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Pedreañez A, Carrero Y, Vargas R, Hernandez-Fonseca JP, Hernandez-Fonseca H, Mosquera JA. Role of Gut Microbiota in Dengue. Rev Med Virol 2024; 34:e2577. [PMID: 39215460 DOI: 10.1002/rmv.2577] [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: 04/28/2024] [Revised: 07/30/2024] [Accepted: 08/12/2024] [Indexed: 09/04/2024]
Abstract
Dengue is a disease caused by a flavivirus (DENV) and transmitted by the bite of a mosquito, primarily the Aedes aegypti and Aedes albopictus species. Previous studies have demonstrated a relationship between the host gut microbiota and the evolution of dengue. It seems to be a bidirectional relationship, in which the DENV can affect the microbiota by inducing alterations related to intestinal permeability, leading to the release of molecules from microbiota dysbiosis that can influence the evolution of dengue. The role of angiotensin II (Ang II) in the microbiota/dengue relationship is not well understood, but it is known that the renin-angiotensin system (RAS) is present in the intestinal tract and interacts with the gut microbiota. The possible effect of Ang II on the microbiota/Ang II/dengue relationship can be summarised as follows: the presence of Ang II induced hypertension, the increase in angiotensinogen, chymase, and microRNAs during the disease, the induction of vascular dysfunction, the production of trimethylamine N-oxide and the brain/microbiota relationship, all of which are elements present in dengue that could be part of the microbiota/Ang II/dengue interactions. These findings suggest the potential use of Ang II synthesis blockers and the use of AT1 receptor antagonists as therapeutic drugs in dengue.
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Affiliation(s)
- Adriana Pedreañez
- Cátedra de Inmunología, Escuela de Bioanálisis, Facultad de Medicina, Universidad del Zulia, Maracaibo, Venezuela
| | - Yenddy Carrero
- Instituto de Investigaciones Clínicas "Dr. Américo Negrette", Facultad de Medicina, Universidad del Zulia, Maracaibo, Venezuela
| | - Renata Vargas
- Instituto de Investigaciones Clínicas "Dr. Américo Negrette", Facultad de Medicina, Universidad del Zulia, Maracaibo, Venezuela
| | - Juan P Hernandez-Fonseca
- Instituto de Investigaciones Clínicas "Dr. Américo Negrette", Facultad de Medicina, Universidad del Zulia, Maracaibo, Venezuela
- Servicio de Microscopia Electrónica, Centro Nacional de Biotecnología (CNB-CSIC), Madrid, España
| | - Hugo Hernandez-Fonseca
- Facultad de Ciencias Veterinarias, Universidad del Zulia, Maracaibo, Venezuela
- Anatomy, Physiology and Pharmacology Department, School of Veterinary Medicine, Saint George's University, Saint George, Grenada
| | - Jesús A Mosquera
- Instituto de Investigaciones Clínicas "Dr. Américo Negrette", Facultad de Medicina, Universidad del Zulia, Maracaibo, Venezuela
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Pedreañez A, Carrero Y, Vargas R, Hernández-Fonseca JP, Mosquera JA. Role of angiotensin II in cellular entry and replication of dengue virus. Arch Virol 2024; 169:121. [PMID: 38753119 DOI: 10.1007/s00705-024-06040-4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/11/2024] [Accepted: 02/19/2024] [Indexed: 05/21/2024]
Abstract
Previous studies have demonstrated the relevance of several soluble molecules in the pathogenesis of dengue. In this regard, a possible role for angiotensin II (Ang II) in the pathophysiology of dengue has been suggested by the observation of a blockade of Ang II in patients with dengue, increased expression of molecules related to Ang II production in the plasma of dengue patients, increased expression of circulating cytokines and soluble molecules related to the action of Ang II, and an apparent relationship between DENV, Ang II effects, and miRNAs. In addition, in ex vivo experiments, the blockade of Ang II AT1 receptor and ACE-1 (angiotensin converting enzyme 1), both of which are involved in Ang II production and its function, inhibits infection of macrophages by DENV, suggesting a role of Ang II in viral entry or in intracellular viral replication of the virus. Here, we discuss the possible mechanisms of Ang II in the entry and replication of DENV. Ang II has the functions of increasing the expression of DENV entry receptors, creation of clathrin-coated vesicles, and increasing phagocytosis, all of which are involved in DENV entry. This hormone also modulates the expression of the Rab5 and Rab7 proteins, which are important in the endosomal processing of DENV during viral replication. This review summarizes the data related to the possible involvement of Ang II in the entry of DENV into cells and its replication.
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Affiliation(s)
- Adriana Pedreañez
- Cátedra de Inmunología, Escuela de Bioanálisis, Facultad de Medicina, Universidad del Zulia, Maracaibo, Venezuela
| | - Yenddy Carrero
- Instituto de Investigaciones Clínicas "Dr. Américo Negrette", Facultad de Medicina, Universidad del Zulia, Maracaibo, Venezuela
| | - Renata Vargas
- Instituto de Investigaciones Clínicas "Dr. Américo Negrette", Facultad de Medicina, Universidad del Zulia, Maracaibo, Venezuela
| | - Juan P Hernández-Fonseca
- Instituto de Investigaciones Clínicas "Dr. Américo Negrette", Facultad de Medicina, Universidad del Zulia, Maracaibo, Venezuela
- Servicio de Microscopia Electrónica del Centro Nacional de Biotecnología (CNB- CSIC), Madrid, España
| | - Jesús Alberto Mosquera
- Instituto de Investigaciones Clínicas "Dr. Américo Negrette", Facultad de Medicina, Universidad del Zulia, Maracaibo, Venezuela.
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Mosquera-Sulbaran JA, Pedreañez A, Carrero Y, Hernandez-Fonseca JP. Angiotensin II and post-streptococcal glomerulonephritis. Clin Exp Nephrol 2024; 28:359-374. [PMID: 38170299 DOI: 10.1007/s10157-023-02446-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/30/2023] [Accepted: 12/04/2023] [Indexed: 01/05/2024]
Abstract
BACKGROUND Post-streptococcal glomerulonephritis (PSGN) is a consequence of the infection by group A beta-hemolytic streptococcus. During this infection, various immunological processes generated by streptococcal antigens are triggered, such as the induction of antibodies and immune complexes. This activation of the immune system involves both innate and acquired immunity. The immunological events that occur at the renal level lead to kidney damage with chronic renal failure as well as resolution of the pathological process (in most cases). Angiotensin II (Ang II) is a molecule with vasopressor and pro-inflammatory capacities, being an important factor in various inflammatory processes. During PSGN some events are defined that make Ang II conceivable as a molecule involved in the inflammatory processes during the disease. CONCLUSION This review is focused on defining which reported events would be related to the presence of this hormone in PSGN.
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Affiliation(s)
- Jesus A Mosquera-Sulbaran
- Facultad de Medicina, Instituto de Investigaciones Clínicas "Dr. Américo Negrette", Universidad del Zulia, Apartado Postal: 23, MaracaiboZulia, 4001-A, Venezuela.
| | - Adriana Pedreañez
- Facultad de Medicina, Cátedra de Inmunología, Escuela de Bioanálisis, Universidad del Zulia, Maracaibo, Venezuela
| | - Yenddy Carrero
- Facultad de Medicina, Instituto de Investigaciones Clínicas "Dr. Américo Negrette", Universidad del Zulia, Apartado Postal: 23, MaracaiboZulia, 4001-A, Venezuela
| | - Juan Pablo Hernandez-Fonseca
- Facultad de Medicina, Instituto de Investigaciones Clínicas "Dr. Américo Negrette", Universidad del Zulia, Apartado Postal: 23, MaracaiboZulia, 4001-A, Venezuela
- Servicio de Microscopia Electrónica del Centro Nacional de Biotecnología, CNB-CSIC, Madrid, Spain
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Ting R, Dutton H, Sorisky A. In vitro studies of the renin-angiotensin system in human adipose tissue/adipocytes and possible relationship to SARS-CoV-2: a scoping review. Adipocyte 2023; 12:2194034. [PMID: 36973648 PMCID: PMC10054178 DOI: 10.1080/21623945.2023.2194034] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/27/2022] [Accepted: 01/02/2023] [Indexed: 03/29/2023] Open
Abstract
The renin-angiotensin system (RAS) operates within adipose tissue. Obesity-related changes can affect adipose RAS, predisposing to hypertension, type 2 diabetes, and possibly severe COVID-19. We evaluated the in vitro research on human adipose RAS and identified gaps in the literature. Medline (Ovid), Embase (Ovid), Web of Science, Scopus, and 1findr were searched to identify relevant studies. Fifty primary studies met our inclusion criteria for analysis. Expression of RAS components (n = 14), role in differentiation (n = 14), association with inflammation (n = 15) or blood pressure (n = 7) were investigated. We found (1) obesity-related changes in RAS were frequently studied (30%); (2) an upswing of articles investigating adipose ACE-2 expression since the COVID-19 pandemic; (3) a paucity of papers on AT2R and Ang (1-7)/MasR which counterbalance Ang II/ART1; (4) weight loss lowered adipose ACE-2 mRNA expression; and (5) angiotensin receptor blockers (ARBs) reduced deleterious effects of angiotensin II. Overall, these studies link Ang II/ATR1 signalling to impaired adipogenesis and a pro-inflammatory dysfunctional adipose tissue, with ATR1 blockade limiting these responses. ACE-2 may mitigate Ang II effects by converting it to Ang(1-7) which binds MasR. More work is needed to understand adipose RAS in various pathologic states such as obesity and COVID-19 infection.T.
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Affiliation(s)
- Ryan Ting
- Faculty of Medicine, University of Ottawa, Ottawa, Canada
| | - Heidi Dutton
- Faculty of Medicine, University of Ottawa, Ottawa, Canada
- Department of Medicine, University of Ottawa, Ottawa, Canada
- The Ottawa Hospital/Ottawa Hospital Research Institute, Ottawa, Canada
| | - Alexander Sorisky
- Faculty of Medicine, University of Ottawa, Ottawa, Canada
- Department of Medicine, University of Ottawa, Ottawa, Canada
- The Ottawa Hospital/Ottawa Hospital Research Institute, Ottawa, Canada
- Department of Biochemistry, Microbiology, and Immunology, University of Ottawa, Ottawa, Canada
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Mosquera-Sulbaran JA, Pedreañez A, Hernandez-Fonseca JP, Hernandez-Fonseca H. Angiotensin II and dengue. Arch Virol 2023; 168:191. [PMID: 37368044 DOI: 10.1007/s00705-023-05814-6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/31/2022] [Accepted: 05/09/2023] [Indexed: 06/28/2023]
Abstract
Dengue is a disease caused by a flavivirus that is transmitted principally by the bite of an Aedes aegypti mosquito and represents a major public-health problem. Many studies have been carried out to identify soluble factors that are involved in the pathogenesis of this infection. Cytokines, soluble factors, and oxidative stress have been reported to be involved in the development of severe disease. Angiotensin II (Ang II) is a hormone with the ability to induce the production of cytokines and soluble factors related to the inflammatory processes and coagulation disorders observed in dengue. However, a direct involvement of Ang II in this disease has not been demonstrated. This review primarily summarizes the pathophysiology of dengue, the role of Ang II in various diseases, and reports that are highly suggestive of the involvement of this hormone in dengue.
