis. Deleting Ceacam1 in endothelial cells caused hyperactivation of VEGFR2/Shc/NF-κB pathway with resultant transcriptional induction of NF-κB targets. These include IL-6 that activates STAT3 inflammatory pathways, in addition to endothelin-1 and PDGF-B profibrogenic effectors. It also induced the association between SHP2 phosphatase and VEGFR2, downregulating the Akt/eNOS pathway and reducing nitric oxide production, a characteristic feature of endothelial dysfunction. Similarly, hepatic inflammation and fibrosis developed in Ldlr-/-VECadCre+Cc1fl/fl mice without an increase in hepatic steatosis. (4) Conclusions: Deleting endothelial cell Ceacam1 caused hepatic and aortic inflammation and fibrosis with increased endothelial dysfunction and oxidative stress in the presence of hypercholesterolemia. However, this did not progress into frank atheroma formation. Because these mice remained insulin sensitive, the study provides an in vivo demonstration that insulin resistance plays a critical role in the pathogenesis of frank atherosclerosis.
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Affiliation(s)
- Raghd Abu Helal
- Department of Biomedical Sciences, Heritage College of Osteopathic Medicine, Ohio University, Athens, OH 45701, USA; (R.A.H.); (H.T.M.); (H.E.G.)
| | - Harrison T. Muturi
- Department of Biomedical Sciences, Heritage College of Osteopathic Medicine, Ohio University, Athens, OH 45701, USA; (R.A.H.); (H.T.M.); (H.E.G.)
| | - Abraham D. Lee
- Center for Diabetes and Endocrine Research, College of Medicine, University of Toledo, Toledo, OH 43606, USA;
- School of Exercise and Rehabilitation Sciences, College of Health and Human Services, University of Toledo, Toledo, OH 43606, USA
| | - Wei Li
- Department of Biomedical Sciences, Joan C. Edwards School of Medicine at Marshall University, Huntington, WV 25755, USA;
| | - Hilda E. Ghadieh
- Department of Biomedical Sciences, Heritage College of Osteopathic Medicine, Ohio University, Athens, OH 45701, USA; (R.A.H.); (H.T.M.); (H.E.G.)
- Center for Diabetes and Endocrine Research, College of Medicine, University of Toledo, Toledo, OH 43606, USA;
- Department of Biomedical Sciences, Faculty of Medicine and Medical Sciences, University of Balamand, El-Koura P.O. Box 100, Lebanon
| | - Sonia M. Najjar
- Department of Biomedical Sciences, Heritage College of Osteopathic Medicine, Ohio University, Athens, OH 45701, USA; (R.A.H.); (H.T.M.); (H.E.G.)
- Center for Diabetes and Endocrine Research, College of Medicine, University of Toledo, Toledo, OH 43606, USA;
- Diabetes Institute, Heritage College of Osteopathic Medicine, Ohio University, Athens, OH 45701, USA
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18
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Xie X. WELL-POSEDNESS OF A MATHEMATICAL MODEL OF DIABETIC ATHEROSCLEROSIS WITH ADVANCED GLYCATION END-PRODUCTS. APPLICABLE ANALYSIS 2022; 101:3989-4013. [PMID: 36188356 PMCID: PMC9524361 DOI: 10.1080/00036811.2022.2060210] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 10/29/2021] [Accepted: 03/25/2022] [Indexed: 06/16/2023]
Abstract
Atherosclerosis is a leading cause of death worldwide; it emerges as a result of multiple dynamical cell processes including hemodynamics, endothelial damage, innate immunity and sterol biochemistry. Making matters worse, nearly 463 million people have diabetes, which increases atherosclerosis-related inflammation, diabetic patients are twice as likely to have a heart attack or stroke. The pathophysiology of diabetic vascular disease is generally understood. Dyslipidemia with increased levels of atherogenic LDL, hyperglycemia, oxidative stress and increased inflammation are factors that increase the risk and accelerate development of atherosclerosis. In a recent paper [53], we have developed mathematical model that includes the effect of hyperglycemia and insulin resistance on plaque growth. In this paper, we propose a more comprehensive mathematical model for diabetic atherosclerosis which include more variables; in particular it includes the variable for Advanced Glycation End-Products (AGEs)concentration. Hyperglycemia trigger vascular damage by forming AGEs, which are not easily metabolized and may accelerate the progression of vascular disease in diabetic patients. The model is given by a system of partial differential equations with a free boundary. We also establish local existence and uniqueness of solution to the model. The methodology is to use Hanzawa transformation to reduce the free boundary to a fixed boundary and reduce the system of partial differential equations to an abstract evolution equation in Banach spaces, and apply the theory of analytic semigroup.
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Affiliation(s)
- Xuming Xie
- Department of Mathematics, Morgan State University, Baltimore, MD 21251
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19
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Sakowicz A. The Targeting of Nuclear Factor Kappa B by Drugs Adopted for the Prevention and Treatment of Preeclampsia. Int J Mol Sci 2022; 23:2881. [PMID: 35270023 PMCID: PMC8911173 DOI: 10.3390/ijms23052881] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/10/2022] [Revised: 02/28/2022] [Accepted: 03/04/2022] [Indexed: 02/01/2023] Open
Abstract
Preeclampsia (PE) is characterised by high levels and activity of the transcription factor Nuclear Factor kappa B (NFĸB) in the maternal blood and placental cells. This factor is responsible for the regulation of over 400 genes known to influence processes related to inflammation, apoptosis and angiogenesis, and cellular responses to oxidative stress and hypoxia. Although high NFĸB activity induces hypoxia and inflammation, which are beneficial for the process of implantation, NFĸB level should be reduced in the later stages of physiological pregnancy to favour maternal immunosuppression and maintain gestation. It is believed that the downregulation of NFĸB activity by pharmacotherapy might be a promising way to treat preeclampsia. Interestingly, many of the drugs adopted for the prevention and treatment of preeclampsia have been found to regulate NFĸB activity. Despite this, further innovation is urgently needed to ensure treatment safety and efficacy. The present article summarizes the current state of knowledge about the drugs recommended by cardiology, obstetrics, and gynaecology societies for the prevention and treatment of preeclampsia with regard to their impact on the cellular regulation of NFĸB pathways.
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Affiliation(s)
- Agata Sakowicz
- Department of Medical Biotechnology, Medical University of Lodz, 90-752 Lodz, Poland
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20
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The Potential of Dietary Bioactive Compounds against SARS-CoV-2 and COVID-19-Induced Endothelial Dysfunction. MOLECULES (BASEL, SWITZERLAND) 2022; 27:molecules27051623. [PMID: 35268723 PMCID: PMC8912066 DOI: 10.3390/molecules27051623] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 11/17/2021] [Revised: 02/25/2022] [Accepted: 02/25/2022] [Indexed: 12/24/2022]
Abstract
COVID-19 is an endothelial disease. All the major comorbidities that increase the risk for severe SARS-CoV-2 infection and severe COVID-19 including old age, obesity, diabetes, hypertension, respiratory disease, compromised immune system, coronary artery disease or heart failure are associated with dysfunctional endothelium. Genetics and environmental factors (epigenetics) are major risk factors for endothelial dysfunction. Individuals with metabolic syndrome are at increased risk for severe SARS-CoV-2 infection and poor COVID-19 outcomes and higher risk of mortality. Old age is a non-modifiable risk factor. All other risk factors are modifiable. This review also identifies dietary risk factors for endothelial dysfunction. Potential dietary preventions that address endothelial dysfunction and its sequelae may have an important role in preventing SARS-CoV-2 infection severity and are key factors for future research to address. This review presents some dietary bioactives with demonstrated efficacy against dysfunctional endothelial cells. This review also covers dietary bioactives with efficacy against SARS-CoV-2 infection. Dietary bioactive compounds that prevent endothelial dysfunction and its sequelae, especially in the gastrointestinal tract, will result in more effective prevention of SARS-CoV-2 variant infection severity and are key factors for future food research to address.
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21
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Maida CD, Daidone M, Pacinella G, Norrito RL, Pinto A, Tuttolomondo A. Diabetes and Ischemic Stroke: An Old and New Relationship an Overview of the Close Interaction between These Diseases. Int J Mol Sci 2022; 23:2397. [PMID: 35216512 PMCID: PMC8877605 DOI: 10.3390/ijms23042397] [Citation(s) in RCA: 76] [Impact Index Per Article: 25.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/30/2022] [Revised: 02/15/2022] [Accepted: 02/19/2022] [Indexed: 12/12/2022] Open
Abstract
Diabetes mellitus is a comprehensive expression to identify a condition of chronic hyperglycemia whose causes derive from different metabolic disorders characterized by altered insulin secretion or faulty insulin effect on its targets or often both mechanisms. Diabetes and atherosclerosis are, from the point of view of cardio- and cerebrovascular risk, two complementary diseases. Beyond shared aspects such as inflammation and oxidative stress, there are multiple molecular mechanisms by which they feed off each other: chronic hyperglycemia and advanced glycosylation end-products (AGE) promote 'accelerated atherosclerosis' through the induction of endothelial damage and cellular dysfunction. These diseases impact the vascular system and, therefore, the risk of developing cardio- and cerebrovascular events is now evident, but the observation of this significant correlation has its roots in past decades. Cerebrovascular complications make diabetic patients 2-6 times more susceptible to a stroke event and this risk is magnified in younger individuals and in patients with hypertension and complications in other vascular beds. In addition, when patients with diabetes and hyperglycemia experience an acute ischemic stroke, they are more likely to die or be severely disabled and less likely to benefit from the one FDA-approved therapy, intravenous tissue plasminogen activator. Experimental stroke models have revealed that chronic hyperglycemia leads to deficits in cerebrovascular structure and function that may explain some of the clinical observations. Increased edema, neovascularization, and protease expression as well as altered vascular reactivity and tone may be involved and point to potential therapeutic targets. Further study is needed to fully understand this complex disease state and the breadth of its manifestation in the cerebrovasculature.
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Affiliation(s)
- Carlo Domenico Maida
- Molecular and Clinical Medicine PhD Programme, University of Palermo, 90127 Palermo, Italy; (C.D.M.); (A.T.)
- U.O.C di Medicina Interna con Stroke Care, Dipartimento di Promozione della Salute, Materno Infantile, Medicina Interna e Specialistica di Eccellenza “G. D’Alessandro” (PROMISE), University of Palermo, Piazza delle Cliniche n.2, 90127 Palermo, Italy; (G.P.); (R.L.N.); (A.P.)
| | - Mario Daidone
- U.O.C di Medicina Interna con Stroke Care, Dipartimento di Promozione della Salute, Materno Infantile, Medicina Interna e Specialistica di Eccellenza “G. D’Alessandro” (PROMISE), University of Palermo, Piazza delle Cliniche n.2, 90127 Palermo, Italy; (G.P.); (R.L.N.); (A.P.)
| | - Gaetano Pacinella
- U.O.C di Medicina Interna con Stroke Care, Dipartimento di Promozione della Salute, Materno Infantile, Medicina Interna e Specialistica di Eccellenza “G. D’Alessandro” (PROMISE), University of Palermo, Piazza delle Cliniche n.2, 90127 Palermo, Italy; (G.P.); (R.L.N.); (A.P.)
| | - Rosario Luca Norrito
- U.O.C di Medicina Interna con Stroke Care, Dipartimento di Promozione della Salute, Materno Infantile, Medicina Interna e Specialistica di Eccellenza “G. D’Alessandro” (PROMISE), University of Palermo, Piazza delle Cliniche n.2, 90127 Palermo, Italy; (G.P.); (R.L.N.); (A.P.)
| | - Antonio Pinto
- U.O.C di Medicina Interna con Stroke Care, Dipartimento di Promozione della Salute, Materno Infantile, Medicina Interna e Specialistica di Eccellenza “G. D’Alessandro” (PROMISE), University of Palermo, Piazza delle Cliniche n.2, 90127 Palermo, Italy; (G.P.); (R.L.N.); (A.P.)
| | - Antonino Tuttolomondo
- Molecular and Clinical Medicine PhD Programme, University of Palermo, 90127 Palermo, Italy; (C.D.M.); (A.T.)
- U.O.C di Medicina Interna con Stroke Care, Dipartimento di Promozione della Salute, Materno Infantile, Medicina Interna e Specialistica di Eccellenza “G. D’Alessandro” (PROMISE), University of Palermo, Piazza delle Cliniche n.2, 90127 Palermo, Italy; (G.P.); (R.L.N.); (A.P.)
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22
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Prasad K, Khan AS, Bhanumathy KK. Does AGE-RAGE Stress Play a Role in the Development of Coronary Artery Disease in Obesity? Int J Angiol 2022; 31:1-9. [PMID: 35221846 PMCID: PMC8881108 DOI: 10.1055/s-0042-1742587] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/19/2022] Open
Abstract
This article deals with the role of AGE (advanced glycation end products)-RAGE (receptor for AGE) stress (AGE/sRAGE) in the development of coronary artery disease (CAD) in obesity. CAD is due to atherosclerosis in coronary artery. The serum/plasma levels of AGE and sRAGE are reduced, while AGE-RAGE stress and expression of RAGE are elevated in obese individuals. However, the levels of AGE are elevated in obese individuals with more than one metabolic syndrome. The increases in the AGE-RAGE stress would elevate the expression and production of atherogenic factors, including reactive oxygen species, nuclear factor-kappa B, cytokines, intercellular adhesion molecule-1, vascular cell adhesion molecule-1, endothelial leukocyte adhesion molecules, monocyte chemoattractant protein-1, granulocyte-macrophage colony-stimulating factor, and growth factors. Low levels of sRAGE would also increase the atherogenic factors. The increases in the AGE-RAGE stress and decreases in the levels of sRAGE would induce development of atherosclerosis, leading to CAD. The therapeutic regimen for AGE-RAGE stress-induced CAD in obesity would include lowering of AGE intake, prevention of AGE formation, degradation of AGE in vivo, suppression of RAGE expression, blockade of AGE-RAGE interaction, downregulation of sRAGE expression, and use of antioxidants. In conclusion, the data suggest that AGE-RAGE stress is involved in the development of CAD in obesity, and the therapeutic interventions to reduce AGE-RAGE would be helpful in preventing, regressing, and slowing the progression of CAD in obesity.
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Affiliation(s)
- Kailash Prasad
- Department of Physiology (APP), College of Medicine, University of Saskatchewan, Saskatoon, Saskatchewan, Canada,Address for correspondence Kailash Prasad, MBBS, MD, PhD, DSc Department of Physiology (APP), College of Medicine, University of Saskatoon107 Wiggins Road, Saskatoon, SK, S7N 5E5Canada
| | - Amal S. Khan
- Community, Health and Epidemiology, College of Medicine, University of Saskatchewan, Saskatoon, Saskatchewan, Canada
| | - Kalpana K. Bhanumathy
- Division of Oncology, Cancer Cluster Unit, College of Medicine, University of Saskatchewan, Saskatoon, Saskatchewan, Canada
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23
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Matsumoto T, Taguchi K, Kobayashi T. Relationships between advanced glycation end products (AGEs), vasoactive substances, and vascular function. J Smooth Muscle Res 2022; 57:94-107. [PMID: 35095032 PMCID: PMC8795595 DOI: 10.1540/jsmr.57.94] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/17/2022] Open
Abstract
Vascular smooth muscle cells (VSMCs) and endothelial cells (ECs) are major cell types that control vascular function, and hence dysfunction of these cells plays a key role in the development and progression of vasculopathies. Abnormal vascular responsiveness to vasoactive substances including vasoconstrictors and vasodilators has been observed in various arteries in diseases including diabetes, hypertension, chronic kidney diseases, and atherosclerosis. Several substances derived from ECs tightly control vascular function, such as endothelium-derived relaxing and contracting factors, and it is known that abnormal vascular signaling of these endothelium-derived substances is often observed in various diseases. Derangement of signaling in VSMCs and altered function influence vascular reactivity to vasoactive substances and tone, which are important determinants of vascular resistance and blood pressure. However, understanding the molecular mechanisms underlying abnormalities of vascular functions in pathological states is difficult because multiple substances interact in the development of these processes. Advanced glycation end products (AGEs), a heterogeneous group of bioactive compounds, are thought to contribute to vascular dysfunction, which in turn cause the development of several diseases including diabetes, hypertension, stroke, and atherosclerosis. A growing body of evidence suggests that AGEs could affect these cells and modulate vascular function. This study is focused on the link between AGEs and functions of ECs and VSMCs, particularly the modulative effects of AGEs on vascular reactivities to vasoactive substances.
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Affiliation(s)
- Takayuki Matsumoto
- Department of Physiology and Morphology, Institute of Medicinal Chemistry, Hoshi University, 2-4-41 Ebara, Shinagawa-ku, Tokyo 142-8501, Japan
| | - Kumiko Taguchi
- Department of Physiology and Morphology, Institute of Medicinal Chemistry, Hoshi University, 2-4-41 Ebara, Shinagawa-ku, Tokyo 142-8501, Japan
| | - Tsuneo Kobayashi
- Department of Physiology and Morphology, Institute of Medicinal Chemistry, Hoshi University, 2-4-41 Ebara, Shinagawa-ku, Tokyo 142-8501, Japan
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24
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Kurakula K, Hagdorn QAJ, van der Feen DE, Vonk Noordegraaf A, Ten Dijke P, de Boer RA, Bogaard HJ, Goumans MJ, Berger RMF. Inhibition of the prolyl isomerase Pin1 improves endothelial function and attenuates vascular remodelling in pulmonary hypertension by inhibiting TGF-β signalling. Angiogenesis 2021; 25:99-112. [PMID: 34379232 PMCID: PMC8813847 DOI: 10.1007/s10456-021-09812-7] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/27/2021] [Accepted: 07/28/2021] [Indexed: 12/13/2022]
Abstract
Pulmonary arterial hypertension (PAH) is a devastating disease, characterized by obstructive pulmonary vascular remodelling ultimately leading to right ventricular (RV) failure and death. Disturbed transforming growth factor-β (TGF-β)/bone morphogenetic protein (BMP) signalling, endothelial cell dysfunction, increased proliferation of smooth muscle cells and fibroblasts, and inflammation contribute to this abnormal remodelling. Peptidyl-prolyl isomerase Pin1 has been identified as a critical driver of proliferation and inflammation in vascular cells, but its role in the disturbed TGF-β/BMP signalling, endothelial cell dysfunction, and vascular remodelling in PAH is unknown. Here, we report that Pin1 expression is increased in cultured pulmonary microvascular endothelial cells (MVECs) and lung tissue of PAH patients. Pin1 inhibitor, juglone significantly decreased TGF-β signalling, increased BMP signalling, normalized their hyper-proliferative, and inflammatory phenotype. Juglone treatment reversed vascular remodelling through reducing TGF-β signalling in monocrotaline + shunt-PAH rat model. Juglone treatment decreased Fulton index, but did not affect or harm cardiac function and remodelling in rats with RV pressure load induced by pulmonary artery banding. Our study demonstrates that inhibition of Pin1 reversed the PAH phenotype in PAH MVECs in vitro and in PAH rats in vivo, potentially through modulation of TGF-β/BMP signalling pathways. Selective inhibition of Pin1 could be a novel therapeutic option for the treatment of PAH.
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Affiliation(s)
- Kondababu Kurakula
- Department of Cell and Chemical Biology, Leiden University Medical Center, Einthovenweg 20, 2333 ZC, Leiden, The Netherlands.
| | - Quint A J Hagdorn
- Department of Paediatric Cardiology, Beatrix Children's Hospital, Center for Congenital Heart Diseases, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands
| | - Diederik E van der Feen
- Department of Paediatric Cardiology, Beatrix Children's Hospital, Center for Congenital Heart Diseases, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands
| | - Anton Vonk Noordegraaf
- Department of Pulmonary Medicine, Amsterdam Cardiovascular Sciences, Amsterdam UMC, Vrije Universiteit Amsterdam, Amsterdam, The Netherlands
| | - Peter Ten Dijke
- Department of Cell and Chemical Biology, Oncode Institute, Leiden University Medical Center, Leiden, The Netherlands
| | - Rudolf A de Boer
- Department of Cardiology, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands
| | - Harm Jan Bogaard
- Department of Pulmonary Medicine, Amsterdam Cardiovascular Sciences, Amsterdam UMC, Vrije Universiteit Amsterdam, Amsterdam, The Netherlands
| | - Marie José Goumans
- Department of Cell and Chemical Biology, Leiden University Medical Center, Einthovenweg 20, 2333 ZC, Leiden, The Netherlands.
| | - Rolf M F Berger
- Department of Paediatric Cardiology, Beatrix Children's Hospital, Center for Congenital Heart Diseases, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands
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O’Brien ST, Neylon OM, O’Brien T. Dyslipidaemia in Type 1 Diabetes: Molecular Mechanisms and Therapeutic Opportunities. Biomedicines 2021; 9:biomedicines9070826. [PMID: 34356890 PMCID: PMC8301346 DOI: 10.3390/biomedicines9070826] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/31/2021] [Revised: 07/09/2021] [Accepted: 07/13/2021] [Indexed: 12/12/2022] Open
Abstract
Cardiovascular disease (CVD) is the leading cause of death in Type 1 Diabetes (T1D). The molecular basis for atherosclerosis in T1D is heavily influenced by hyperglycaemia and its atherogenic effects on LDL. Ongoing research into the distinct pathophysiology of atherosclerosis in T1D offers exciting opportunities for novel approaches to calculate CVD risk in patients with T1D and to manage this risk appropriately. Currently, despite the increased risk of CVD in the T1D population, there are few tools available for estimating the risk of CVD in younger patients. This poses significant challenges for clinicians in selecting which patients might benefit from lipid-lowering therapies over the long term. The current best practice guidance for the management of dyslipidaemia in T1D is generally based on evidence from patients with T2D and the opinion of experts in the field. In this review article, we explore the unique pathophysiology of atherosclerosis in T1D, with a specific focus on hyperglycaemia-induced damage and atherogenic LDL modifications. We also discuss the current clinical situation of managing these patients across paediatric and adult populations, focusing on the difficulties posed by a lack of strong evidence and various barriers to treatment.