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Affiliation(s)
- Jesus A Mosquera-Sulbaran
- Instituto de Investigaciones Clínicas "Dr. Américo Negrette", Facultad de Medicina, Universidad del Zulia, Maracaibo, 4001-A, Venezuela.
| | - Adriana Pedreañez
- Cátedra de Inmunología, Escuela de Bioanálisis, Facultad de Medicina, Universidad del Zulia, Maracaibo, Venezuela
| | - Juan Pablo Hernandez-Fonseca
- Instituto de Investigaciones Clínicas "Dr. Américo Negrette", Facultad de Medicina, Universidad del Zulia, Maracaibo, 4001-A, Venezuela
- Servicio de Microscopia Electronica del Centro Nacional de Biotecnologia (CNB- CSIC) Madrid, Madrid, España
| | - Hugo Hernandez-Fonseca
- Department of Anatomy, Physiology and Pharmacology, School of Veterinary Medicine, Saint George's University, True Blue, West Indies, Grenada
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Rizk JG, Gupta A, Lazo JG, Sardar P, Henry BM, Lavie CJ, Effron MB. To Anticoagulate or Not to Anticoagulate in COVID-19: Lessons after 2 Years. Semin Thromb Hemost 2023; 49:62-72. [PMID: 35468641 DOI: 10.1055/s-0042-1744302] [Citation(s) in RCA: 11] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/10/2023]
Abstract
A hypercoagulable state associated with coronavirus disease 2019 (COVID-19) has been well documented and is believed to be strongly supported by a proinflammatory state. The hypercoagulable state in turn results in increased incidence of arterial and venous thromboembolism (VTE) seen in hospitalized COVID-19 when compared with hospitalized non-COVID-19 patient cohorts. Moreover, patients with arterial or VTE and COVID-19 have higher mortality compared with COVID-19 patients without arterial or VTE. Prevention of arterial or VTE thus remains an essential question in the management of COVID-19 patients, especially because of high rates of reported microvascular and macrovascular thrombosis. This has prompted multiple randomized control trials (RCTs) evaluating different anticoagulation strategies in COVID-19 patients at various stages of the disease. Herein, we review findings from RCTs in the past 2 years of antithrombotic therapy in critically ill hospitalized patients, noncritically ill hospitalized patients, patients postdischarge from the hospital, and outpatients. RCTs in critically ill patients demonstrated therapeutic dose anticoagulation does not improve outcomes and has more bleeding than prophylaxis dose anticoagulant in these patients. Trials in noncritically ill hospitalized patients showed a therapeutic dose anticoagulation with a heparin formulation might improve clinical outcomes. Anticoagulation with a direct oral anticoagulant posthospital discharge may improve outcomes, although there is a large RCT in progress. Nonhospitalized COVID-19 patients have an insufficient burden of events to be candidates for antithrombotic therapy. Anticoagulation in pregnant and lactating patients with COVID-19, as well as antiplatelet therapy for COVID-19, is also reviewed.
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Affiliation(s)
- John G Rizk
- Department of Pharmaceutical Health Services Research, University of Maryland School of Pharmacy, Baltimore, Maryland
| | - Aashish Gupta
- John Ochsner Heart and Vascular Institute, Ochsner Clinical School-The University of Queensland School of Medicine, New Orleans, Louisiana
| | - Jose G Lazo
- UCSF Medical Center, University of California, San Francisco, San Francisco, California
| | - Partha Sardar
- John Ochsner Heart and Vascular Institute, Ochsner Clinical School-The University of Queensland School of Medicine, New Orleans, Louisiana
| | - Brandon Michael Henry
- Cardiac Intensive Care Unit, The Heart Institute, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio.,Disease Prevention and Intervention & Population Health Programs, Texas Biomedical Research Institute, San Antonio, Texas
| | - Carl J Lavie
- John Ochsner Heart and Vascular Institute, Ochsner Clinical School-The University of Queensland School of Medicine, New Orleans, Louisiana
| | - Mark B Effron
- John Ochsner Heart and Vascular Institute, Ochsner Clinical School-The University of Queensland School of Medicine, New Orleans, Louisiana
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Mosquera-Sulbarán J, Ryder E, Pedreáñez A, Vargas R. Angiotensin II and human obesity. A narrative review of the pathogenesis. INVESTIGACIÓN CLÍNICA 2022. [DOI: 10.54817/ic.v63n4a09] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 11/25/2022]
Abstract
Angiotensin II (Ang II) is a hormone and the main effector of the renin-angiotensin system (RAS). This peptide has crucial pathophysiologi-cal effects on hypertension, cardiac hypertrophy, endothelial proliferation, in-flammation and tissue remodelling through G protein-coupled receptors. The pro-inflammatory role of Ang II has been reported in various inflammatory pro-cesses. Obesity is linked to a chronic inflammatory process which in turn is the cause of some of its morbidities. Ang II is related to the comorbidities related to the comorbidities of obesity, which include alterations in the heart, kid-ney, hypertension and coagulation. In this regard, activation of AT1 receptors by Ang II can induce an inflammatory process mediated by the transcription factor NF-kB, triggering inflammation in various systems that are related to the comorbidities observed in obesity. The aim of this review was to highlight the pro-inflammatory effects of Ang II and the alterations induced by this hor-mone in various organs and systems in obesity. The search was done since 1990 through Medline, EMBASE and PubMed, using the keywords: angiotensin II; an-giotensin II, obesity; angiotensin II, kidney, obesity; angiotensin II, coagulation, obesity; angiotensin II, inflammation, obesity; angiotensin II, adipose tissue, obesity; angiotensin II, hypertension, obesity; angiotensin II, insulin resistance, obesity; angiotensin II, adiponectin, leptin, obesity; angiotensin II, COVID-19, obesity. Angiotensin II through its interaction with its AT1 receptor, can induce alterations in diverse systems that are related to the comorbidities observed in obesity. Therapeutic strategies to decrease the production and action of Ang II could improve the clinical conditions in individuals with obesity.
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Affiliation(s)
- Jesús Mosquera-Sulbarán
- Instituto de Investigaciones Clínicas “Dr. Américo Negrette”, Facultad de Medicina, Universidad del Zulia, Maracaibo, Venezuela
| | - Elena Ryder
- Instituto de Investigaciones Clínicas “Dr. Américo Negrette”, Facultad de Medicina, Universidad del Zulia, Maracaibo, Venezuela
| | - Adriana Pedreáñez
- Cátedra de Inmunología, Escuela de Bioanálisis, Facultad de Medicina, Universidad del Zulia, Maracaibo, Venezuela
| | - Renata Vargas
- Instituto de Investigaciones Clínicas “Dr. Américo Negrette”, Facultad de Medicina, Universidad del Zulia, Maracaibo, Venezuela
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8
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Abramicheva PA, Plotnikov EY. Hormonal Regulation of Renal Fibrosis. Life (Basel) 2022; 12:737. [PMID: 35629404 PMCID: PMC9143586 DOI: 10.3390/life12050737] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/19/2022] [Revised: 05/11/2022] [Accepted: 05/13/2022] [Indexed: 11/16/2022] Open
Abstract
Fibrosis is a severe complication of many acute and chronic kidney pathologies. According to current concepts, an imbalance in the synthesis and degradation of the extracellular matrix by fibroblasts is considered the key cause of the induction and progression of fibrosis. Nevertheless, inflammation associated with the damage of tissue cells is among the factors promoting this pathological process. Most of the mechanisms accompanying fibrosis development are controlled by various hormones, which makes humoral regulation an attractive target for therapeutic intervention. In this vein, it is particularly interesting that the kidney is the source of many hormones, while other hormones regulate renal functions. The normal kidney physiology and pathogenesis of many kidney diseases are sex-dependent and thus modulated by sex hormones. Therefore, when choosing therapy, it is necessary to focus on the sex-associated characteristics of kidney functioning. In this review, we considered renal fibrosis from the point of view of vasoactive and reproductive hormone imbalance. The hormonal therapy possibilities for the treatment or prevention of kidney fibrosis are also discussed.
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Affiliation(s)
- Polina A. Abramicheva
- Belozersky Institute of Physico-Chemical Biology, Lomonosov Moscow State University, 119991 Moscow, Russia;
| | - Egor Y. Plotnikov
- Belozersky Institute of Physico-Chemical Biology, Lomonosov Moscow State University, 119991 Moscow, Russia;
- Kulakov National Medical Research Center of Obstetrics, Gynecology and Perinatology, 117997 Moscow, Russia
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Badran M, Gozal D. PAI-1: A Major Player in the Vascular Dysfunction in Obstructive Sleep Apnea? Int J Mol Sci 2022; 23:5516. [PMID: 35628326 PMCID: PMC9141273 DOI: 10.3390/ijms23105516] [Citation(s) in RCA: 13] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/13/2022] [Revised: 05/05/2022] [Accepted: 05/12/2022] [Indexed: 02/04/2023] Open
Abstract
Obstructive sleep apnea is a chronic and prevalent condition that is associated with endothelial dysfunction, atherosclerosis, and imposes excess overall cardiovascular risk and mortality. Despite its high prevalence and the susceptibility of CVD patients to OSA-mediated stressors, OSA is still under-recognized and untreated in cardiovascular practice. Moreover, conventional OSA treatments have yielded either controversial or disappointing results in terms of protection against CVD, prompting the need for the identification of additional mechanisms and associated adjuvant therapies. Plasminogen activator inhibitor-1 (PAI-1), the primary inhibitor of tissue-type plasminogen activator (tPA) and urinary-type plasminogen activator (uPA), is a key regulator of fibrinolysis and cell migration. Indeed, elevated PAI-1 expression is associated with major cardiovascular adverse events that have been attributed to its antifibrinolytic activity. However, extensive evidence indicates that PAI-1 can induce endothelial dysfunction and atherosclerosis through complex interactions within the vasculature in an antifibrinolytic-independent matter. Elevated PAI-1 levels have been reported in OSA patients. However, the impact of PAI-1 on OSA-induced CVD has not been addressed to date. Here, we provide a comprehensive review on the mechanisms by which OSA and its most detrimental perturbation, intermittent hypoxia (IH), can enhance the transcription of PAI-1. We also propose causal pathways by which PAI-1 can promote atherosclerosis in OSA, thereby identifying PAI-1 as a potential therapeutic target in OSA-induced CVD.
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Affiliation(s)
- Mohammad Badran
- Department of Child Health and Child Health Research Institute, School of Medicine, University of Missouri, 400 N Keene St, Suite 010, Columbia, MO 65201, USA;
| | - David Gozal
- Department of Child Health and Child Health Research Institute, School of Medicine, University of Missouri, 400 N Keene St, Suite 010, Columbia, MO 65201, USA;
- Department of Medical Pharmacology and Physiology, School of Medicine, University of Missouri, Columbia, MO 65201, USA
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10
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Bruno ME, Mukherjee S, Stromberg AJ, Saito H, Starr ME. Visceral fat-specific regulation of plasminogen activator inhibitor-1 in aged septic mice. J Cell Physiol 2022; 237:706-719. [PMID: 34369600 PMCID: PMC8810697 DOI: 10.1002/jcp.30551] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/25/2021] [Revised: 07/20/2021] [Accepted: 07/23/2021] [Indexed: 01/03/2023]
Abstract
Elevated plasma levels of plasminogen activator inhibitor-1 (PAI-1) are documented in patients with sepsis and levels positively correlate with disease severity and mortality. Our previous work demonstrated that visceral adipose tissues (VAT) are a major source of PAI-1, especially in the aged (murine endotoxemia), that circulating PAI-1 protein levels match the trajectory of PAI-1 transcript levels in VAT (clinical sepsis), and that PAI-1 in both VAT and plasma are positively associated with acute kidney injury (AKI) in septic patients. In the current study utilizing preclinical sepsis models, PAI-1 tissue distribution was examined and cellular sources, as well as mechanisms mediating PAI-1 induction in VAT, were identified. In aged mice with sepsis, PAI-1 gene expression was significantly higher in VAT than in other major organs. VAT PAI-1 gene expression correlated with PAI-1 protein levels in both VAT and plasma. Moreover, VAT and plasma levels of PAI-1 were positively associated with AKI markers, modeling our previous clinical data. Using explant cultures of VAT, we determined that PAI-1 is secreted robustly in response to recombinant transforming growth factor β (TGFβ) and tumor necrosis factor α (TNFα) treatment; however, neutralization was effective only for TNFα indicating that TGFβ is not an endogenous modulator of PAI-1. Within VAT, TNFα was localized to neutrophils and macrophages. PAI-1 protein levels were fourfold higher in stromal vascular fraction (SVF) cells compared with mature adipocytes, and among SVF cells, both immune and nonimmune compartments expressed PAI-1 in a similar fashion. PAI-1 was localized predominantly to macrophages within the immune compartment and preadipocytes and endothelial cells within the nonimmune compartment. Collectively, these results indicate that induction and secretion of PAI-1 from VAT is facilitated by a complex interaction among immune and nonimmune cells. As circulating PAI-1 contributes to AKI in sepsis, understanding PAI-1 regulation in VAT could yield novel strategies for reducing systemic consequences of PAI-1 overproduction.