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Affiliation(s)
- Stephen T. O’Brien
- Department of Paediatrics, University Hospital Limerick, V94 F858 Limerick, Ireland; (S.T.O.); (O.M.N.)
| | - Orla M. Neylon
- Department of Paediatrics, University Hospital Limerick, V94 F858 Limerick, Ireland; (S.T.O.); (O.M.N.)
| | - Timothy O’Brien
- Department of Medicine, School of Medicine, National University of Ireland, H91 TK33 Galway, Ireland
- Correspondence:
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Chiappalupi S, Salvadori L, Donato R, Riuzzi F, Sorci G. Hyperactivated RAGE in Comorbidities as a Risk Factor for Severe COVID-19-The Role of RAGE-RAS Crosstalk. Biomolecules 2021; 11:biom11060876. [PMID: 34204735 PMCID: PMC8231494 DOI: 10.3390/biom11060876] [Citation(s) in RCA: 22] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/06/2021] [Revised: 06/04/2021] [Accepted: 06/08/2021] [Indexed: 02/07/2023] Open
Abstract
The receptor for advanced glycation-end products (RAGE) is a multiligand receptor with a role in inflammatory and pulmonary pathologies. Hyperactivation of RAGE by its ligands has been reported to sustain inflammation and oxidative stress in common comorbidities of severe COVID-19. RAGE is essential to the deleterious effects of the renin-angiotensin system (RAS), which participates in infection and multiorgan injury in COVID-19 patients. Thus, RAGE might be a major player in severe COVID-19, and appears to be a useful therapeutic molecular target in infections by SARS-CoV-2. The role of RAGE gene polymorphisms in predisposing patients to severe COVID-19 is discussed. .
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Affiliation(s)
- Sara Chiappalupi
- Department of Medicine and Surgery, University of Perugia, 06132 Perugia, Italy; (S.C.); (F.R.)
- Interuniversity Institute of Myology (IIM), 06132 Perugia, Italy;
| | - Laura Salvadori
- Interuniversity Institute of Myology (IIM), 06132 Perugia, Italy;
- Department of Translational Medicine, University of Piemonte Orientale, 28100 Novara, Italy
| | - Rosario Donato
- Interuniversity Institute of Myology (IIM), 06132 Perugia, Italy;
- Correspondence: (R.D.); (G.S.); Tel.: +39-075-585-8258 (G.S.)
| | - Francesca Riuzzi
- Department of Medicine and Surgery, University of Perugia, 06132 Perugia, Italy; (S.C.); (F.R.)
- Interuniversity Institute of Myology (IIM), 06132 Perugia, Italy;
- Consorzio Interuniversitario Biotecnologie (CIB), 34127 Trieste, Italy
| | - Guglielmo Sorci
- Department of Medicine and Surgery, University of Perugia, 06132 Perugia, Italy; (S.C.); (F.R.)
- Interuniversity Institute of Myology (IIM), 06132 Perugia, Italy;
- Consorzio Interuniversitario Biotecnologie (CIB), 34127 Trieste, Italy
- Centro Universitario di Ricerca Sulla Genomica Funzionale (CURGeF), University of Perugia, 06132 Perugia, Italy
- Correspondence: (R.D.); (G.S.); Tel.: +39-075-585-8258 (G.S.)
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Wang XH, Ao QG, Cheng QL. Caloric restriction inhibits renal artery ageing by reducing endothelin-1 expression. ANNALS OF TRANSLATIONAL MEDICINE 2021; 9:979. [PMID: 34277779 PMCID: PMC8267285 DOI: 10.21037/atm-21-2218] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 04/07/2021] [Accepted: 05/28/2021] [Indexed: 12/31/2022]
Abstract
Background The renal artery plays a central role in renal perfusion and is critical for proper renal function. Ageing is an independent risk factor for both impaired renal function and vascular disorders, and associated with an increase in the expression of the vasoconstrictor endothelin-1 (ET-1), and caloric restriction (CR) without malnutrition has been shown to be an effective inhibitor of renal dysfunction induced by ageing. The objective of this study was to determine whether CR-mediated alleviation of renal dysfunction is mediated by ET-1 expression. Methods The young (2 months, 2 M) and old (12 months, 12 M) Sprague-Dawley male rats were used and fed ad libitum. The 12-month-old rats were further divided into 12 M and 12 M-caloric restriction (CR) (30% calorie restriction). After 8 weeks, the renal tissues were showed by PAS staining, and age-related metabolic parameters and renal functions were detected in each group of rats. The inflammatory cytokines of interleukin (IL)-6, IL-1β, tumor necrosis factor alpha (TNF-α), and transforming growth factor beta 1 (TGF-β1) were analyzed using ELISA. The mRNA and protein expression in the renal artery were analysis by qRT-PCR and Immunoblot analysis. Results Ageing was associated with significant increases in 24 h urine protein content and serum triglyceride and cholesterol in 12 M rats, both of which were significantly inhibited in 12 M-CR. The mRNA expression and the secretion of IL-6, IL-1β, TNF-α, and TGF-β1 in the renal artery was significantly increased with ageing and inhibited by CR. CR also inhibited ageing-induced Edn1 (encoding ET-1) mRNA and protein expression in the renal artery. In addition, CR could regulate ET-1 expression by inhibiting the activation of NF-κB signaling and activation and induction in the expression of NF-E2-related factor 2 (Nrf2) and histone deacetylase and gene repressor sirtuin 1 (SIRT1), both of which play a central role in mitigating oxidative stress in young rats. Conclusions Moderate CR can reverse the ageing related kidney dysfunction by reducing the ET-1 expression. CR might be used as an alternative to prevent the ageing induced renal artery dysfunction.
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Affiliation(s)
- Xiao-Hua Wang
- Department of Nephrology, The Second Medical Center, Chinese PLA General Hospital, Beijing, China
| | - Qiang-Guo Ao
- Department of Nephrology, The Second Medical Center, Chinese PLA General Hospital, Beijing, China
| | - Qing-Li Cheng
- Department of Nephrology, The Second Medical Center, Chinese PLA General Hospital, Beijing, China
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Abstract
Coronary artery atherosclerosis and atherosclerotic plaque rupture cause coronary artery disease (CAD). Advanced glycation end products (AGE) and its cell receptor RAGE, and soluble receptor (sRAGE) and endogenous secretory RAGE (esRAGE) may be involved in the development of atherosclerosis. AGE and its interaction with RAGE are atherogenic, while sRAGE and esRAGE have antiatherogenic effects. AGE-RAGE stress is a ratio of AGE/sRAGE. A high AGE-RAGE stress results in development and progression of CAD and vice-versa. AGE levels in serum and skin, AGE/sRAGE in patients with CAD, and expression of RAGE in animal model of atherosclerosis were higher, while serum levels of esRAGE were lower in patients with CAD compared with controls. Serum levels of sRAGE in CAD patients were contradictory, increased or decreased. This contradictory data may be due to type of patients used, because the sRAGE levels are elevated in diabetics and end-stage renal disease. AGE/sRAGE ratio is elevated in patients with reduced or elevated levels of serum sRAGE. It is to stress that AGE, RAGE, sRAGE, or esRAGE individually cannot serve as universal biomarker. AGE and sRAGE should be measured simultaneously to assess the AGE-RAGE stress. The treatment of CAD should be targeted at reduction in AGE levels, prevention of AGE formation, degradation of AGE in vivo, suppression of RAGE expression, blockade of RAGE, elevation of sRAGE, and use of antioxidants. In conclusion, AGE-RAGE stress would initiate the development and progression of atherosclerosis. Treatment modalities would prevent, regress, and slow the progression of CAD.
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Affiliation(s)
- Kailash Prasad
- Department of Physiology (APP), College of Medicine, University of Saskatchewan, Saskatoon, Canada
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Uremic Toxins, Oxidative Stress, Atherosclerosis in Chronic Kidney Disease, and Kidney Transplantation. OXIDATIVE MEDICINE AND CELLULAR LONGEVITY 2021; 2021:6651367. [PMID: 33628373 PMCID: PMC7895596 DOI: 10.1155/2021/6651367] [Citation(s) in RCA: 43] [Impact Index Per Article: 10.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 10/31/2020] [Revised: 01/25/2021] [Accepted: 01/29/2021] [Indexed: 12/21/2022]
Abstract
Patients with chronic kidney disease (CKD) are at a high risk for cardiovascular disease (CVD), and approximately half of all deaths among patients with CKD are a direct result of CVD. The premature cardiovascular disease extends from mild to moderate CKD stages, and the severity of CVD and the risk of death increase with a decline in kidney function. Successful kidney transplantation significantly decreases the risk of death relative to long-term dialysis treatment; nevertheless, the prevalence of CVD remains high and is responsible for approximately 20-35% of mortality in renal transplant recipients. The prevalence of traditional and nontraditional risk factors for CVD is higher in patients with CKD and transplant recipients compared with the general population; however, it can only partly explain the highly increased cardiovascular burden in CKD patients. Nontraditional risk factors, unique to CKD patients, include proteinuria, disturbed calcium, and phosphate metabolism, anemia, fluid overload, and accumulation of uremic toxins. This accumulation of uremic toxins is associated with systemic alterations including inflammation and oxidative stress which are considered crucial in CKD progression and CKD-related CVD. Kidney transplantation can mitigate the impact of some of these nontraditional factors, but they typically persist to some degree following transplantation. Taking into consideration the scarcity of data on uremic waste products, oxidative stress, and their relation to atherosclerosis in renal transplantation, in the review, we discussed the impact of uremic toxins on vascular dysfunction in CKD patients and kidney transplant recipients. Special attention was paid to the role of native and transplanted kidney function.
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Yulianti E, Sunarti, Wahyuningsih MSH. The effect of Kappaphycus alvarezii fraction on plasma glucose, Advanced Glycation End-products formation, and renal RAGE gene expression. Heliyon 2021; 7:e05978. [PMID: 33521358 PMCID: PMC7820565 DOI: 10.1016/j.heliyon.2021.e05978] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/22/2020] [Revised: 10/07/2020] [Accepted: 01/11/2021] [Indexed: 12/18/2022] Open
Abstract
BACKGROUND Kappaphycus alvarezii (Doty) Doty ex P.C.Silva is a red algae with antioxidant and antiglycation activities. Algae still have not been widely used for treating diabetes, especially to prevent complications. The purpose of this study was to examine the effect of active fractions from Kappaphycus alvarezii on plasma glucose level, glycation process and renal RAGE gene expression. METHODS This study used bioassay-guided fractionation, consisting of three stages: extraction, partition, and fractionation. These processes were monitored with Thin Layer Chromatography and the BSA-Glucose method to select the best extract with antiglycation activity (calculated as the percentage of inhibition and IC50). The selected active fraction from four fractions was further used for in vivo study, which was conducted with hyperglycemic Wistar male rats. Plasma glucose level was measured using GOD-PAP methods, while plasma glycated albumin (GA) and Nε- (carboxymethyl) lysine (CML) levels were measured using ELISA. Renal RAGE gene expression was analyzed using qPCR. RESULTS Fraction II was selected as the active fraction of Kappaphycus alvarezii showing antiglycation activity with the highest percentage of inhibition and the lowest IC50. This fraction significantly reduced plasma GA and CML levels, but it did not significantly reduce plasma glucose level. Furthermore, renal RAGE gene expression was lower in the diabetic rat group treated with this active fraction compared to the untreated group. CONCLUSIONS This study successfully identified an active fraction of Kappaphycus alvarezii with antiglycation activity to reduce plasma GA and CML levels as well as renal RAGE gene expression. Therefore, this fraction could be developed as a potential candidate for treating diabetes.
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Affiliation(s)
- Evy Yulianti
- Department of Biology Education, Faculty of Mathematics and Science, Universitas Negeri Yogyakarta, Yogyakarta, Indonesia
- Doctoral Candidate at Department of Pharmacology and Therapy, Faculty of Medicine, Public Health and Nursing, Universitas Gadjah Mada, Yogyakarta, Indonesia
| | - Sunarti
- Department of Biochemistry, Faculty of Medicine, Public Health and Nursing, Universitas Gadjah Mada, Yogyakarta, Indonesia
| | - Mae Sri Hartati Wahyuningsih
- Department of Pharmacology and Therapy, Faculty of Medicine, Public Health and Nursing, Universitas Gadjah Mada, Yogyakarta, Indonesia
- Herbal Medical Center, Faculty of Medicine, Public Health, and Nursing, Universitas Gadjah Mada, Yogyakarta, Indonesia
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Cardiovascular disease in type 1 diabetes: A review of epidemiological data and underlying mechanisms. DIABETES & METABOLISM 2020; 46:442-449. [PMID: 32998054 DOI: 10.1016/j.diabet.2020.09.001] [Citation(s) in RCA: 61] [Impact Index Per Article: 12.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 07/10/2020] [Revised: 08/27/2020] [Accepted: 09/05/2020] [Indexed: 12/15/2022]
Abstract
Cardiovascular disease (CVD) is highly prevalent in patients with type 1 diabetes (T1D) and a major cause of mortality. CVD arises earlier in life in T1D patients and is responsible for a significant reduction of at least 11 years' life expectancy. Also, the incidence of CVD is much more pronounced in patients with T1D onset at an earlier age. However, the factors responsible for increased atherosclerosis and CVD in T1D are not yet totally clarified. In addition to the usual cardiovascular (CV) risk factors, chronic hyperglycaemia plays an important role by promoting oxidative stress, vascular inflammation, monocyte adhesion, arterial wall thickening and endothelial dysfunction. Diabetic nephropathy and cardiac autonomic neuropathy are also associated with increased CVD in T1D. In fact, the CVD risk remains significantly increased even in well-controlled T1D patients who have no additional CV risk factors, indicating that other potential factors are likely to be involved. Hypoglycemia and glucose variability could enhance CV disease by promoting oxidative stress, vascular inflammation and endothelial dysfunction. Furthermore, even well-controlled T1D patients show significant qualitative and functional abnormalities of lipoproteins that are likely to be implicated in the development of atherosclerosis and premature CVD. In addition, recent data suggest that a dysfunctional immune system, which is typical of autoimmune T1D, might also promote CVD possibly through inflammatory pathways. Moreover, overweight and obese T1D patients can manifest additional CV risk through pathophysiological mechanisms resembling those observed in type 2 diabetes (T2D).
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Six I, Flissi N, Lenglet G, Louvet L, Kamel S, Gallet M, Massy ZA, Liabeuf S. Uremic Toxins and Vascular Dysfunction. Toxins (Basel) 2020; 12:toxins12060404. [PMID: 32570781 PMCID: PMC7354618 DOI: 10.3390/toxins12060404] [Citation(s) in RCA: 42] [Impact Index Per Article: 8.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/14/2020] [Revised: 06/15/2020] [Accepted: 06/17/2020] [Indexed: 02/07/2023] Open
Abstract
Vascular dysfunction is an essential element found in many cardiovascular pathologies and in pathologies that have a cardiovascular impact such as chronic kidney disease (CKD). Alteration of vasomotricity is due to an imbalance between the production of relaxing and contracting factors. In addition to becoming a determining factor in pathophysiological alterations, vascular dysfunction constitutes the first step in the development of atherosclerosis plaques or vascular calcifications. In patients with CKD, alteration of vasomotricity tends to emerge as being a new, less conventional, risk factor. CKD is characterized by the accumulation of uremic toxins (UTs) such as phosphate, para-cresyl sulfate, indoxyl sulfate, and FGF23 and, consequently, the deleterious role of UTs on vascular dysfunction has been explored. This accumulation of UTs is associated with systemic alterations including inflammation, oxidative stress, and the decrease of nitric oxide production. The present review proposes to summarize our current knowledge of the mechanisms by which UTs induce vascular dysfunction.
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Affiliation(s)
- Isabelle Six
- UR 7517 UPJV, Pathophysiological Mechanisms and Consequences of Cardiovascular Calcifications (MP3CV), Picardie Jules Verne University, 80025 Amiens, France; (N.F.); (G.L.); (L.L.); (S.K.); (M.G.); (S.L.)
- Correspondence: ; Tel./Fax: +03-22-82-54-25
| | - Nadia Flissi
- UR 7517 UPJV, Pathophysiological Mechanisms and Consequences of Cardiovascular Calcifications (MP3CV), Picardie Jules Verne University, 80025 Amiens, France; (N.F.); (G.L.); (L.L.); (S.K.); (M.G.); (S.L.)
| | - Gaëlle Lenglet
- UR 7517 UPJV, Pathophysiological Mechanisms and Consequences of Cardiovascular Calcifications (MP3CV), Picardie Jules Verne University, 80025 Amiens, France; (N.F.); (G.L.); (L.L.); (S.K.); (M.G.); (S.L.)
| | - Loïc Louvet
- UR 7517 UPJV, Pathophysiological Mechanisms and Consequences of Cardiovascular Calcifications (MP3CV), Picardie Jules Verne University, 80025 Amiens, France; (N.F.); (G.L.); (L.L.); (S.K.); (M.G.); (S.L.)
| | - Said Kamel
- UR 7517 UPJV, Pathophysiological Mechanisms and Consequences of Cardiovascular Calcifications (MP3CV), Picardie Jules Verne University, 80025 Amiens, France; (N.F.); (G.L.); (L.L.); (S.K.); (M.G.); (S.L.)
- Amiens-Picardie University Hospital, Human Biology Center, 80054 Amiens, France
| | - Marlène Gallet
- UR 7517 UPJV, Pathophysiological Mechanisms and Consequences of Cardiovascular Calcifications (MP3CV), Picardie Jules Verne University, 80025 Amiens, France; (N.F.); (G.L.); (L.L.); (S.K.); (M.G.); (S.L.)
| | - Ziad A. Massy
- Service de Néphrologie et Dialyse, Assistance Publique—Hôpitaux de Paris (APHP), Hôpital Universitaire Ambroise Paré, 92100 Boulogne Billancourt, France;
- INSERM U1018, Equipe 5, CESP (Centre de Recherche en Épidémiologie et Santé des Populations), Université Paris Saclay et Université Versailles Saint Quentin en Yvelines, 94800 Villejuif, France
| | - Sophie Liabeuf
- UR 7517 UPJV, Pathophysiological Mechanisms and Consequences of Cardiovascular Calcifications (MP3CV), Picardie Jules Verne University, 80025 Amiens, France; (N.F.); (G.L.); (L.L.); (S.K.); (M.G.); (S.L.)
- Pharmacology Department, Amiens University Hospital, 80025 Amiens, France
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Ruze R, Xiong YC, Li JW, Zhong MW, Xu Q, Yan ZB, Zhu JK, Cheng YG, Hu SY, Zhang GY. Sleeve gastrectomy ameliorates endothelial function and prevents lung cancer by normalizing endothelin-1 axis in obese and diabetic rats. World J Gastroenterol 2020; 26:2599-2617. [PMID: 32523314 PMCID: PMC7265138 DOI: 10.3748/wjg.v26.i20.2599] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/14/2020] [Revised: 04/13/2020] [Accepted: 05/15/2020] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND Previous evidence has implied that obesity is an independent risk factor for developing cancer. Being closely related to obesity, type 2 diabetes mellitus provides a suitable environment for the formation and metastasis of tumors through multiple pathways. Although bariatric surgeries are effective in preventing and lowering the risk of various types of cancer, the underlying mechanisms of this effect are not clearly elucidated.
AIM To uncover the role and effect of sleeve gastrectomy (SG) in preventing lung cancer in obese and diabetic rats.
METHODS SG was performed on obese and diabetic Wistar rats, and the postoperative transcriptional and translational alterations of the endothelin-1 (ET-1) axis in the lungs were compared to sham-operated obese and diabetic rats and age-matched healthy controls to assess the improvements in endothelial function and risk of developing lung cancer at the postoperative 4th, 8th, and 12th weeks. The risk was also evaluated using nuclear phosphorylation of H2A histone family member X as a marker of DNA damage (double-strand break).
RESULTS Compared to obese and diabetic sham-operated rats, SG brought a significant reduction to body weight, food intake, and fasting blood glucose while improving oral glucose tolerance and insulin sensitivity. In addition, ameliorated levels of gene and protein expression in the ET-1 axis as well as reduced DNA damage indicated improved endothelial function and a lower risk of developing lung cancer after the surgery.
CONCLUSION Apart from eliminating metabolic disorders, SG improves endothelial function and plays a protective role in preventing lung cancer via normalized ET-1 axis and reduced DNA damage.