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Affiliation(s)
- Maria E.C. Bruno
- Aging and Critical Care Research Laboratory, University of Kentucky, Lexington, Kentucky 40536, USA,Department of Surgery, University of Kentucky, Lexington, Kentucky 40536, USA
| | - Sujata Mukherjee
- Aging and Critical Care Research Laboratory, University of Kentucky, Lexington, Kentucky 40536, USA,Department of Pharmacology and Nutritional Sciences, University of Kentucky, Lexington, Kentucky 40536, USA
| | - Arnold J. Stromberg
- Department of Statistics, University of Kentucky, Lexington, Kentucky 40536, USA
| | - Hiroshi Saito
- Aging and Critical Care Research Laboratory, University of Kentucky, Lexington, Kentucky 40536, USA,Department of Surgery, University of Kentucky, Lexington, Kentucky 40536, USA,Department of Pharmacology and Nutritional Sciences, University of Kentucky, Lexington, Kentucky 40536, USA,Department of Physiology, University of Kentucky, Lexington, Kentucky 40536, USA
| | - Marlene E. Starr
- Aging and Critical Care Research Laboratory, University of Kentucky, Lexington, Kentucky 40536, USA,Department of Surgery, University of Kentucky, Lexington, Kentucky 40536, USA,Department of Pharmacology and Nutritional Sciences, University of Kentucky, Lexington, Kentucky 40536, USA
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11
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Surabhi G, Dhara S, Maneesh A, Chakraborty K, Valluru L, Chenchula SR. Polygalacto-fucopyranose from marine alga as a prospective antihypertensive lead. Int J Biol Macromol 2021; 183:589-599. [PMID: 33933545 DOI: 10.1016/j.ijbiomac.2021.04.140] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/20/2021] [Revised: 04/16/2021] [Accepted: 04/22/2021] [Indexed: 01/24/2023]
Abstract
Consumption of marine alga-based polysaccharides as additional functional foods can endow with health benefits by diminishing the risk of chronic diseases. A polygalacto-fucopyranose characterized as [→1)-2, 4-SO3-α-Fucp-(3 → 1)-{2-SO3-α-Fucp-(3→}] with [(4 → 1)-6-OAc-β-Galp-(4→] side chain isolated from marine alga Sargassum wightii exhibited potential antihypertensive activity. Upon treatment with studied polygalactofucan (50 mg/kg BW), serum hypertension biomarkers troponin-T (1.3 pg/mL), troponin-I (1.2 μg/dL) and angiotensin-II converting enzyme (0.18 pg/mL) were significantly recovered in hypertensive rats compared to disease control. Serum cardiovascular risk indices of diseased rats were significantly decreased (< 10%, p < 0.05) after administration of the studied galactofucan (50 mg/kg BW) related to hypertension group (> 17%), and were comparable with standard antihypertensive agent telmisartan (8.3-10.2% at 2 mg/kg BW). The studied compound was safe for consumption as obvious from the high LD50 value (>5 g/kg), and could be developed as a prospective functional food ingredient attenuating the pathophysiological attributes causing hypertension-related conditions.
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Affiliation(s)
- Gangadhar Surabhi
- Department of Biotechnology, Dravidian University, Kuppam 517426, Andhra Pradesh, India
| | - Shubhajit Dhara
- Marine Bioprospecting Section of Marine Biotechnology Division, Central Marine Fisheries Research Institute, Ernakulam North P.O., P.B. No. 1603, Cochin 682018, Kerala, India; Department of Chemistry, Mangalore University, Mangalagangothri 574199, Karnataka State, India
| | - Anusree Maneesh
- Marine Bioprospecting Section of Marine Biotechnology Division, Central Marine Fisheries Research Institute, Ernakulam North P.O., P.B. No. 1603, Cochin 682018, Kerala, India; Department of Chemistry, Mangalore University, Mangalagangothri 574199, Karnataka State, India
| | - Kajal Chakraborty
- Marine Bioprospecting Section of Marine Biotechnology Division, Central Marine Fisheries Research Institute, Ernakulam North P.O., P.B. No. 1603, Cochin 682018, Kerala, India.
| | - Lokanatha Valluru
- Department of Biotechnology, Dravidian University, Kuppam 517426, Andhra Pradesh, India.
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Yan T, Xiao R, Wang N, Shang R, Lin G. Obesity and severe coronavirus disease 2019: molecular mechanisms, paths forward, and therapeutic opportunities. Theranostics 2021; 11:8234-8253. [PMID: 34373739 PMCID: PMC8343994 DOI: 10.7150/thno.59293] [Citation(s) in RCA: 17] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/10/2021] [Accepted: 06/20/2021] [Indexed: 01/08/2023] Open
Abstract
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) appears to have higher pathogenicity among patients with obesity. Obesity, termed as body mass index greater than 30 kg/m2, has now been demonstrated to be important comorbidity for disease severity during coronavirus disease 2019 (COVID-19) pandemic and associated with adverse events. Unraveling mechanisms behind this phenomenon can assist scientists, clinicians, and policymakers in responding appropriately to the COVID-19 pandemic. In this review, we systemically delineated the potential mechanistic links between obesity and worsening COVID-19 from altered physiology, underlying diseases, metabolism, immunity, cytokine storm, and thrombosis. Problematic ventilation caused by obesity and preexisting medical disorders exacerbate organ dysfunction for patients with obesity. Chronic metabolic disorders, including dyslipidemia, hyperglycemia, vitamin D deficiency, and polymorphisms of metabolism-related genes in obesity, probably aid SARS-CoV-2 intrusion and impair antiviral responses. Obesity-induced inadequate antiviral immunity (interferon, natural killer cells, invariant natural killer T cell, dendritic cell, T cells, B cell) at the early stage of SARS-CoV-2 infection leads to delayed viral elimination, increased viral load, and expedited viral mutation. Cytokine storm, with the defective antiviral immunity, probably contributes to tissue damage and pathological progression, resulting in severe symptoms and poor prognosis. The prothrombotic state, driven in large part by endothelial dysfunction, platelet hyperactivation, hypercoagulability, and impaired fibrinolysis in obesity, also increases the risk of severe COVID-19. These mechanisms in the susceptibility to severe condition also open the possibility for host-directed therapies in population with obesity. By bridging work done in these fields, researchers can gain a holistic view of the paths forward and therapeutic opportunities to break the vicious cycle of obesity and its devastating complications in the next emerging pandemic.
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Affiliation(s)
- Tiantian Yan
- Military Burn Center, the 990th Hospital of People's Liberation Army Joint Logistics Support Force, Zhumadian, Henan, China
| | - Rong Xiao
- Military Burn Center, the 990th Hospital of People's Liberation Army Joint Logistics Support Force, Zhumadian, Henan, China
| | - Nannan Wang
- Military Burn Center, the 990th Hospital of People's Liberation Army Joint Logistics Support Force, Zhumadian, Henan, China
| | - Ruoyu Shang
- State Key Laboratory of Trauma, Burns, and Combined Injury, Institute of Burn Research, the First Affiliated Hospital of Army Medical University (the Third Military Medical University), Chongqing Key Laboratory for Disease Proteomics, Chongqing, China
| | - Guoan Lin
- Military Burn Center, the 990th Hospital of People's Liberation Army Joint Logistics Support Force, Zhumadian, Henan, China
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13
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Agarwal KA, Kyriazis PP, Lecker SH. RAAS-Blockade in COVID-19: The Ace of Spades? Indian J Nephrol 2021; 31:423-424. [PMID: 34584367 PMCID: PMC8443096 DOI: 10.4103/ijn.ijn_322_20] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/03/2020] [Revised: 08/28/2020] [Accepted: 09/04/2020] [Indexed: 12/02/2022] Open
Affiliation(s)
- Krishna A. Agarwal
- Department of Medicine, Beth Israel Deaconess Medical Center, Boston, MA, USA
| | | | - Stewart H. Lecker
- Department of Medicine, Beth Israel Deaconess Medical Center, Boston, MA, USA
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14
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PAI-1 in Diabetes: Pathophysiology and Role as a Therapeutic Target. Int J Mol Sci 2021; 22:ijms22063170. [PMID: 33804680 PMCID: PMC8003717 DOI: 10.3390/ijms22063170] [Citation(s) in RCA: 51] [Impact Index Per Article: 12.8] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/25/2021] [Revised: 03/16/2021] [Accepted: 03/17/2021] [Indexed: 12/14/2022] Open
Abstract
Hypofibrinolysis is a key abnormality in diabetes and contributes to the adverse vascular outcome in this population. Plasminogen activator inhibitor (PAI)-1 is an important regulator of the fibrinolytic process and levels of this antifibrinolytic protein are elevated in diabetes and insulin resistant states. This review describes both the physiological and pathological role of PAI-1 in health and disease, focusing on the mechanism of action as well as protein abnormalities in vascular disease with special focus on diabetes. Attempts at inhibiting protein function, using different techniques, are also discussed including direct and indirect interference with production as well as inhibition of protein function. Developing PAI-1 inhibitors represents an alternative approach to managing hypofibrinolysis by targeting the pathological abnormality rather than current practice that relies on profound inhibition of the cellular and/or acellular arms of coagulation, and which can be associated with increased bleeding events. The review offers up-to-date knowledge on the mechanisms of action of PAI-1 together with the role of altering protein function to improve hypofirbinolysis. Developing PAI-1 inhibitors may form for the basis of future new class of antithrombotic agents that reduce vascular complications in diabetes.
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15
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Karolyi M, Pawelka E, Omid S, Kelani H, Mader T, Baumgartner S, Laferl H, Traugott M, Seitz T, Zoufaly A, Wenisch C. Late onset pulmonary embolism in young male otherwise healthy COVID-19 patients. Eur J Clin Microbiol Infect Dis 2020; 40:633-635. [PMID: 32965656 PMCID: PMC7509817 DOI: 10.1007/s10096-020-04044-x] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/15/2020] [Accepted: 09/18/2020] [Indexed: 11/29/2022]
Abstract
SARS-CoV-2 infection is associated with increased risk of thrombosis in severely ill patients but little is known about the risk in outpatients with mild to moderate disease. Our case series consists of four male otherwise healthy patients between 32 and 50 years of age. Initial symptoms completely resolved but they developed new onset of dyspnea and thoracic pain at days 14 to 26. CT scan revealed pulmonary embolism in all patients which led to hospitalization. Standard anticoagulation practice needs to be re-evaluated and may be considered for certain outpatients with COVID-19.