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Affiliation(s)
- Rexiati Ruze
- Department of General Surgery, Shandong Provincial Qianfoshan Hospital, Shandong University, Jinan 250014, Shandong Province, China
| | - Ya-Cheng Xiong
- Department of General Surgery, Shandong Provincial Qianfoshan Hospital, Shandong University, Jinan 250014, Shandong Province, China
| | - Jian-Wen Li
- Department of General Surgery, Ruijin Hospital, Shanghai Jiaotong University School of Medicine, Shanghai 200025, China
| | - Ming-Wei Zhong
- Department of General Surgery, The First Affiliated Hospital of Shandong First Medical University, Jinan 250014, Shandong Province, China
| | - Qian Xu
- Department of General Surgery, Shandong Provincial Qianfoshan Hospital, Shandong University, Jinan 250014, Shandong Province, China
| | - Zhi-Bo Yan
- Department of General Surgery, Qilu Hospital of Shandong University, Jinan 250012, Shandong Province, China
| | - Jian-Kang Zhu
- Department of General Surgery, The First Affiliated Hospital of Shandong First Medical University, Jinan 250014, Shandong Province, China
| | - Yu-Gang Cheng
- Department of General Surgery, The First Affiliated Hospital of Shandong First Medical University, Jinan 250014, Shandong Province, China
| | - San-Yuan Hu
- Department of General Surgery, The First Affiliated Hospital of Shandong First Medical University, Jinan 250014, Shandong Province, China
| | - Guang-Yong Zhang
- Department of General Surgery, The First Affiliated Hospital of Shandong First Medical University, Jinan 250014, Shandong Province, China
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Prasad K, Bhanumathy KK. AGE-RAGE Axis in the Pathophysiology of Chronic Lower Limb Ischemia and a Novel Strategy for Its Treatment. Int J Angiol 2020; 29:156-167. [PMID: 33041612 DOI: 10.1055/s-0040-1710045] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/12/2023] Open
Abstract
This review focuses on the role of advanced glycation end products (AGEs) and its cell receptor (RAGE) and soluble receptor (sRAGE) in the pathogenesis of chronic lower limb ischemia (CLLI) and its treatment. CLLI is associated with atherosclerosis in lower limb arteries. AGE-RAGE axis which comprises of AGE, RAGE, and sRAGE has been implicated in atherosclerosis and restenosis. It may be involved in atherosclerosis of lower limb resulting in CLLI. Serum and tissue levels of AGE, and expression of RAGE are elevated, and the serum levels of sRAGE are decreased in CLLI. It is known that AGE, and AGE-RAGE interaction increase the generation of various atherogenic factors including reactive oxygen species, nuclear factor-kappa B, cell adhesion molecules, cytokines, monocyte chemoattractant protein-1, granulocyte macrophage-colony stimulating factor, and growth factors. sRAGE acts as antiatherogenic factor because it reduces the generation of AGE-RAGE-induced atherogenic factors. Treatment of CLLI should be targeted at lowering AGE levels through reduction of dietary intake of AGE, prevention of AGE formation and degradation of AGE, suppression of RAGE expression, blockade of AGE-RAGE binding, elevation of sRAGE by upregulating sRAGE expression, and exogenous administration of sRAGE, and use of antioxidants. In conclusion, AGE-RAGE stress defined as a shift in the balance between stressors (AGE, RAGE) and antistressor (sRAGE) in favor of stressors, initiates the development of atherosclerosis resulting in CLLI. Treatment modalities would include reduction of AGE levels and RAGE expression, RAGE blocker, elevation of sRAGE, and antioxidants for prevention, regression, and slowing of progression of CLLI.
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Affiliation(s)
- Kailash Prasad
- Department of Physiology (APP), College of Medicine, University of Saskatchewan, Saskatoon, SK, Canada
| | - Kalpana K Bhanumathy
- Division of Oncology, Cancer Cluster Unit, College of Medicine, University of Saskatchewan, Saskatoon, SK, Canada
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Grantham CE, Hull KL, Graham-Brown MP, March DS, Burton JO. The Potential Cardiovascular Benefits of Low-Glucose Degradation Product, Biocompatible Peritoneal Dialysis Fluids: A Review of the Literature. Perit Dial Int 2020; 37:375-383. [DOI: 10.3747/pdi.2016.00228] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/26/2016] [Accepted: 02/06/2017] [Indexed: 01/08/2023] Open
Abstract
Cardiovascular mortality in the end-stage renal disease (ESRD) population remains the leading cause of death. Targeting traditional cardiovascular risk factors has proven unsuccessful in this patient population, and therefore attention has turned to risk factors related to chronic kidney disease (CKD). The toxicity of high-glucose peritoneal dialysis (PD) solutions has been well documented. The breakdown of glucose into glucose degradation products (GDP) and advanced glycation end-products (AGE) has the ability to alter cell viability and cause premature apoptosis and is strongly correlated with interstitial fibrosis and microvascular sclerosis. Biocompatible solutions have been introduced to combat the hostile milieu to which PD patients are exposed.Given the considerable cardiovascular burden for PD patients, little is known about the cardiovascular impact the new biocompatible solutions may have. This review analyzes the existing literature regarding the mechanisms through which low-GDP solutions may modulate cardiovascular risk. Interventions using low-GDP solutions have provided encouraging changes in structural cardiovascular measures such as left ventricular mass (LVM), although metabolic changes from reduced GDP and AGE exposure yield inconclusive results on vascular remodelling. It is thought that the local effects of reduced glucose exposure may improve membrane integrity and therefore fluid status. Further research in the form of a robust randomized controlled trial should be carried out to assess the true extent of the cardiovascular benefits these biocompatible solutions may hold.
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Affiliation(s)
- Charlotte E. Grantham
- Department of Infection, Immunity and Inflammation, University of Leicester, Leicester, UK
- University of Leicester, Leicester, UK; John Walls Renal Unit, University of Leicester, Leicester, UK
| | - Katherine L. Hull
- University of Leicester, Leicester, UK; John Walls Renal Unit, University of Leicester, Leicester, UK
| | - Matthew P.M. Graham-Brown
- Department of Infection, Immunity and Inflammation, University of Leicester, Leicester, UK
- University of Leicester, Leicester, UK; John Walls Renal Unit, University of Leicester, Leicester, UK
- Leicester General Hospital, Leicester, UK; National College of Sport and Exercise Medicine, University of Leicester, Leicester, UK
| | - Daniel S. March
- Department of Infection, Immunity and Inflammation, University of Leicester, Leicester, UK
- University of Leicester, Leicester, UK; John Walls Renal Unit, University of Leicester, Leicester, UK
| | - James O. Burton
- Department of Infection, Immunity and Inflammation, University of Leicester, Leicester, UK
- University of Leicester, Leicester, UK; John Walls Renal Unit, University of Leicester, Leicester, UK
- University of Loughborough, Loughborough, UK; and Department of Cardiovascular Sciences, University of Leicester, Leicester, UK
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Tentolouris A, Eleftheriadou I, Tzeravini E, Tsilingiris D, Paschou SA, Siasos G, Tentolouris N. Endothelium as a Therapeutic Target in Diabetes Mellitus: From Basic Mechanisms to Clinical Practice. Curr Med Chem 2020; 27:1089-1131. [PMID: 30663560 DOI: 10.2174/0929867326666190119154152] [Citation(s) in RCA: 22] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/07/2018] [Revised: 12/28/2018] [Accepted: 01/09/2019] [Indexed: 12/12/2022]
Abstract
Endothelium plays an essential role in human homeostasis by regulating arterial blood pressure, distributing nutrients and hormones as well as providing a smooth surface that modulates coagulation, fibrinolysis and inflammation. Endothelial dysfunction is present in Diabetes Mellitus (DM) and contributes to the development and progression of macrovascular disease, while it is also associated with most of the microvascular complications such as diabetic retinopathy, nephropathy and neuropathy. Hyperglycemia, insulin resistance, hyperinsulinemia and dyslipidemia are the main factors involved in the pathogenesis of endothelial dysfunction. Regarding antidiabetic medication, metformin, gliclazide, pioglitazone, exenatide and dapagliflozin exert a beneficial effect on Endothelial Function (EF); glimepiride and glibenclamide, dipeptidyl peptidase-4 inhibitors and liraglutide have a neutral effect, while studies examining the effect of insulin analogues, empagliflozin and canagliflozin on EF are limited. In terms of lipid-lowering medication, statins improve EF in subjects with DM, while data from short-term trials suggest that fenofibrate improves EF; ezetimibe also improves EF but further studies are required in people with DM. The effect of acetylsalicylic acid on EF is dose-dependent and lower doses improve EF while higher ones do not. Clopidogrel improves EF, but more studies in subjects with DM are required. Furthermore, angiotensin- converting-enzyme inhibitors /angiotensin II receptor blockers improve EF. Phosphodiesterase type 5 inhibitors improve EF locally in the corpus cavernosum. Finally, cilostazol exerts favorable effect on EF, nevertheless, more data in people with DM are required.
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Affiliation(s)
- Anastasios Tentolouris
- Diabetes Center, 1st Department of Propaedeutic Internal Medicine, Medical School, National and Kapodistrian University of Athens, Laiko General Hospital, Athens, Greece
| | - Ioanna Eleftheriadou
- Diabetes Center, 1st Department of Propaedeutic Internal Medicine, Medical School, National and Kapodistrian University of Athens, Laiko General Hospital, Athens, Greece
| | - Evangelia Tzeravini
- Diabetes Center, 1st Department of Propaedeutic Internal Medicine, Medical School, National and Kapodistrian University of Athens, Laiko General Hospital, Athens, Greece
| | - Dimitrios Tsilingiris
- Diabetes Center, 1st Department of Propaedeutic Internal Medicine, Medical School, National and Kapodistrian University of Athens, Laiko General Hospital, Athens, Greece
| | - Stavroula A Paschou
- Diabetes Center, 1st Department of Propaedeutic Internal Medicine, Medical School, National and Kapodistrian University of Athens, Laiko General Hospital, Athens, Greece
| | - Gerasimos Siasos
- First Department of Cardiology, Hippokration Hospital, National and Kapodistrian University of Athens Medical School, Athens, Greece
| | - Nikolaos Tentolouris
- Diabetes Center, 1st Department of Propaedeutic Internal Medicine, Medical School, National and Kapodistrian University of Athens, Laiko General Hospital, Athens, Greece
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Cavero-Redondo I, Soriano-Cano A, Álvarez-Bueno C, Cunha PG, Martínez-Hortelano JA, Garrido-Miguel M, Berlanga-Macías C, Martínez-Vizcaíno V. Skin Autofluorescence-Indicated Advanced Glycation End Products as Predictors of Cardiovascular and All-Cause Mortality in High-Risk Subjects: A Systematic Review and Meta-analysis. J Am Heart Assoc 2019; 7:e009833. [PMID: 30371199 PMCID: PMC6222966 DOI: 10.1161/jaha.118.009833] [Citation(s) in RCA: 55] [Impact Index Per Article: 9.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/09/2023]
Abstract
Background Chronic deposits of advanced glycation end products produced by enzymatic glycation have been suggested as predictors of atherosclerotic‐related disorders. This study aimed to estimate the relationship between advanced glycation end products indicated by skin autofluorescence levels and the risk of cardiovascular and all‐cause mortality based on data from observational studies. Methods and Results We systematically searched Medline, Embase, the Cochrane Central Register of Controlled Trials, the Cochrane Database of Systematic Reviews, and the Web of Science databases from their inceptions until November 2017 for observational studies addressing the association of advanced glycation end products by skin autofluorescence levels with cardiovascular and all‐cause mortality. The DerSimonian and Laird random‐effects method was used to compute pooled estimates of hazard ratios and their respective 95% confidence intervals for the risk of cardiovascular and all‐cause mortality associated with levels of advanced glycation end products by skin autofluorescence. Ten published studies were included in the systematic review and meta‐analysis. Higher skin autofluorescence levels were significantly associated with a higher pooled risk estimate for cardiovascular mortality (hazard ratio: 2.06; 95% confidence interval, 1.58–2.67), which might not be important to moderate heterogeneity (I2=34.7%; P=0.163), and for all‐cause mortality (hazard ratio: 1.91; 95% confidence interval, 1.42–2.56) with substantial heterogeneity (I2=60.8%; P=0.0.18). Conclusions Our data suggest that skin autofluorescence levels could be considered predictors of all‐cause mortality and cardiovascular mortality in patients at high and very high risk.