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Affiliation(s)
- M Karolyi
- Department for Infectious Diseases and Tropical Medicine, Kaiser-Franz-Josef Hospital, Kundratstraße 3, 1100, Vienna, Austria.
| | - E Pawelka
- Department for Infectious Diseases and Tropical Medicine, Kaiser-Franz-Josef Hospital, Kundratstraße 3, 1100, Vienna, Austria
| | - S Omid
- Department for Infectious Diseases and Tropical Medicine, Kaiser-Franz-Josef Hospital, Kundratstraße 3, 1100, Vienna, Austria
| | - H Kelani
- Department for Infectious Diseases and Tropical Medicine, Kaiser-Franz-Josef Hospital, Kundratstraße 3, 1100, Vienna, Austria
| | - T Mader
- Department for Infectious Diseases and Tropical Medicine, Kaiser-Franz-Josef Hospital, Kundratstraße 3, 1100, Vienna, Austria
| | - S Baumgartner
- Department for Infectious Diseases and Tropical Medicine, Kaiser-Franz-Josef Hospital, Kundratstraße 3, 1100, Vienna, Austria
| | - H Laferl
- Department for Infectious Diseases and Tropical Medicine, Kaiser-Franz-Josef Hospital, Kundratstraße 3, 1100, Vienna, Austria
| | - M Traugott
- Department for Infectious Diseases and Tropical Medicine, Kaiser-Franz-Josef Hospital, Kundratstraße 3, 1100, Vienna, Austria
| | - T Seitz
- Department for Infectious Diseases and Tropical Medicine, Kaiser-Franz-Josef Hospital, Kundratstraße 3, 1100, Vienna, Austria
| | - A Zoufaly
- Department for Infectious Diseases and Tropical Medicine, Kaiser-Franz-Josef Hospital, Kundratstraße 3, 1100, Vienna, Austria
| | - C Wenisch
- Department for Infectious Diseases and Tropical Medicine, Kaiser-Franz-Josef Hospital, Kundratstraße 3, 1100, Vienna, Austria
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16
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Henry BM, Vikse J, Benoit S, Favaloro EJ, Lippi G. Hyperinflammation and derangement of renin-angiotensin-aldosterone system in COVID-19: A novel hypothesis for clinically suspected hypercoagulopathy and microvascular immunothrombosis. Clin Chim Acta 2020; 507:167-173. [PMID: 32348783 PMCID: PMC7195008 DOI: 10.1016/j.cca.2020.04.027] [Citation(s) in RCA: 262] [Impact Index Per Article: 52.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/18/2020] [Revised: 04/23/2020] [Accepted: 04/24/2020] [Indexed: 02/06/2023]
Abstract
Early clinical evidence suggests that severe cases of coronavirus disease 2019 (COVID-19), caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), are frequently characterized by hyperinflammation, imbalance of renin-angiotensin-aldosterone system, and a particular form of vasculopathy, thrombotic microangiopathy, and intravascular coagulopathy. In this paper, we present an immunothrombosis model of COVID-19. We discuss the underlying pathogenesis and the interaction between multiple systems, resulting in propagation of immunothrombosis, which through investigation in the coming weeks, may lead to both an improved understanding of COVID-19 pathophysiology and identification of innovative and efficient therapeutic targets to reverse the otherwise unfavorable clinical outcome of many of these patients.
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Affiliation(s)
- Brandon Michael Henry
- Cardiac Intensive Care Unit, The Heart Institute, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, USA.
| | - Jens Vikse
- Clinical Immunology Unit, Stavanger University Hospital, Stavanger, Norway
| | - Stefanie Benoit
- Division of Nephrology and Hypertension, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, USA; Department of Pediatrics, University of Cincinnati, College of Medicine, Cincinnati, OH, USA
| | - Emmanuel J Favaloro
- Department of Haematology, Sydney Centres for Thrombosis and Haemostasis, Institute of Clinical Pathology and Medical Research, NSW Health Pathology, Westmead Hospital, Westmead, New South Wales, Australia; School of Biomedical Sciences, Charles Sturt University, Wagga Wagga, New South Wales, Australia
| | - Giuseppe Lippi
- Section of Clinical Biochemistry, Department of Neuroscience, Biomedicine and Movement, University of Verona, Verona, Italy
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17
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Ito K. Effect of water-extractive components from funazushi, a fermented crucian carp, on the activity of fibrinolytic factors. JOURNAL OF THE SCIENCE OF FOOD AND AGRICULTURE 2020; 100:2482-2487. [PMID: 31960427 DOI: 10.1002/jsfa.10269] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 09/05/2019] [Revised: 01/14/2020] [Accepted: 01/21/2020] [Indexed: 06/10/2023]
Abstract
BACKGROUND Japanese fermented foods, including funazushi, have have been studied insufficiently. Related research into fermented products has led to the hope that they might have positive effects on blood circulation, including anti-thrombosis effects. The possible antithrombotic effects of funazushi on the fibrinolytic system were examined. RESULTS The administration of extracts from funazushi increased the activity of plasmin and tissue plasminogen activators in the fibrinolytic system but decreased the activity of plasminogen activator inhibitor type-1 (PAI-1). This decrease was positively correlated with the decreased plasma triglyceride levels. Funazushi extract directly inhibited PAI-1 activity in vitro despite alimentary enzyme digestion, although direct PAI-1 inhibition was not observed in an extract from salted crucian carp. CONCLUSION These results suggest that funazushi extracts are closely involved in the antithrombotic effects of the fibrinolytic system, and that they exert their effect through a reduction in PAI-1 activity. The findings also indicate that fermentation processing is necessary to achieve the antithrombotic effects of funazushi. © 2020 Society of Chemical Industry.
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Affiliation(s)
- Koji Ito
- Department of Marine Bioscience, Fukui Prefectural University, Obama, Japan
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18
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Miesbach W. Pathological Role of Angiotensin II in Severe COVID-19. TH OPEN 2020; 4:e138-e144. [PMID: 32607467 PMCID: PMC7319800 DOI: 10.1055/s-0040-1713678] [Citation(s) in RCA: 68] [Impact Index Per Article: 13.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/16/2020] [Accepted: 05/19/2020] [Indexed: 01/08/2023] Open
Abstract
The activated renin-angiotensin system induces a prothrombotic state resulting from the imbalance between coagulation and fibrinolysis. Angiotensin II is the central effector molecule of the activated renin-angiotensin system and is degraded by the angiotensin-converting enzyme 2 to angiotensin (1-7). The novel coronavirus infection (classified as COVID-19) is caused by the new coronavirus SARS-CoV-2 and is characterized by an exaggerated inflammatory response that can lead to severe manifestations such as acute respiratory distress syndrome, sepsis, and death in a proportion of patients, mostly elderly patients with preexisting comorbidities. SARS-CoV-2 uses the angiotensin-converting enzyme 2 receptor to enter the target cells, resulting in activation of the renin-angiotensin system. After downregulating the angiotensin-converting enzyme 2, the vasoconstrictor angiotensin II is increasingly produced and its counterregulating molecules angiotensin (1-7) reduced. Angiotensin II increases thrombin formation and impairs fibrinolysis. Elevated levels were strongly associated with viral load and lung injury in patients with severe COVID-19. Therefore, the complex clinical picture of patients with severe complications of COVID-19 is triggered by the various effects of highly expressed angiotensin II on vasculopathy, coagulopathy, and inflammation. Future treatment options should focus on blocking the thrombogenic and inflammatory properties of angiotensin II in COVID-19 patients.
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Affiliation(s)
- Wolfgang Miesbach
- Department of Haemostaseology and Haemophilia Center, Institute of Transfusion Medicine, Medical Clinic 2, University Hospital Frankfurt, Frankfurt, Germany
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19
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Miesbach W, Makris M. COVID-19: Coagulopathy, Risk of Thrombosis, and the Rationale for Anticoagulation. Clin Appl Thromb Hemost 2020; 26:1076029620938149. [PMID: 32677459 PMCID: PMC7370334 DOI: 10.1177/1076029620938149] [Citation(s) in RCA: 258] [Impact Index Per Article: 51.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/12/2020] [Revised: 05/17/2020] [Accepted: 06/08/2020] [Indexed: 01/08/2023] Open
Abstract
The novel coronavirus infection (COVID-19) is caused by the new coronavirus SARS-CoV-2 and is characterized by an exaggerated inflammatory response that can lead to severe manifestations such as adult respiratory syndrome, sepsis, coagulopathy, and death in a proportion of patients. Among other factors and direct viral effects, the increase in the vasoconstrictor angiotensin II, the decrease in the vasodilator angiotensin, and the sepsis-induced release of cytokines can trigger a coagulopathy in COVID-19. A coagulopathy has been reported in up to 50% of patients with severe COVID-19 manifestations. An increase in d-dimer is the most significant change in coagulation parameters in severe COVID-19 patients, and progressively increasing values can be used as a prognostic parameter indicating a worse outcome. Limited data suggest a high incidence of deep vein thrombosis and pulmonary embolism in up to 40% of patients, despite the use of a standard dose of low-molecular-weight heparin (LMWH) in most cases. In addition, pulmonary microvascular thrombosis has been reported and may play a role in progressive lung failure. Prophylactic LMWH has been recommended by the International Society on Thrombosis and Haemostasis (ISTH) and the American Society of Hematology (ASH), but the best effective dosage is uncertain. Adapted to the individual risk of thrombosis and the d-dimer value, higher doses can be considered, especially since bleeding events in COVID-19 are rare. Besides the anticoagulant effect of LMWH, nonanticoagulant properties such as the reduction in interleukin 6 release have been shown to improve the complex picture of coagulopathy in patients with COVID-19.
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Affiliation(s)
- Wolfgang Miesbach
- Department of Haemostaseology and Hemophilia Center, Medical Clinic 2, Institute of Transfusion Medicine, University Hospital Frankfurt, Germany
| | - Michael Makris
- Department of Infection, Immunity and Cardiovascular Disease, University of Sheffield, United Kingdom
- Sheffield Haemophilia and Thrombosis Centre, Royal Hallamshire Hospital, Sheffield, United Kingdom
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20
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Angiotensin II: A New Vasopressor for the Treatment of Distributive Shock. Clin Ther 2019; 41:2594-2610. [PMID: 31668356 DOI: 10.1016/j.clinthera.2019.09.014] [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: 07/02/2019] [Revised: 09/23/2019] [Accepted: 09/24/2019] [Indexed: 11/23/2022]
Abstract
PURPOSE Angiotensin II (ATII) is a potent endogenous vasoconstrictor that has recently garnered regulatory approval for the treatment of distributive shock, including septic shock. Traditional vasoactive substances used in the management of distributive shock include norepinephrine, epinephrine, phenylephrine, and vasopressin. However, their use can be associated with deleterious adverse drug effects, such as splanchnic vasoconstriction and associated hypoperfusion. The purpose of this review is to describe ATII, including its pharmacologic mechanisms, pharmacokinetic profile, evidence of efficacy and tolerability, and potential role in contemporary critical care practice. METHODS Peer-reviewed clinical trials and relevant treatment guidelines published from 1966 to September 14, 2019, were identified from Medline/PubMed using the following search terms: angiotensin II OR angiotensin 2 AND shock OR septic shock OR vasodilatory shock. Pertinent review articles were reviewed for additional studies for inclusion and discussion. The final decision on the inclusion of studies in the current review was based on the expert opinion of the authors. FINDINGS On the basis of the available evidence, ATII is effective at elevating blood pressure in patients with distributive shock and appears to reduce the dose of concurrent vasopressors to maintain adequate blood pressure. ATII has been investigated for other causes of shock; however, robust evidence of off-label indications is lacking and is much needed. Clinical and cost benefits compared with traditional vasopressors have yet to be established. IMPLICATIONS ATII represents a welcome addition to the armamentarium of critical care clinicians. Enthusiasm for the use of ATII should be balanced with the current gaps in our understanding of ATII in patients with shock. Until further evidence provides more clinically meaningful benefits, as well as cost-effectiveness compared with currently available vasopressors, critical care clinicians should reserve ATII for salvage therapy in patients with septic shock.
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21
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Patsouras MD, Vlachoyiannopoulos PG. Evidence of epigenetic alterations in thrombosis and coagulation: A systematic review. J Autoimmun 2019; 104:102347. [PMID: 31607428 DOI: 10.1016/j.jaut.2019.102347] [Citation(s) in RCA: 24] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/29/2019] [Accepted: 10/03/2019] [Indexed: 02/07/2023]
Abstract
Thrombosis in the context of Cardiovascular disease (CVD) affects mainly the blood vessels supplying the heart, brain and peripheries and it is the leading cause of death worldwide. The pathophysiological thrombotic mechanisms are largely unknown. Heritability contributes to a 30% of the incidence of CVD. The remaining variation can be explained by life style factors such as smoking, dietary and exercise habits, environmental exposure to toxins, and drug usage and other comorbidities. Epigenetic variation can be acquired or inherited and constitutes an interaction between genes and the environment. Epigenetics have been implicated in atherosclerosis, ischemia/reperfusion damage and the cardiovascular response to hypoxia. Epigenetic regulators of gene expression are mainly the methylation of CpG islands, histone post translational modifications (PTMs) and microRNAs (miRNAs). These epigenetic regulators control gene expression either through activation or silencing. Epigenetic control is mostly dynamic and can potentially be manipulated to prevent or reverse the uncontrolled expression of genes, a trait that renders them putative therapeutic targets. In the current review, we systematically studied and present available data on epigenetic alterations implicated in thrombosis derived from human studies. Evidence of epigenetic alterations is observed in several thrombotic diseases such as Coronary Artery Disease and Cerebrovascular Disease, Preeclampsia and Antiphospholipid Syndrome. Differential CpG methylation and specific histone PTMs that control transcription of prothrombotic and proinflammatory genes have also been associated with predisposing factors of thrombosis and CVD, such us smoking, air pollution, hypertriglyceridemia, occupational exposure to particulate matter and comorbidities including cancer, Chronic Obstructive Pulmonary Disease and Chronic Kidney Disease. These clinical observations are further supported by in vitro experiments and indicate that epigenetic regulation affects the pathophysiology of thrombotic disorders with potential diagnostic or therapeutic utility.
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Affiliation(s)
- M D Patsouras
- Department of Pathophysiology, School of Medicine, National and Kapodistrian University of Athens, Greece
| | - P G Vlachoyiannopoulos
- Department of Pathophysiology, School of Medicine, National and Kapodistrian University of Athens, Greece.
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22
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Braschi A. Potential Protective Role of Blood Pressure-Lowering Drugs on the Balance between Hemostasis and Fibrinolysis in Hypertensive Patients at Rest and During Exercise. Am J Cardiovasc Drugs 2019; 19:133-171. [PMID: 30714087 DOI: 10.1007/s40256-018-00316-2] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/17/2022]
Abstract
In patients with hypertension, the triad represented by endothelial dysfunction, platelet hyperactivity, and altered fibrinolytic function disturbs the equilibrium between hemostasis and fibrinolysis and translates into a hypercoagulable state, which underlies the risk of thrombotic complications. This article reviews the scientific evidence regarding some biological effects of antihypertensive drugs, which can protect patients from the adverse consequences of hypertensive disease, improving endothelial function, enhancing antioxidant activity, and restoring equilibrium between hemostatic and fibrinolytic factors. These protective effects appear not to be mediated through blood pressure reduction and are not shared by all molecules of the same pharmacological class.
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Affiliation(s)
- Annabella Braschi
- Ambulatory of Cardiovascular Diseases, Via col. Romey n.10, 91100, Trapani, Italy.
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23
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Dapper C, Schuster F, Stölting I, Vogt F, Castro e Souza LA, Alenina N, Bader M, Raasch W. The antiobese effect of AT1 receptor blockade is augmented in mice lacking Mas. Naunyn Schmiedebergs Arch Pharmacol 2019; 392:865-877. [DOI: 10.1007/s00210-019-01643-0] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/10/2018] [Accepted: 03/01/2019] [Indexed: 02/06/2023]
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24
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Bauer SR, Sacha GL, Lam SW. Safe Use of Vasopressin and Angiotensin II for Patients with Circulatory Shock. Pharmacotherapy 2018; 38:851-861. [DOI: 10.1002/phar.2147] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/11/2022]
Affiliation(s)
- Seth R. Bauer
- Department of Pharmacy; Cleveland Clinic; Cleveland Ohio
| | | | - Simon W. Lam
- Department of Pharmacy; Cleveland Clinic; Cleveland Ohio
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25
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Agarwal P, Agarwal R. Trabecular meshwork ECM remodeling in glaucoma: could RAS be a target? Expert Opin Ther Targets 2018; 22:629-638. [PMID: 29883239 DOI: 10.1080/14728222.2018.1486822] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/11/2023]
Abstract
INTRODUCTION Disturbances of extracellular matrix (ECM) homeostasis in trabecular meshwork (TM) cause increased aqueous outflow resistance leading to elevated intraocular pressure (IOP) in glaucomatous eyes. Therefore, restoration of ECM homeostasis is a rational approach to prevent disease progression. Since renin-angiotensin system (RAS) inhibition positively alters ECM homeostasis in cardiovascular pathologies involving pressure and volume overload, it is likely that RAS inhibitors reduce IOP primarily by restoring ECM homeostasis. Areas covered: Current evidence showing the presence of RAS components in ocular tissue and its role in regulating aqueous humor dynamics is briefly summarized. The role of RAS in ECM remodeling is discussed both in terms of its effects on ECM synthesis and its breakdown. The mechanisms of ECM remodeling involving interactions of RAS with transforming growth factor-β, Wnt/β-catenin signaling, bone morphogenic proteins, connective tissue growth factor, and matrix metalloproteinases in ocular tissue are discussed. Expert opinion: Current literature strongly indicates a significant role of RAS in ECM remodeling in TM of hypertensive eyes. Hence, IOP-lowering effect of RAS inhibitors may primarily be attributed to restoration of ECM homeostasis in aqueous outflow pathways rather than its vascular effects. However, the mechanistic targets for RAS inhibitors have much wider distribution and consequences, which remain relatively unexplored in TM.
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Affiliation(s)
- Puneet Agarwal
- a Department of Ophthalmology , International Medical University, IMU Clinical School , Seremban , Malaysia
| | - Renu Agarwal
- b Universiti Teknologi MARA, Faculty of Medicine , UiTM Sg Buloh Campus , Sungai Buloh , Selangor , Malaysia
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26
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Jung RG, Simard T, Labinaz A, Ramirez FD, Di Santo P, Motazedian P, Rochman R, Gaudet C, Faraz MA, Beanlands RS, Hibbert B. Role of plasminogen activator inhibitor-1 in coronary pathophysiology. Thromb Res 2018; 164:54-62. [DOI: 10.1016/j.thromres.2018.02.135] [Citation(s) in RCA: 25] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/23/2017] [Revised: 02/03/2018] [Accepted: 02/15/2018] [Indexed: 01/13/2023]
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27
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Rabieian R, Boshtam M, Zareei M, Kouhpayeh S, Masoudifar A, Mirzaei H. Plasminogen Activator Inhibitor Type-1 as a Regulator of Fibrosis. J Cell Biochem 2017; 119:17-27. [PMID: 28520219 DOI: 10.1002/jcb.26146] [Citation(s) in RCA: 121] [Impact Index Per Article: 15.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/26/2017] [Accepted: 05/17/2017] [Indexed: 12/17/2022]
Abstract
Fibrosis is known as a frequent and irreversible pathological condition which is associated with organ failure. Tissue fibrosis is a central process in a variety of chronic progressive diseases such as diabetes, hypertension, and persistent inflammation. This state could contribute to chronic injury and the initiation of tissue repair. Fibrotic disorders represent abnormal wound healing with defective matrix turnover and clearance that lead to excessive accumulation of extracellular matrix components. A variety of identified growth factors, cytokines, and persistently activated myofibroblasts have critical roles in the pathogenesis of fibrosis. Irrespective of etiology, the transforming growth factor-β pathway is the major driver of fibrotic response. Plasminogen activator inhibitor-1 (PAI-1) is a crucial downstream target of this pathway. Transforming growth factor-β positively regulates PAI-1 gene expression via two main pathways including Smad-mediated canonical and non-canonical pathways. Overexpression of PAI-1 reduces extracellular matrix degradation via perturbing the plasminogen activation system. Indeed, elevated PAI-1 levels inhibit proteolytic activity of tissue plasminogen activator and urokinase plasminogen activator which could contribute to a variety of inflammatory elements in the injury site and to excessive matrix deposition. This review summarizes the current knowledge of critical pathways that regulate PAI-1 gene expression and suggests effective approaches for the treatment of fibrotic disease. J. Cell. Biochem. 119: 17-27, 2018. © 2017 Wiley Periodicals, Inc.
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Affiliation(s)
- Reyhaneh Rabieian
- Department of Genetics and Molecular Biology, Isfahan University of Medical Sciences, Isfahan, Iran
| | - Maryam Boshtam
- Isfahan Cardiovascular Research Center, Cardiovascular Research Institute, Isfahan University of Medical Sciences, Isfahan, Iran
| | - Mahshid Zareei
- Department of Biology, School of Sciences, University of Isfahan, Isfahan, Iran
| | - Shirin Kouhpayeh
- Department of Immunology, School of Medicine, Isfahan University of Medical Sciences, Isfahan, Iran
| | - Aria Masoudifar
- Department of Molecular Biotechnology, Cell Science Research Center, Royan Institute for Biotechnology, ACECR, Isfahan, Iran
| | - Hamed Mirzaei
- Department of Medical Biotechnology, School of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
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Chen R, Yan J, Liu P, Wang Z, Wang C. Plasminogen activator inhibitor links obesity and thrombotic cerebrovascular diseases: The roles of PAI-1 and obesity on stroke. Metab Brain Dis 2017; 32:667-673. [PMID: 28378106 DOI: 10.1007/s11011-017-0007-3] [Citation(s) in RCA: 21] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/13/2016] [Accepted: 03/30/2017] [Indexed: 12/18/2022]
Abstract
One of the global socioeconomic phenomena occurred during the last decades is the increased prevalence of obesity, with direct consequence on the risk of developing thrombotic disorders. As the physiological inhibitor of tissue plasminogen activator (tPA) and urokinase plasminogen activator (uPA), plasminogen activator inhibitor-1 (PAI-1) is well known for its role in fibrinolysis. More and more evidences have shown that PAI-1 involves in physiopathologic mechanisms of many diseases and metabolic disorder. Increased serum level of PAI-1 has been observed in obesity and it also contributes to the development of adipose tissue and then has effects on obesity. Meantime, obesity affects also the PAI-1 levels. These evidences indicate the complicated interaction between PAI-1 and obesity. Many clinic studies have confirmed that obesity relates to the stroke outcome although there are many contradictory results. Simultaneously, correlation is found between plasma PAI-1 and thrombotic cerebrovascular diseases. This article reviews contemporary knowledge regarding the complex interplay of obesity, PAI-1 and stroke.
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Affiliation(s)
- Rui Chen
- Department of Cardiology, Affiliated Hospital of Jiangsu University, Zhenjiang, Jiangsu, 212001, China
| | - Jinchuan Yan
- Department of Cardiology, Affiliated Hospital of Jiangsu University, Zhenjiang, Jiangsu, 212001, China.
| | - Peijing Liu
- Department of Cardiology, Affiliated Hospital of Jiangsu University, Zhenjiang, Jiangsu, 212001, China
| | - Zhongqun Wang
- Department of Cardiology, Affiliated Hospital of Jiangsu University, Zhenjiang, Jiangsu, 212001, China
| | - Cuiping Wang
- Department of Cardiology, Affiliated Hospital of Jiangsu University, Zhenjiang, Jiangsu, 212001, China
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Infusion of angiotensin II increases fibrinolysis in healthy individuals but not in patients with familial combined hyperlipidemia. Blood Coagul Fibrinolysis 2016; 27:113-6. [PMID: 26340459 DOI: 10.1097/mbc.0000000000000393] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/26/2022]
Abstract
Impaired fibrinolysis is related to insulin resistance, also a characteristic feature of familial combined hyperlipidemia (FCHL). The renin-angiotensin (Ang) system is upregulated with insulin resistance, and there is crosstalk between Ang II and insulin-signalling pathways. We studied the fibrinolytic effects of a 3-h systemic Ang II infusion in 16 patients with FCHL and 16 controls, and placebo infusion in eight individuals. Baseline plasminogen activator inhibitor-1 (PAI-1) activity, plasmin-antiplasmin complex, insulin resistance and C-reactive protein were higher in patients with FCHL than in controls. PAI-1 activity decreased during Ang II, similar in patients with FCHL and controls, and by placebo. Plasmin-antiplasmin complex was unaffected by Ang II in FCHL but increased in controls. Patients with FCHL show signs of insulin resistance, low-grade inflammation and impaired fibrinolysis. Ang II enhances fibrinolysis in controls but not in patients with FCHL, suggesting that patients with FCHL are not capable of increasing tissue plasminogen activator activity in response to Ang II. Ang II has no short-term effects on PAI-1 activity.
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Abstract
Recent discoveries suggest that adipose tissue can synthesise and secrete mediators that contribute to the pathogenesis of type 2 diabetes mellitus and cardiovascular disease, leading to the concept of `adipose tissue as an endocrine organ'. These mediators include tumour necrosis factor-α, interleukin-6, adiponectin, resistin, plasminogen activator inhibitor type 1 and angiotensin II. They modify the activity of regulatory enzymes in adipocyte metabolism, alter the release of non-esterified fatty acids and affect glucose uptake. They may also have direct actions on the vascular endothelium. The diverse effects of these mediators support the notion that inflammation plays a role in metabolic and vascular disease, at least in part via adipocyte-derived cytokines.