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Affiliation(s)
- Ivan Cavero-Redondo
- 1 Universidad de Castilla-La Mancha Health and Social Research Center Cuenca Spain
| | - Alba Soriano-Cano
- 1 Universidad de Castilla-La Mancha Health and Social Research Center Cuenca Spain
| | - Celia Álvarez-Bueno
- 1 Universidad de Castilla-La Mancha Health and Social Research Center Cuenca Spain
| | - Pedro G Cunha
- 2 Center for the Research and Treatment of Arterial Hypertension and Cardiovascular Risk Internal Medicine Department Guimarães Portugal.,3 School of Medicine Minho University Braga Portugal.,4 Life and Health Science Research Institute (ICVS)/3B's PT Government Associate Laboratory Braga/Guimarães Portugal
| | | | | | | | - Vicente Martínez-Vizcaíno
- 1 Universidad de Castilla-La Mancha Health and Social Research Center Cuenca Spain.,5 Universidad Autónoma de Chile Facultad de Ciencias de la Salud Talca Chile
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de Andrade CM, Rey FM, Cintra ACO, Sampaio SV, Torqueti MR. Effects of crotoxin, a neurotoxin from Crotalus durissus terrificus snake venom, on human endothelial cells. Int J Biol Macromol 2019; 134:613-621. [PMID: 31071401 DOI: 10.1016/j.ijbiomac.2019.05.019] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/02/2019] [Revised: 05/04/2019] [Accepted: 05/04/2019] [Indexed: 01/03/2023]
Abstract
Vascular endothelium plays an important modulatory role due to the production of molecules that mediate vasomotricity, inflammation, and leukocyte adhesion and rolling. Here we addressed whether crotoxin (25-200 μg/mL) - the main component of Crotalus durissus terrificus snake venom - interferes with cell viability, apotosis/necrosis, and cell response to oxidative stress in human umbilical vein endothelial cells (HUVEC) in vitro. We also examined whether crotoxin alters the levels of interleukins, adhesion molecules, and endothelial vasoactive factors in HUVEC cells treated or not with lipopolysaccharide (LPS; 1 μg/mL; 24 h). Crotoxin was not cytotoxic towards HUVEC cells, and downregulated the LPS-induced production of adhesion molecules (VCAM-1, ICAM-1, and E-selectin), vasoactive factors (endothelin-1 and prostaglandin I2), and interleukins (IL-6, IL-8, and IL1β), as well as protected cells against H2O2-induced oxidative stress. Hence, crotoxin played anti-inflammatory, antioxidant, immunomodulating, and vasoactive actions on HUVEC cells, in vitro. Considering that the initial stages of atherosclerosis is characterized by vasoconstriction, increased levels of adhesion molecules, inflammatory cytokines, and oxidative stress in the vascular endothelium; and crotoxin downmodulated all these events, our findings indicate that the actions of crotoxin here demonstrated suggest that it may have an anti-atherogenic action in vivo, which deserves to be tested in future studies.
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Affiliation(s)
- Camila M de Andrade
- Department of Clinical Analyses, Toxicology and Food Sciences, School of Pharmaceutical Sciences of Ribeirão Preto, University of São Paulo, Ribeirão Preto, SP, Brazil.
| | - Fernanda M Rey
- Ribeirão Preto Medical School, University of São Paulo, Ribeirão Preto, SP, Brazil
| | - Adélia Cristina O Cintra
- Department of Clinical Analyses, Toxicology and Food Sciences, School of Pharmaceutical Sciences of Ribeirão Preto, University of São Paulo, Ribeirão Preto, SP, Brazil
| | - Suely V Sampaio
- Department of Clinical Analyses, Toxicology and Food Sciences, School of Pharmaceutical Sciences of Ribeirão Preto, University of São Paulo, Ribeirão Preto, SP, Brazil
| | - Maria Regina Torqueti
- Department of Clinical Analyses, Toxicology and Food Sciences, School of Pharmaceutical Sciences of Ribeirão Preto, University of São Paulo, Ribeirão Preto, SP, Brazil
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Prasad K. AGE-RAGE Stress in the Pathophysiology of Pulmonary Hypertension and its Treatment. Int J Angiol 2019; 28:71-79. [PMID: 31384104 DOI: 10.1055/s-0039-1687818] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022] Open
Abstract
Pulmonary hypertension (PH) is a rare and fatal disease characterized by elevation of pulmonary artery pressure ≥ 25 mm Hg. There are five groups of PH: (1) pulmonary artery (PA) hypertension (PAH), (2) PH due to heart diseases, (3) PH associated with lung diseases/hypoxia, (4) PH associated with chronic obstruction of PA, and (5) PH due to unclear and/or multifactorial mechanisms. The pathophysiologic mechanisms of group 1 have been studied in detail; however, those for groups 2 to 5 are not that well known. PH pathology is characterized by smooth muscle cells (SMC) proliferation, muscularization of peripheral PA, accumulation of extracellular matrix (ECM), plexiform lesions, thromboembolism, and recanalization of thrombi. Advanced glycation end products (AGE) and its receptor (RAGE) and soluble RAGE (sRAGE) appear to be involved in the pathogenesis of PH. AGE and its interaction with RAGE induce vascular hypertrophy through proliferation of vascular SMC, accumulation of ECM, and suppression of apoptosis. Reactive oxygen species (ROS) generated by interaction of AGE and RAGE modulates SMC proliferation, attenuate apoptosis, and constricts PA. Increased stiffness in the artery due to vascular hypertrophy, and vasoconstriction due to ROS resulted in PH. The data also suggest that reduction in consumption and formation of AGE, suppression of RAGE expression, blockage of RAGE ligand binding, elevation of sRAGE levels, and antioxidants may be novel therapeutic targets for prevention, regression, and slowing of progression of PH. In conclusion, AGE-RAGE stress may be involved in the pathogenesis of PH and the therapeutic targets should be the AGE-RAGE axis.
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Affiliation(s)
- Kailash Prasad
- Department of Physiology, College of Medicine, University of Saskatchewan, Saskatoon, Canada
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Biswas S, Chakrabarti S. Increased Extracellular Matrix Protein Production in Chronic Diabetic Complications: Implications of Non-Coding RNAs. Noncoding RNA 2019; 5:E30. [PMID: 30909482 PMCID: PMC6468528 DOI: 10.3390/ncrna5010030] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/08/2019] [Revised: 03/16/2019] [Accepted: 03/18/2019] [Indexed: 12/16/2022] Open
Abstract
Management of chronic diabetic complications remains a major medical challenge worldwide. One of the characteristic features of all chronic diabetic complications is augmented production of extracellular matrix (ECM) proteins. Such ECM proteins are deposited in all tissues affected by chronic complications, ultimately causing organ damage and dysfunction. A contributing factor to this pathogenetic process is glucose-induced endothelial damage, which involves phenotypic transformation of endothelial cells (ECs). This phenotypic transition of ECs, from a quiescent state to an activated dysfunctional state, can be mediated through alterations in the synthesis of cellular proteins. In this review, we discussed the roles of non-coding RNAs, specifically microRNAs (miRNAs) and long non-coding RNAs (lncRNAs), in such processes. We further outlined other epigenetic mechanisms regulating the biogenesis and/or function of non-coding RNAs. Overall, we believe that better understanding of such molecular processes may lead to the development of novel biomarkers and therapeutic strategies in the future.
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Affiliation(s)
- Saumik Biswas
- Department of Pathology and Laboratory Medicine, Western University, London, ON N6A5A5, Canada.
| | - Subrata Chakrabarti
- Department of Pathology and Laboratory Medicine, Western University, London, ON N6A5A5, Canada.
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Blocking C/EBP β protects vascular endothelial cells from injury induced by intermittent hypoxia. Sleep Breath 2019; 23:953-962. [PMID: 30680681 DOI: 10.1007/s11325-018-1759-7] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/31/2018] [Revised: 11/12/2018] [Accepted: 11/15/2018] [Indexed: 12/13/2022]
Abstract
BACKGROUND Intermittent hypoxia (IH) can damage endothelial cells and lead to apoptosis in obstructive sleep apnea-hypopnea syndrome (OSAHS). Hypoxia induces apoptosis in endothelial cells via upregulation of endothelin-1 (ET-1) and hypoxia inducible factor-1 alpha (HIF-1α) plays a key role in the hypoxic stress response. PURPOSE We investigated an approach to diminish the negative effect of HIF-1α while maintaining its protective effect. METHODS Human umbilical vein endothelial cells (HUVECs) were subjected to sustained hypoxia (SH) or IH for 24 h, and the responses of HIF-1α, CCAAT/enhancer binding protein beta (C/EBP β), and endothelin-1 (ET-1) were assessed by western blotting. A luciferase reporter system was employed to verify the potential binding site (transcription factor binding site, TFBS) for C/EBP β in the ET-1 promoter. The specificity of regulation of ET-1 by HIF-1α via C/EBP β was evaluated by a lentiviral system. The effects of silencing of C/EBP β on IH-induced apoptosis, vascular endothelial growth factor (VEGF) protein levels, proliferation, and in vitro tube formation were studied. RESULTS We found that IH significantly increased HIF-1α, C/EBP β, and ET-1 in HUVECs. Knockdown of HIF-1α or C/EBP β inhibited the upregulation of ET-1 induced by IH. Blocking C/EBP β impaired IH-induced apoptosis but did not affect VEGF expression, proliferation, or in vitro tube formation. C/EBP β was shown to mediate increased ET-1 transcription by HIF-1α through the TFBS, 5'-GTTGCCTGTTG-3', in ET-1 promoter. CONCLUSION Silencing of C/EBP β can suppress apoptosis but does not affect the protective role of HIF-1α in the hypoxic stress response.
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Pant T, Mishra MK, Bai X, Ge ZD, Bosnjak ZJ, Dhanasekaran A. Microarray analysis of long non-coding RNA and mRNA expression profiles in diabetic cardiomyopathy using human induced pluripotent stem cell-derived cardiomyocytes. Diab Vasc Dis Res 2019; 16:57-68. [PMID: 30482051 DOI: 10.1177/1479164118813888] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
AIM This study aims to investigate the altered expression signature of long non-coding RNAs, mRNAs and deregulated pathways related to diabetic cardiomyopathy disease pathogenesis. METHOD We utilize the previously established in vitro diabetic cardiomyopathy model of human induced pluripotent stem cell-derived human cardiomyocytes to perform long non-coding RNA and mRNA expression analysis on glucose (11 mM), endothelin-1 (10 nM) and cortisol (1 µM) stimulated human induced pluripotent stem cell-derived human cardiomyocytes to interrogate diabetic cardiomyopathy associated RNA expression profile. RESULT Out of 20,730 mRNAs and 40,173 long non-coding RNAs being screened, 2046 long non-coding RNAs and 1582 mRNAs were differentially regulated (fold change > 2, p < 0.05) between diabetic cardiomyopathy and control group, of which more than half were intergenic and antisense long non-coding RNAs. Most of the coding transcripts were associated with processes like inflammation, structural reorganization, metabolism, smooth muscle contraction, focal adhesion and repair contributing towards the development of diabetic cardiomyopathy. The subgroup analysis further revealed 411 long non-coding RNAs being co-expressed with neighbouring genes. However, our coding-non-coding co-expression analysis showed an overall 48,155 co-expression network connections. In addition to that, the long non-coding RNAs with highest network connections were profoundly enriched for focal adhesion, cell-matrix adhesion and muscle contraction. CONCLUSION These results provide comprehensive data about the pathways and regulatory mechanisms associated with diabetic cardiomyopathy and indicate that long non-coding RNAs may play a crucial role in diabetic cardiomyopathy.
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Affiliation(s)
- Tarun Pant
- 1 Department of Medicine, Medical College of Wisconsin, Milwaukee, WI, USA
- 2 Centre for Biotechnology, Anna University, Chennai, India
| | - Manoj K Mishra
- 3 Department of Physiology, Medical College of Wisconsin, Milwaukee, WI, USA
| | - Xiaowen Bai
- 3 Department of Physiology, Medical College of Wisconsin, Milwaukee, WI, USA
- 4 Department of Cell Biology, Neurobiology and Anatomy, Medical College of Wisconsin, Milwaukee, WI, USA
| | - Zhi-Dong Ge
- 5 Department of Ophthalmology, Stanford University School of Medicine, Stanford, CA, USA
| | - Zeljko J Bosnjak
- 1 Department of Medicine, Medical College of Wisconsin, Milwaukee, WI, USA
- 3 Department of Physiology, Medical College of Wisconsin, Milwaukee, WI, USA
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The C9ORF72 Gene, Implicated in Amyotrophic Lateral Sclerosis and Frontotemporal Dementia, Encodes a Protein That Functions in Control of Endothelin and Glutamate Signaling. Mol Cell Biol 2018; 38:MCB.00155-18. [PMID: 30150298 DOI: 10.1128/mcb.00155-18] [Citation(s) in RCA: 29] [Impact Index Per Article: 4.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/02/2018] [Accepted: 08/15/2018] [Indexed: 02/08/2023] Open
Abstract
A GGGGCC repeat expansion in the C9ORF72 (C9) gene is the most common known cause of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia. Several mechanisms have been proposed to account for its toxicity, including the possibility that reduced C9 protein levels contribute to disease. To investigate this possibility, we examined the effects of reduced C9 levels in several cell systems. We first showed that C9 knockdown (KD) in U87 glioblastoma cells results in striking morphological changes, including vacuolization and alterations in cell size. Unexpectedly, RNA analysis revealed changes in expression of many genes, including genes involved in endothelin (EDN) signaling and immune system pathways and multiple glutamate cycling genes (e.g., EAAT2), which were verified in several cell models, including astrocytes and brain samples from C9-positive patients. Consistent with deregulation of the glutamate cycling genes, elevated intracellular glutamate was detected in both KD cells and patient astrocytes. Importantly, levels of mRNAs encoding EDN1 and its receptors, known to be elevated in ALS, were sharply increased by C9 KD, likely resulting from an observed activation of NF-κB signaling and/or a possible role of a C9 isoform in gene control.
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Fournet M, Bonté F, Desmoulière A. Glycation Damage: A Possible Hub for Major Pathophysiological Disorders and Aging. Aging Dis 2018; 9:880-900. [PMID: 30271665 PMCID: PMC6147582 DOI: 10.14336/ad.2017.1121] [Citation(s) in RCA: 168] [Impact Index Per Article: 24.0] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/22/2017] [Accepted: 11/21/2017] [Indexed: 12/25/2022] Open
Abstract
Glycation is both a physiological and pathological process which mainly affects proteins, nucleic acids and lipids. Exogenous and endogenous glycation produces deleterious reactions that take place principally in the extracellular matrix environment or within the cell cytosol and organelles. Advanced glycation end product (AGE) formation begins by the non-enzymatic glycation of free amino groups by sugars and aldehydes which leads to a succession of rearrangements of intermediate compounds and ultimately to irreversibly bound products known as AGEs. Epigenetic factors, oxidative stress, UV and nutrition are important causes of the accumulation of chemically and structurally different AGEs with various biological reactivities. Cross-linked proteins, deriving from the glycation process, present both an altered structure and function. Nucleotides and lipids are particularly vulnerable targets which can in turn favor DNA mutation or a decrease in cell membrane integrity and associated biological pathways respectively. In mitochondria, the consequences of glycation can alter bioenergy production. Under physiological conditions, anti-glycation defenses are sufficient, with proteasomes preventing accumulation of glycated proteins, while lipid turnover clears glycated products and nucleotide excision repair removes glycated nucleotides. If this does not occur, glycation damage accumulates, and pathologies may develop. Glycation-induced biological products are known to be mainly associated with aging, neurodegenerative disorders, diabetes and its complications, atherosclerosis, renal failure, immunological changes, retinopathy, skin photoaging, osteoporosis, and progression of some tumors.
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Affiliation(s)
- Maxime Fournet
- 1University of Limoges, Faculty of Pharmacy, Department of Physiology, EA 6309, F-87025 Limoges, France
| | | | - Alexis Desmoulière
- 3University of Limoges, Faculty of Pharmacy, Department of Physiology, EA 6309, F-87025 Limoges, France
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Kaur R, Kaur M, Singh J. Endothelial dysfunction and platelet hyperactivity in type 2 diabetes mellitus: molecular insights and therapeutic strategies. Cardiovasc Diabetol 2018; 17:121. [PMID: 30170601 PMCID: PMC6117983 DOI: 10.1186/s12933-018-0763-3] [Citation(s) in RCA: 408] [Impact Index Per Article: 58.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/19/2018] [Accepted: 08/20/2018] [Indexed: 12/14/2022] Open
Abstract
The incidence and prevalence of diabetes mellitus is rapidly increasing worldwide at an alarming rate. Type 2 diabetes mellitus (T2DM) is the most prevalent form of diabetes, accounting for approximately 90-95% of the total diabetes cases worldwide. Besides affecting the ability of body to use glucose, it is associated with micro-vascular and macro-vascular complications. Augmented atherosclerosis is documented to be the key factor leading to vascular complications in T2DM patients. The metabolic milieu of T2DM, including insulin resistance, hyperglycemia and release of excess free fatty acids, along with other metabolic abnormalities affects vascular wall by a series of events including endothelial dysfunction, platelet hyperactivity, oxidative stress and low-grade inflammation. Activation of these events further enhances vasoconstriction and promotes thrombus formation, ultimately resulting in the development of atherosclerosis. All these evidences are supported by the clinical trials reporting the importance of endothelial dysfunction and platelet hyperactivity in the pathogenesis of atherosclerotic vascular complications. In this review, an attempt has been made to comprehensively compile updated information available in context of endothelial and platelet dysfunction in T2DM.
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Affiliation(s)
- Raminderjit Kaur
- Department of Molecular Biology & Biochemistry, Guru Nanak Dev University, Amritsar, Punjab, India
| | - Manpreet Kaur
- Department of Human Genetics, Guru Nanak Dev University, Amritsar, Punjab, India
| | - Jatinder Singh
- Department of Molecular Biology & Biochemistry, Guru Nanak Dev University, Amritsar, Punjab, India.
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Nafisa A, Gray SG, Cao Y, Wang T, Xu S, Wattoo FH, Barras M, Cohen N, Kamato D, Little PJ. Endothelial function and dysfunction: Impact of metformin. Pharmacol Ther 2018; 192:150-162. [PMID: 30056057 DOI: 10.1016/j.pharmthera.2018.07.007] [Citation(s) in RCA: 91] [Impact Index Per Article: 13.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
Cardiovascular and metabolic diseases remain the leading cause of morbidity and mortality worldwide. Endothelial dysfunction is a key player in the initiation and progression of cardiovascular and metabolic diseases. Current evidence suggests that the anti-diabetic drug metformin improves insulin resistance and protects against endothelial dysfunction in the vasculature. Hereby, we provide a timely review on the protective effects and molecular mechanisms of metformin in preventing endothelial dysfunction and cardiovascular and metabolic diseases.
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Affiliation(s)
- Asma Nafisa
- School of Pharmacy, University of Queensland, Pharmacy Australia Centre of Excellence, Woolloongabba, QLD, Australia.
| | - Susan G Gray
- School of Pharmacy, University of Queensland, Pharmacy Australia Centre of Excellence, Woolloongabba, QLD, Australia.
| | - Yingnan Cao
- Xinhua College of Sun Yat-sen University, Tianhe District, Guangzhou, China
| | - Tinghuai Wang
- Xinhua College of Sun Yat-sen University, Tianhe District, Guangzhou, China.
| | - Suowen Xu
- Aab Cardiovascular Research Institute, Department of Medicine, University of Rochester School of Medicine and Dentistry, Rochester, NY, USA.
| | - Feroza H Wattoo
- Department of Biochemistry, PMAS Arid Agriculture University, Shamasabad, Muree Road, Rawalpindi 4600, Pakistan..
| | - Michael Barras
- Dept. of Pharmacy, Princess Alexandra Hospital, 199 Ipswich Rd, Woolloongabba, QLD 4102, Australia.
| | - Neale Cohen
- Baker Heart and Diabetes Institute, Melbourne, 3004, Victoria, Australia.
| | - Danielle Kamato
- School of Pharmacy, University of Queensland, Pharmacy Australia Centre of Excellence, Woolloongabba, QLD, Australia; Xinhua College of Sun Yat-sen University, Tianhe District, Guangzhou, China.
| | - Peter J Little
- School of Pharmacy, University of Queensland, Pharmacy Australia Centre of Excellence, Woolloongabba, QLD, Australia; Xinhua College of Sun Yat-sen University, Tianhe District, Guangzhou, China.