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Affiliation(s)
- Colin Perry
- University Departments of Medicine, Glasgow Royal Infirmary, Glasgow, G31 2ER
| | - Naveed Sattar
- Pathological Biochemistry, Glasgow Royal Infirmary, Glasgow, G31 2ER
| | - John Petrie
- University Departments of Medicine, Glasgow Royal Infirmary, Glasgow, G31 2ER,
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Muñoz-Durango N, Fuentes CA, Castillo AE, González-Gómez LM, Vecchiola A, Fardella CE, Kalergis AM. Role of the Renin-Angiotensin-Aldosterone System beyond Blood Pressure Regulation: Molecular and Cellular Mechanisms Involved in End-Organ Damage during Arterial Hypertension. Int J Mol Sci 2016; 17:E797. [PMID: 27347925 PMCID: PMC4964362 DOI: 10.3390/ijms17070797] [Citation(s) in RCA: 165] [Impact Index Per Article: 18.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/24/2016] [Revised: 05/02/2016] [Accepted: 05/10/2016] [Indexed: 01/07/2023] Open
Abstract
Arterial hypertension is a common condition worldwide and an important predictor of several complicated diseases. Arterial hypertension can be triggered by many factors, including physiological, genetic, and lifestyle causes. Specifically, molecules of the renin-angiotensin-aldosterone system not only play important roles in the control of blood pressure, but they are also associated with the genesis of arterial hypertension, thus constituting a need for pharmacological interventions. Chronic high pressure generates mechanical damage along the vascular system, heart, and kidneys, which are the principal organs affected in this condition. In addition to mechanical stress, hypertension-induced oxidative stress, chronic inflammation, and the activation of reparative mechanisms lead to end-organ damage, mainly due to fibrosis. Clinical trials have demonstrated that renin-angiotensin-aldosterone system intervention in hypertensive patients lowers morbidity/mortality and inflammatory marker levels as compared to placebo patients, evidencing that this system controls more than blood pressure. This review emphasizes the detrimental effects that a renin-angiotensin-aldosterone system (RAAS) imbalance has on health considerations above and beyond high blood pressure, such as fibrotic end-organ damage.
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Affiliation(s)
- Natalia Muñoz-Durango
- Millenium Institute on Immunology and Immunotherapy, Departamento de Genética Molecular y Microbiología, Facultad de Ciencias Biológicas, Pontificia Universidad Católica de Chile, 8330025 Santiago, Chile.
| | - Cristóbal A Fuentes
- Millenium Institute on Immunology and Immunotherapy, Departamento de Endocrinología, Escuela de Medicina, Pontificia Universidad Católica de Chile, 8330074 Santiago, Chile.
| | - Andrés E Castillo
- Millenium Institute on Immunology and Immunotherapy, Departamento de Endocrinología, Escuela de Medicina, Pontificia Universidad Católica de Chile, 8330074 Santiago, Chile.
| | - Luis Martín González-Gómez
- Millenium Institute on Immunology and Immunotherapy, Departamento de Endocrinología, Escuela de Medicina, Pontificia Universidad Católica de Chile, 8330074 Santiago, Chile.
| | - Andrea Vecchiola
- Millenium Institute on Immunology and Immunotherapy, Departamento de Endocrinología, Escuela de Medicina, Pontificia Universidad Católica de Chile, 8330074 Santiago, Chile.
| | - Carlos E Fardella
- Millenium Institute on Immunology and Immunotherapy, Departamento de Endocrinología, Escuela de Medicina, Pontificia Universidad Católica de Chile, 8330074 Santiago, Chile.
| | - Alexis M Kalergis
- Millenium Institute on Immunology and Immunotherapy, Departamento de Genética Molecular y Microbiología, Facultad de Ciencias Biológicas, Pontificia Universidad Católica de Chile, 8330025 Santiago, Chile.
- Millenium Institute on Immunology and Immunotherapy, Departamento de Endocrinología, Escuela de Medicina, Pontificia Universidad Católica de Chile, 8330074 Santiago, Chile.
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Alponti RF, Alves PL, Silveira PF. Novel adipocyte aminopeptidases are selectively upregulated by insulin in healthy and obese rats. J Endocrinol 2016; 228:97-104. [PMID: 26577934 DOI: 10.1530/joe-15-0266] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 11/17/2015] [Indexed: 12/17/2022]
Abstract
The lack of a complete assembly of the sensitivity of subcellular aminopeptidase (AP) activities to insulin in different pathophysiological conditions has hampered the complete view of the adipocyte metabolic pathways and its implications in these conditions. Here we investigated the influence of insulin on basic AP (APB), neutral puromycin-sensitive AP (PSA), and neutral puromycin-insensitive AP (APM) in high and low density microsomal and plasma membrane fractions from adipocytes of healthy and obese rats. Catalytic activities of these enzymes were fluorometrically monitoring in these fractions with or without insulin stimulus. Canonical traffic such as insulin-regulated AP was not detected for these novel adipocyte APs in healthy and obese rats. However, insulin increased APM in low density microsomal and plasma membrane fractions from healthy rats, APB in high density microsomal fraction from obese rats and PSA in plasma membrane fraction from healthy rats. A new concept of intracellular compartment-dependent upregulation of AP enzyme activities by insulin emerges from these data. This relatively selective regulation has pathophysiological significance, since these enzymes are well known to act as catalysts and receptor of peptides directly related to energy metabolism. Overall, the regulation of each one of these enzyme activities reflects certain dysfunction in obese individuals.
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Affiliation(s)
- Rafaela Fadoni Alponti
- Laboratory of PharmacologyUnit of Translational Endocrine Physiology and Pharmacology, Instituto Butantan, Avenida Vital Brasil, 1500, CEP05503-900 Sao Paulo, BrazilDepartment of PhysiologyUniversidade de Sao Paulo, Sao Paulo, Brazil Laboratory of PharmacologyUnit of Translational Endocrine Physiology and Pharmacology, Instituto Butantan, Avenida Vital Brasil, 1500, CEP05503-900 Sao Paulo, BrazilDepartment of PhysiologyUniversidade de Sao Paulo, Sao Paulo, Brazil
| | - Patricia Lucio Alves
- Laboratory of PharmacologyUnit of Translational Endocrine Physiology and Pharmacology, Instituto Butantan, Avenida Vital Brasil, 1500, CEP05503-900 Sao Paulo, BrazilDepartment of PhysiologyUniversidade de Sao Paulo, Sao Paulo, Brazil
| | - Paulo Flavio Silveira
- Laboratory of PharmacologyUnit of Translational Endocrine Physiology and Pharmacology, Instituto Butantan, Avenida Vital Brasil, 1500, CEP05503-900 Sao Paulo, BrazilDepartment of PhysiologyUniversidade de Sao Paulo, Sao Paulo, Brazil
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ITO K. Inhibitory effect of water extractive components from heshiko and narezushi on plasma PAI-1 activity in rats. ACTA ACUST UNITED AC 2016. [DOI: 10.2491/jjsth.27.349] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/21/2022]
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Clark JL, Zahradka P, Taylor CG. Efficacy of flavonoids in the management of high blood pressure. Nutr Rev 2015; 73:799-822. [PMID: 26491142 DOI: 10.1093/nutrit/nuv048] [Citation(s) in RCA: 70] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/05/2023] Open
Abstract
Plant compounds such as flavonoids have been reported to exert beneficial effects in cardiovascular disease, including hypertension. Information on the effects of isolated individual flavonoids for management of high blood pressure, however, is more limited. This review is focused on the flavonoids, as isolated outside of the food matrix, from the 5 main subgroups consumed in the Western diet (flavones, flavonols, flavanones, flavan-3-ols, and anthocyanins), along with their effects on hypertension, including the potential mechanisms for regulating blood pressure. Flavonoids from all 5 subgroups have been shown to attenuate a rise in or to reduce blood pressure during several pathological conditions (hypertension, metabolic syndrome, and diabetes mellitus). Flavones, flavonols, flavanones, and flavanols were able to modulate blood pressure by restoring endothelial function, either directly, by affecting nitric oxide levels, or indirectly, through other pathways. Quercetin had the most consistent blood pressure-lowering effect in animal and human studies, irrespective of dose, duration, or disease status. However, further research on the safety and efficacy of the flavonoids is required before any of them can be used by humans, presumably in supplement form, at the doses required for therapeutic benefit.
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Affiliation(s)
- Jaime L Clark
- J.L. Clark, P. Zahradka, and C.G. Taylor are with the Department of Human Nutritional Sciences, University of Manitoba, Manitoba, Canada. P. Zahradka and C.G. Taylor are with the Department of Physiology and Pathophysiology, University of Manitoba, Manitoba, Canada. J.L. Clark, P. Zahradka, and C.G. Taylor are with the Canadian Centre for Agri-Food Research in Health and Medicine, St Boniface Research Centre, Winnipeg, Manitoba, Canada
| | - Peter Zahradka
- J.L. Clark, P. Zahradka, and C.G. Taylor are with the Department of Human Nutritional Sciences, University of Manitoba, Manitoba, Canada. P. Zahradka and C.G. Taylor are with the Department of Physiology and Pathophysiology, University of Manitoba, Manitoba, Canada. J.L. Clark, P. Zahradka, and C.G. Taylor are with the Canadian Centre for Agri-Food Research in Health and Medicine, St Boniface Research Centre, Winnipeg, Manitoba, Canada
| | - Carla G Taylor
- J.L. Clark, P. Zahradka, and C.G. Taylor are with the Department of Human Nutritional Sciences, University of Manitoba, Manitoba, Canada. P. Zahradka and C.G. Taylor are with the Department of Physiology and Pathophysiology, University of Manitoba, Manitoba, Canada. J.L. Clark, P. Zahradka, and C.G. Taylor are with the Canadian Centre for Agri-Food Research in Health and Medicine, St Boniface Research Centre, Winnipeg, Manitoba, Canada.
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Karnik SS, Unal H, Kemp JR, Tirupula KC, Eguchi S, Vanderheyden PML, Thomas WG. International Union of Basic and Clinical Pharmacology. XCIX. Angiotensin Receptors: Interpreters of Pathophysiological Angiotensinergic Stimuli [corrected]. Pharmacol Rev 2015; 67:754-819. [PMID: 26315714 PMCID: PMC4630565 DOI: 10.1124/pr.114.010454] [Citation(s) in RCA: 225] [Impact Index Per Article: 22.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022] Open
Abstract
The renin angiotensin system (RAS) produced hormone peptides regulate many vital body functions. Dysfunctional signaling by receptors for RAS peptides leads to pathologic states. Nearly half of humanity today would likely benefit from modern drugs targeting these receptors. The receptors for RAS peptides consist of three G-protein-coupled receptors—the angiotensin II type 1 receptor (AT1 receptor), the angiotensin II type 2 receptor (AT2 receptor), the MAS receptor—and a type II trans-membrane zinc protein—the candidate angiotensin IV receptor (AngIV binding site). The prorenin receptor is a relatively new contender for consideration, but is not included here because the role of prorenin receptor as an independent endocrine mediator is presently unclear. The full spectrum of biologic characteristics of these receptors is still evolving, but there is evidence establishing unique roles of each receptor in cardiovascular, hemodynamic, neurologic, renal, and endothelial functions, as well as in cell proliferation, survival, matrix-cell interaction, and inflammation. Therapeutic agents targeted to these receptors are either in active use in clinical intervention of major common diseases or under evaluation for repurposing in many other disorders. Broad-spectrum influence these receptors produce in complex pathophysiological context in our body highlights their role as precise interpreters of distinctive angiotensinergic peptide cues. This review article summarizes findings published in the last 15 years on the structure, pharmacology, signaling, physiology, and disease states related to angiotensin receptors. We also discuss the challenges the pharmacologist presently faces in formally accepting newer members as established angiotensin receptors and emphasize necessary future developments.