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Yang H, Mao W, Rodriguez-Aguayo C, Mangala LS, Bartholomeusz G, Iles LR, Jennings NB, Ahmed AA, Sood AK, Lopez-Berestein G, Lu Z, Bast RC. Paclitaxel Sensitivity of Ovarian Cancer Can be Enhanced by Knocking Down Pairs of Kinases that Regulate MAP4 Phosphorylation and Microtubule Stability. Clin Cancer Res 2018; 24:5072-5084. [PMID: 30084832 DOI: 10.1158/1078-0432.ccr-18-0504] [Citation(s) in RCA: 25] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/11/2018] [Revised: 05/08/2018] [Accepted: 06/27/2018] [Indexed: 01/11/2023]
Abstract
Purpose: Most patients with ovarian cancer receive paclitaxel chemotherapy, but less than half respond. Pre-treatment microtubule stability correlates with paclitaxel response in ovarian cancer cell lines. Microtubule stability can be increased by depletion of individual kinases. As microtubule stability can be regulated by phosphorylation of microtubule-associated proteins (MAPs), we reasoned that depletion of pairs of kinases that regulate phosphorylation of MAPs could induce microtubule stabilization and paclitaxel sensitization.Experimental Design: Fourteen kinases known to regulate paclitaxel sensitivity were depleted individually in 12 well-characterized ovarian cancer cell lines before measuring proliferation in the presence or absence of paclitaxel. Similar studies were performed by depleting all possible pairs of kinases in six ovarian cancer cell lines. Pairs that enhanced paclitaxel sensitivity across multiple cell lines were studied in depth in cell culture and in two xenograft models.Results: Transfection of siRNA against 10 of the 14 kinases enhanced paclitaxel sensitivity in at least six of 12 cell lines. Dual knockdown of IKBKB/STK39 or EDN2/TBK1 enhanced paclitaxel sensitivity more than silencing single kinases. Sequential knockdown was superior to concurrent knockdown. Dual silencing of IKBKB/STK39 or EDN2/TBK1 stabilized microtubules by inhibiting phosphorylation of p38 and MAP4, inducing apoptosis and blocking cell cycle more effectively than silencing individual kinases. Knockdown of IKBKB/STK39 or EDN2/TBK1 enhanced paclitaxel sensitivity in two ovarian xenograft models.Conclusions: Sequential knockdown of dual kinases increased microtubule stability by decreasing p38-mediated phosphorylation of MAP4 and enhanced response to paclitaxel in ovarian cancer cell lines and xenografts, suggesting a strategy to improve primary therapy. Clin Cancer Res; 24(20); 5072-84. ©2018 AACR.
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Affiliation(s)
- Hailing Yang
- Department of Experimental Therapeutics, University of Texas, M.D. Anderson Cancer Center, Houston, Texas
| | - Weiqun Mao
- Department of Experimental Therapeutics, University of Texas, M.D. Anderson Cancer Center, Houston, Texas
| | - Cristian Rodriguez-Aguayo
- Department of Experimental Therapeutics, University of Texas, M.D. Anderson Cancer Center, Houston, Texas.,Center for RNA Interference and Non-Coding RNA, University of Texas, M.D. Anderson Cancer Center, Houston, Texas
| | - Lingegowda S Mangala
- Center for RNA Interference and Non-Coding RNA, University of Texas, M.D. Anderson Cancer Center, Houston, Texas.,Department of Gynecologic Oncology and Reproductive Medicine, University of Texas, M.D. Anderson Cancer Center, Houston, Texas
| | - Geoffrey Bartholomeusz
- Department of Experimental Therapeutics, University of Texas, M.D. Anderson Cancer Center, Houston, Texas
| | - Lakesla R Iles
- Department of Experimental Therapeutics, University of Texas, M.D. Anderson Cancer Center, Houston, Texas
| | - Nicholas B Jennings
- Center for RNA Interference and Non-Coding RNA, University of Texas, M.D. Anderson Cancer Center, Houston, Texas
| | - Ahmed Ashour Ahmed
- Ovarian Cancer Cell Laboratory, Weatherall Institute of Molecular Medicine, University of Oxford, Headington, Oxford, United Kingdom.,Nuffield Department of Women's & Reproductive Health, University of Oxford, Women's Centre, John Radcliffe Hospital, Oxford, United Kingdom
| | - Anil K Sood
- Center for RNA Interference and Non-Coding RNA, University of Texas, M.D. Anderson Cancer Center, Houston, Texas.,Department of Gynecologic Oncology and Reproductive Medicine, University of Texas, M.D. Anderson Cancer Center, Houston, Texas
| | - Gabriel Lopez-Berestein
- Department of Experimental Therapeutics, University of Texas, M.D. Anderson Cancer Center, Houston, Texas.,Center for RNA Interference and Non-Coding RNA, University of Texas, M.D. Anderson Cancer Center, Houston, Texas
| | - Zhen Lu
- Department of Experimental Therapeutics, University of Texas, M.D. Anderson Cancer Center, Houston, Texas
| | - Robert C Bast
- Department of Experimental Therapeutics, University of Texas, M.D. Anderson Cancer Center, Houston, Texas.
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49
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BISWAS S, FENG B, THOMAS A, CHEN S, AREF-ESHGHI E, SADIKOVIC B, CHAKRABARTI S. Endothelin-1 Regulation Is Entangled in a Complex Web of Epigenetic Mechanisms in Diabetes. Physiol Res 2018; 67:S115-S125. [DOI: 10.33549/physiolres.933836] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022] Open
Abstract
Endothelial cells (ECs) are primary targets of glucose-induced tissue damage. As a result of hyperglycemia, endothelin-1 (ET-1) is upregulated in organs affected by chronic diabetic complications. The objective of the present study was to identify novel transcriptional mechanisms that influence ET-1 regulation in diabetes. We carried out the investigation in microvascular ECs using multiple approaches. ECs were incubated with 5 mM glucose (NG) or 25 mM glucose (HG) and analyses for DNA methylation, histone methylation, or long non-coding RNA- mediated regulation of ET-1 mRNA were then performed. DNA methylation array analyses demonstrated the presence of hypomethylation in the proximal promoter and 5’ UTR/first exon regions of EDN1 following HG culture. Further, globally blocking DNA methylation or histone methylation significantly increased ET-1 mRNA expressions in both NG and HG-treated HRECs. While, knocking down the pathogenetic lncRNAs ANRIL, MALAT1, and ZFAS1 subsequently prevented the glucose-induced upregulation of ET-1 transcripts. Based on our past and present findings, we present a novel paradigm that reveals a complex web of epigenetic mechanisms regulating glucose-induced transcription of ET-1. Improving our understanding of such processes may lead to better targeted therapies.
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Affiliation(s)
| | | | | | | | | | | | - S. CHAKRABARTI
- Department of Pathology and Laboratory Medicine, Western University, London, Ontario, Canada
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50
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Eelen G, de Zeeuw P, Treps L, Harjes U, Wong BW, Carmeliet P. Endothelial Cell Metabolism. Physiol Rev 2018; 98:3-58. [PMID: 29167330 PMCID: PMC5866357 DOI: 10.1152/physrev.00001.2017] [Citation(s) in RCA: 377] [Impact Index Per Article: 53.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/05/2017] [Revised: 06/19/2017] [Accepted: 06/22/2017] [Indexed: 02/06/2023] Open
Abstract
Endothelial cells (ECs) are more than inert blood vessel lining material. Instead, they are active players in the formation of new blood vessels (angiogenesis) both in health and (life-threatening) diseases. Recently, a new concept arose by which EC metabolism drives angiogenesis in parallel to well-established angiogenic growth factors (e.g., vascular endothelial growth factor). 6-Phosphofructo-2-kinase/fructose-2,6-bisphosphatase-3-driven glycolysis generates energy to sustain competitive behavior of the ECs at the tip of a growing vessel sprout, whereas carnitine palmitoyltransferase 1a-controlled fatty acid oxidation regulates nucleotide synthesis and proliferation of ECs in the stalk of the sprout. To maintain vascular homeostasis, ECs rely on an intricate metabolic wiring characterized by intracellular compartmentalization, use metabolites for epigenetic regulation of EC subtype differentiation, crosstalk through metabolite release with other cell types, and exhibit EC subtype-specific metabolic traits. Importantly, maladaptation of EC metabolism contributes to vascular disorders, through EC dysfunction or excess angiogenesis, and presents new opportunities for anti-angiogenic strategies. Here we provide a comprehensive overview of established as well as newly uncovered aspects of EC metabolism.
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Affiliation(s)
- Guy Eelen
- Laboratory of Angiogenesis and Vascular Metabolism, Department of Oncology, KU Leuven, Leuven, Belgium; and Laboratory of Angiogenesis and Vascular Metabolism, Center for Cancer Biology, VIB, Leuven, Belgium
| | - Pauline de Zeeuw
- Laboratory of Angiogenesis and Vascular Metabolism, Department of Oncology, KU Leuven, Leuven, Belgium; and Laboratory of Angiogenesis and Vascular Metabolism, Center for Cancer Biology, VIB, Leuven, Belgium
| | - Lucas Treps
- Laboratory of Angiogenesis and Vascular Metabolism, Department of Oncology, KU Leuven, Leuven, Belgium; and Laboratory of Angiogenesis and Vascular Metabolism, Center for Cancer Biology, VIB, Leuven, Belgium
| | - Ulrike Harjes
- Laboratory of Angiogenesis and Vascular Metabolism, Department of Oncology, KU Leuven, Leuven, Belgium; and Laboratory of Angiogenesis and Vascular Metabolism, Center for Cancer Biology, VIB, Leuven, Belgium
| | - Brian W Wong
- Laboratory of Angiogenesis and Vascular Metabolism, Department of Oncology, KU Leuven, Leuven, Belgium; and Laboratory of Angiogenesis and Vascular Metabolism, Center for Cancer Biology, VIB, Leuven, Belgium
| | - Peter Carmeliet
- Laboratory of Angiogenesis and Vascular Metabolism, Department of Oncology, KU Leuven, Leuven, Belgium; and Laboratory of Angiogenesis and Vascular Metabolism, Center for Cancer Biology, VIB, Leuven, Belgium
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