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Affiliation(s)
- Sadashiva S Karnik
- Department of Molecular Cardiology, Lerner Research Institute of Cleveland Clinic, Cleveland, Ohio (S.S.K., H.U., J.R.K., K.C.T.); Cardiovascular Research Center, Temple University School of Medicine, Philadelphia, Pennsylvania (S.E.); Faculty of Sciences and Bioengineering Sciences, Vrije Universiteit Brussel, Brussels, Belgium (P.M.L.V.); and Department of General Physiology, School of Biomedical Sciences, The University of Queensland, Brisbane, Queensland, Australia (W.G.T.)
| | - Hamiyet Unal
- Department of Molecular Cardiology, Lerner Research Institute of Cleveland Clinic, Cleveland, Ohio (S.S.K., H.U., J.R.K., K.C.T.); Cardiovascular Research Center, Temple University School of Medicine, Philadelphia, Pennsylvania (S.E.); Faculty of Sciences and Bioengineering Sciences, Vrije Universiteit Brussel, Brussels, Belgium (P.M.L.V.); and Department of General Physiology, School of Biomedical Sciences, The University of Queensland, Brisbane, Queensland, Australia (W.G.T.)
| | - Jacqueline R Kemp
- Department of Molecular Cardiology, Lerner Research Institute of Cleveland Clinic, Cleveland, Ohio (S.S.K., H.U., J.R.K., K.C.T.); Cardiovascular Research Center, Temple University School of Medicine, Philadelphia, Pennsylvania (S.E.); Faculty of Sciences and Bioengineering Sciences, Vrije Universiteit Brussel, Brussels, Belgium (P.M.L.V.); and Department of General Physiology, School of Biomedical Sciences, The University of Queensland, Brisbane, Queensland, Australia (W.G.T.)
| | - Kalyan C Tirupula
- Department of Molecular Cardiology, Lerner Research Institute of Cleveland Clinic, Cleveland, Ohio (S.S.K., H.U., J.R.K., K.C.T.); Cardiovascular Research Center, Temple University School of Medicine, Philadelphia, Pennsylvania (S.E.); Faculty of Sciences and Bioengineering Sciences, Vrije Universiteit Brussel, Brussels, Belgium (P.M.L.V.); and Department of General Physiology, School of Biomedical Sciences, The University of Queensland, Brisbane, Queensland, Australia (W.G.T.)
| | - Satoru Eguchi
- Department of Molecular Cardiology, Lerner Research Institute of Cleveland Clinic, Cleveland, Ohio (S.S.K., H.U., J.R.K., K.C.T.); Cardiovascular Research Center, Temple University School of Medicine, Philadelphia, Pennsylvania (S.E.); Faculty of Sciences and Bioengineering Sciences, Vrije Universiteit Brussel, Brussels, Belgium (P.M.L.V.); and Department of General Physiology, School of Biomedical Sciences, The University of Queensland, Brisbane, Queensland, Australia (W.G.T.)
| | - Patrick M L Vanderheyden
- Department of Molecular Cardiology, Lerner Research Institute of Cleveland Clinic, Cleveland, Ohio (S.S.K., H.U., J.R.K., K.C.T.); Cardiovascular Research Center, Temple University School of Medicine, Philadelphia, Pennsylvania (S.E.); Faculty of Sciences and Bioengineering Sciences, Vrije Universiteit Brussel, Brussels, Belgium (P.M.L.V.); and Department of General Physiology, School of Biomedical Sciences, The University of Queensland, Brisbane, Queensland, Australia (W.G.T.)
| | - Walter G Thomas
- Department of Molecular Cardiology, Lerner Research Institute of Cleveland Clinic, Cleveland, Ohio (S.S.K., H.U., J.R.K., K.C.T.); Cardiovascular Research Center, Temple University School of Medicine, Philadelphia, Pennsylvania (S.E.); Faculty of Sciences and Bioengineering Sciences, Vrije Universiteit Brussel, Brussels, Belgium (P.M.L.V.); and Department of General Physiology, School of Biomedical Sciences, The University of Queensland, Brisbane, Queensland, Australia (W.G.T.)
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Okochi M, Kuboyama M, Tanaka M, Honda H. Design of a dual-function peptide probe as a binder of angiotensin II and an inducer of silver nanoparticle aggregation for use in label-free colorimetric assays. Talanta 2015; 142:235-9. [PMID: 26003717 DOI: 10.1016/j.talanta.2015.04.054] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/31/2015] [Accepted: 04/17/2015] [Indexed: 01/21/2023]
Abstract
Label-free colorimetric assays using metallic nanoparticles have received much recent attention, for their application in simple and sensitive methods for detection of biomolecules. Short peptide probes that can bind to analyte biomolecules are attractive ligands in molecular nanotechnology; however, identification of biological recognition motifs is usually based on trial-and-error experiments. Herein, a peptide probe was screened for colorimetric detection of angiotensin II (Ang II) using a mechanism for non-crosslinking aggregation of silver nanoparticles (AgNPs). The dual-function peptides, which bind to the analyte and induce AgNP aggregation, were identified using a two-step strategy: (1) screening of an Ang II-binding peptide from an Ang II receptor sequence library, using SPOT technology, which enable peptides synthesis on cellulose membranes via an Fmoc method and (2) selection of peptide probes that effectively induce aggregation of AgNPs using a photolinker modified peptide array. Using the identified peptide probe, KGKNKRRR, aggregation of AgNPs was detected by observation of a pink color in the absence of Ang II, whereas AgNPs remained dispersed in the presence of Ang II (yellow). The color changes were not observed in the presence of other hormone molecules. Ang II could be detected within 15 min, with a detection limit of 10 µM, by measuring the ratio of absorbance at 400 nm and 568 nm; the signal could also be observed with the naked eye. These data suggest that the peptide identified here could be used as a probe for simple and rapid colorimetric detection of Ang II. This strategy for the identification of functional peptides shows promise for the development of colorimetric detection of various diagnostically important biomolecules.
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Affiliation(s)
- Mina Okochi
- Department of Biotechnology, School of Engineering, Nagoya University, Furo-cho, Chikusa-ku, Nagoya 464-8603, Japan; Department of Chemical Engineering, Graduate School of Science and Engineering, Tokyo Institute of Technology, 2-12-1-S1-24, O-okayama, Meguro-ku, Tokyo 152-8552, Japan.
| | - Masashi Kuboyama
- Department of Biotechnology, School of Engineering, Nagoya University, Furo-cho, Chikusa-ku, Nagoya 464-8603, Japan
| | - Masayoshi Tanaka
- Department of Chemical Engineering, Graduate School of Science and Engineering, Tokyo Institute of Technology, 2-12-1-S1-24, O-okayama, Meguro-ku, Tokyo 152-8552, Japan
| | - Hiroyuki Honda
- Department of Biotechnology, School of Engineering, Nagoya University, Furo-cho, Chikusa-ku, Nagoya 464-8603, Japan
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Gordan R, Gwathmey JK, Xie LH. Autonomic and endocrine control of cardiovascular function. World J Cardiol 2015; 7:204-214. [PMID: 25914789 PMCID: PMC4404375 DOI: 10.4330/wjc.v7.i4.204] [Citation(s) in RCA: 372] [Impact Index Per Article: 37.2] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/20/2014] [Revised: 01/22/2015] [Accepted: 02/12/2015] [Indexed: 02/07/2023] Open
Abstract
The function of the heart is to contract and pump oxygenated blood to the body and deoxygenated blood to the lungs. To achieve this goal, a normal human heart must beat regularly and continuously for one’s entire life. Heartbeats originate from the rhythmic pacing discharge from the sinoatrial (SA) node within the heart itself. In the absence of extrinsic neural or hormonal influences, the SA node pacing rate would be about 100 beats per minute. Heart rate and cardiac output, however, must vary in response to the needs of the body’s cells for oxygen and nutrients under varying conditions. In order to respond rapidly to the changing requirements of the body’s tissues, the heart rate and contractility are regulated by the nervous system, hormones, and other factors. Here we review how the cardiovascular system is controlled and influenced by not only a unique intrinsic system, but is also heavily influenced by the autonomic nervous system as well as the endocrine system.
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Ekholm M, Kahan T, Jörneskog G, Brinck J, Wallén NH. Haemostatic and inflammatory alterations in familial hypercholesterolaemia, and the impact of angiotensin II infusion. J Renin Angiotensin Aldosterone Syst 2015; 16:328-38. [PMID: 25908220 DOI: 10.1177/1470320315575848] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/20/2014] [Accepted: 01/30/2015] [Indexed: 12/27/2022] Open
Abstract
INTRODUCTION We examined potential prothrombotic and proinflammatory effects of angiotensin II in 16 otherwise healthy familial hypercholesterolaemia subjects and 16 matched controls. METHODS Markers of fibrinolysis, thrombin generation and inflammation were assessed in plasma before, during and 1h after a 3h intravenous infusion of angiotensin II. In addition, placebo experiments with saline infusion were carried out. RESULTS Baseline plasminogen activator inhibitor type-1 activity and plasmin-antiplasmin-complex concentrations were similar in FH and controls, as were interleukin-6, leukocyte counts and C-reactive protein. Fibrinogen levels were higher in FH, and we observed a greater thrombin generating potential in FH (calibrated automated thrombogram), but no signs of elevated thrombin generation in vivo (prothrombin fragment 1+2). During angiotensin infusion plasminogen activator inhibitor type-1 activity decreased and plasmin-antiplasmin-complex concentrations increased similarly in FH and controls. Total and maximal amount of thrombin generated was unchanged, as were prothrombin-fragment-1+2 levels. Interleukin-6 and leukocyte counts increased similarly in both groups during angiotensin infusion, while fibrinogen tended to increase in FH and increased in controls. During saline infusion plasminogen activator inhibitor type-1 activity and prothrombin fragment 1+2 concentrations fell, whereas other markers were unchanged. CONCLUSIONS FH exhibits an increased thrombin generation potential, an intact fibrinolysis, and has no convincing signs of inflammation. Angiotensin has proinflammatory effects, and might have minor profibrinolytic and procoagulatory effects.
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Affiliation(s)
- Mikael Ekholm
- Karolinska Institutet, Department of Clinical Sciences, Danderyd Hospital, Division of Cardiovascular Medicine, Stockholm, Sweden Department of Internal Medicine, Ryhov County Hospital, Jönköping, Sweden
| | - Thomas Kahan
- Karolinska Institutet, Department of Clinical Sciences, Danderyd Hospital, Division of Cardiovascular Medicine, Stockholm, Sweden
| | - Gun Jörneskog
- Karolinska Institutet, Department of Clinical Sciences, Danderyd Hospital, Division of Internal Medicine, Stockholm, Sweden
| | - Jonas Brinck
- Department of Medicine, Karolinska University Hospital, Huddinge, Sweden
| | - N Håkan Wallén
- Karolinska Institutet, Department of Clinical Sciences, Danderyd Hospital, Division of Cardiovascular Medicine, Stockholm, Sweden
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Kataoka Y, Nicholls SJ. Imaging of atherosclerotic plaques in obesity: excessive fat accumulation, plaque progression and vulnerability. Expert Rev Cardiovasc Ther 2014; 12:1471-89. [PMID: 25355677 DOI: 10.1586/14779072.2014.975210] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/20/2022]
Abstract
Obesity is becoming a major health issue in the world due to sedentary lifestyles and increasing intake of Western diets. Obesity is associated with metabolic abnormalities and atherosclerotic cardiovascular diseases. Adipose tissue has been increasingly considered to play a critical role in inducing metabolic disturbances and promoting atherogenesis. Arterial wall imaging permits direct visualization of atheroma burden in various vascular beds. In addition, recent advances in imaging technology help characterize components, microstructures and functional features of atherosclerotic plaques. These imaging modalities have contributed to elucidating factors associated with atherosclerosis in obese patients. Also, it provides opportunities to evaluate the effect of novel therapies on plaques in the setting of obesity. The findings of recent imaging studies and the clinical implications will be reviewed.
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Affiliation(s)
- Yu Kataoka
- South Australian Health & Medical Research Institute, University of Adelaide, Adelaide, SA, 5000, Australia
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The renin-angiotensin system in adipose tissue and its metabolic consequences during obesity. J Nutr Biochem 2013; 24:2003-15. [PMID: 24120291 DOI: 10.1016/j.jnutbio.2013.07.002] [Citation(s) in RCA: 108] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/19/2013] [Revised: 05/24/2013] [Accepted: 07/22/2013] [Indexed: 02/07/2023]
Abstract
Obesity is a worldwide disease that is accompanied by several metabolic abnormalities such as hypertension, hyperglycemia and dyslipidemia. The accelerated adipose tissue growth and fat cell hypertrophy during the onset of obesity precedes adipocyte dysfunction. One of the features of adipocyte dysfunction is dysregulated adipokine secretion, which leads to an imbalance of pro-inflammatory, pro-atherogenic versus anti-inflammatory, insulin-sensitizing adipokines. The production of renin-angiotensin system (RAS) components by adipocytes is exacerbated during obesity, contributing to the systemic RAS and its consequences. Increased adipose tissue RAS has been described in various models of diet-induced obesity (DIO) including fructose and high-fat feeding. Up-regulation of the adipose RAS by DIO promotes inflammation, lipogenesis and reactive oxygen species generation and impairs insulin signaling, all of which worsen the adipose environment. Consequently, the increase of circulating RAS, for which adipose tissue is partially responsible, represents a link between hypertension, insulin resistance in diabetes and inflammation during obesity. However, other nutrients and food components such as soy protein attenuate adipose RAS, decrease adiposity, and improve adipocyte functionality. Here, we review the molecular mechanisms by which adipose RAS modulates systemic RAS and how it is enhanced in obesity, which will explain the simultaneous development of metabolic syndrome alterations. Finally, dietary interventions that prevent obesity and adipocyte dysfunction will maintain normal RAS concentrations and effects, thus preventing metabolic diseases that are associated with RAS enhancement.
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Carroll WX, Kalupahana NS, Booker SL, Siriwardhana N, LeMieux M, Saxton AM, Moustaid-Moussa N. Angiotensinogen gene silencing reduces markers of lipid accumulation and inflammation in cultured adipocytes. Front Endocrinol (Lausanne) 2013; 4:10. [PMID: 23483012 PMCID: PMC3593681 DOI: 10.3389/fendo.2013.00010] [Citation(s) in RCA: 25] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/17/2012] [Accepted: 01/28/2013] [Indexed: 01/30/2023] Open
Abstract
Inflammatory adipokines secreted from adipose tissue are major contributors to obesity-associated inflammation and other metabolic dysfunctions. We and others have recently documented the contribution of adipose tissue renin-angiotensin system to the pathogenesis of obesity, inflammation, and insulin resistance. We hypothesized that adipocyte-derived angiotensinogen (Agt) plays a critical role in adipogenesis and/or lipogenesis as well as inflammation. This was tested using 3T3-L1 adipocytes, stably transfected with Agt-shRNA or scrambled Sc-shRNA as a control. Transfected preadipocytes were differentiated and used to investigate the role of adipose Agt through microarray and PCR analyses and adipokine profiling. As expected, Agt gene silencing significantly reduced the expression of Agt and its hormone product angiotensin II (Ang II), as well as lipid accumulation in 3T3-L1 adipocytes. Microarray studies identified several genes involved in lipid metabolism and inflammatory pathways which were down-regulated by Agt gene inactivation, such as glycerol-3-phosphate dehydrogenase 1 (Gpd1), serum amyloid A 3 (Saa3), nucleotide-binding oligomerization domain containing 1 (Nod1), and signal transducer and activator of transcription 1 (Stat1). Mouse adipogenesis PCR arrays revealed lower expression levels of adipogenic/lipogenic genes such as peroxisome proliferator activated receptor gamma (PPARγ), sterol regulatory element binding transcription factor 1 (Srebf1), adipogenin (Adig), and fatty acid binding protein 4 (Fabp4). Further, silencing of Agt gene significantly lowered expression of pro-inflammatory adipokines including interleukin-6 (IL-6), tumor necrosis factor-alpha (TNF-α), and monocyte chemotactic protein-1 (MCP-1). In conclusion, this study directly demonstrates critical effects of Agt in adipocyte metabolism and inflammation and further support a potential role for adipose Agt in the pathogenesis of obesity-associated metabolic alterations.
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Affiliation(s)
- Wenting X. Carroll
- Department of Animal Science, University of TennesseeKnoxville, TN, USA
- Obesity Research Center, University of TennesseeKnoxville, TN, USA
| | - Nishan S. Kalupahana
- Department of Physiology, Faculty of Medicine, University of PeradeniyaPeradeniya, Sri Lanka
| | - Suzanne L. Booker
- Department of Animal Science, University of TennesseeKnoxville, TN, USA
- Obesity Research Center, University of TennesseeKnoxville, TN, USA
| | - Nalin Siriwardhana
- Nutritional Sciences Program, College of Human Sciences, Texas Tech UniversityLubbock, TX, USA
| | - Monique LeMieux
- Nutritional Sciences Program, College of Human Sciences, Texas Tech UniversityLubbock, TX, USA
| | - Arnold M. Saxton
- Department of Animal Science, University of TennesseeKnoxville, TN, USA
- Obesity Research Center, University of TennesseeKnoxville, TN, USA
| | - Naima Moustaid-Moussa
- Nutritional Sciences Program, College of Human Sciences, Texas Tech UniversityLubbock, TX, USA
- *Correspondence: Naima Moustaid-Moussa, Nutritional Sciences Program, College of Human Sciences, Texas Tech University, 1301 Akron Street, Lubbock, TX 79409, USA. e-mail:
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Kalupahana NS, Moustaid-Moussa N. The adipose tissue renin-angiotensin system and metabolic disorders: a review of molecular mechanisms. Crit Rev Biochem Mol Biol 2012; 47:379-90. [PMID: 22720713 DOI: 10.3109/10409238.2012.694843] [Citation(s) in RCA: 67] [Impact Index Per Article: 5.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022]
Abstract
The renin-angiotensin system (RAS) is classically known for its role in regulation of blood pressure, fluid and electrolyte balance. In this system, angiotensinogen (Agt), the obligate precursor of all bioactive angiotensin peptides, undergoes two enzymatic cleavages by renin and angiotensin converting enzyme (ACE) to produce angiotensin I (Ang I) and angiotensin II (Ang II), respectively. The contemporary view of RAS has become more complex with the discovery of additional angiotensin degradation pathways such as ACE2. All components of the RAS are expressed in and have independent regulation of adipose tissue. This local adipose RAS exerts important auto/paracrine functions in modulating lipogenesis, lipolysis, adipogenesis as well as systemic and adipose tissue inflammation. Mice with adipose-specific Agt overproduction have a 30% increase in plasma Agt levels and develop hypertension and insulin resistance, while mice with adipose-specific Agt knockout have a 25% reduction in Agt plasma levels, demonstrating endocrine actions of adipose RAS. Emerging evidence also points towards a role of RAS in regulation of energy balance. Because adipose RAS is overactivated in many obesity conditions, it is considered a potential candidate linking obesity to hypertension, insulin resistance and other metabolic derangements.
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Affiliation(s)
- Nishan S Kalupahana
- Obesity Research Center, The University of Tennessee (UT), Knoxville, TN, USA
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The role of PAI-1 and adiponectin on the inflammatory state and energy balance in obese adolescents with metabolic syndrome. Inflammation 2012; 35:944-51. [PMID: 22038064 DOI: 10.1007/s10753-011-9397-2] [Citation(s) in RCA: 24] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/14/2023]
Abstract
Obesity is a chronic inflammatory disease and is considered a risk factor for metabolic syndrome. In this study, 57 obese adolescents with and without metabolic syndrome underwent 1 year of weight loss therapy. At baseline, the metabolic syndrome (MS) patients presented higher values of PAI-1 than the non-metabolic syndrome patients (n-MS). After therapy, significant improvements in anthropometrics and biochemical, inflammatory, and neuroendocrine variables were observed in both groups. However, the n-MS group presented better results than the MS group. Indeed, we found positive correlations in both groups between PAI-1 and neuropeptide Y (NPY) and between PAI-1 and NPY/AgRP. Inflammatory biomarkers may thus play a role in energy balance. The clinical trial registration number is NCT01358773.
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Skurk T, van Harmelen V, Blum WF, Hauner H. Angiotensin II Promotes Leptin Production in Cultured Human Fat Cells by an ERK1/2-dependent Pathway. ACTA ACUST UNITED AC 2012; 13:969-73. [PMID: 15976138 DOI: 10.1038/oby.2005.113] [Citation(s) in RCA: 58] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/08/2022]
Abstract
OBJECTIVE The fat cell hormone leptin is known to be implicated in the pathogenesis of hypertension and cardiovascular disease. Here we tested whether angiotensin (Ang) II is involved in the control of leptin release from human adipocytes. RESEARCH METHODS AND PROCEDURES Leptin secretion was assessed from in vitro differentiated human adipocytes by radioimmunoassay. Western blot experiments were used to test for the signaling pathway activated by Ang II. RESULTS Ang II increased leptin secretion into the culture medium in a dose- and time-dependent fashion. At 10(-5) M Ang II, the leptin concentration in the medium was increased at 24 hours by 500+/-222% compared with control cultures (p<0.05). This effect was also seen at the mRNA level. Similar effects were seen after exposure of fat cells to Ang III and Ang IV. Preincubation of fat cells with candesartan, an angiotensin II type 1 receptor antagonist, or the extracellular-signal-regulated kinases 1 and 2 inhibitor UO126 completely abolished the effect of Ang II on leptin production. The peroxisome proliferator-activated receptor-gamma agonist troglitazone modestly attenuated leptin release. DISCUSSION In conclusion, Ang II and its metabolites stimulated leptin production in human adipocytes. This effect is mediated through an extracellular-signal-regulated kinases 1 and 2-dependent pathway and includes the angiotensin II type 1 receptor subtype.
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Affiliation(s)
- Thomas Skurk
- Else Kröner-Fresenius-Centre for Nutritional Medicine, Technical University Munich, Am Forum 5, 85350 Freising-Weihenstephan, Germany.
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45
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van der Zijl NJ, Moors CCM, Goossens GH, Blaak EE, Diamant M. Does interference with the renin-angiotensin system protect against diabetes? Evidence and mechanisms. Diabetes Obes Metab 2012; 14:586-95. [PMID: 22226145 DOI: 10.1111/j.1463-1326.2012.01559.x] [Citation(s) in RCA: 28] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/01/2023]
Abstract
Agents interfering with the renin-angiotensin system (RAS) were consistently shown to lower the incidence of type 2 diabetes mellitus (T2DM), as compared to other antihypertensive drugs, in hypertensive high-risk populations. The mechanisms underlying this protective effect of RAS blockade using angiotensin-converting enzyme inhibitors or angiotensin-receptor blockers on glucose metabolism are not fully understood. In this article, we will review the evidence from randomized controlled trials and discuss the proposed mechanisms as to how RAS interference may delay the onset of T2DM. In particular, as T2DM is characterized by β-cell dysfunction and obesity-related insulin resistance, we address the mechanisms that underlie RAS blockade-induced improvement in β-cell function and insulin sensitivity.
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Affiliation(s)
- N J van der Zijl
- Diabetes Center, Department of Internal Medicine, VU University Medical Center, Amsterdam, The Netherlands.
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46
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Ekström M, Liska J, Eriksson P, Sverremark-Ekström E, Tornvall P. Stimulated in vivo synthesis of plasminogen activator inhibitor-1 in human adipose tissue. Thromb Haemost 2012; 108:485-92. [PMID: 22740034 DOI: 10.1160/th11-11-0822] [Citation(s) in RCA: 24] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/30/2011] [Accepted: 05/07/2012] [Indexed: 11/05/2022]
Abstract
Plasminogen activator inhibitor type-1 (PAI-1) is one of the most important inhibitors of endogenous fibrinolysis. Adipose tissue is a suggested source of the elevated plasma levels of PAI-1 in obesity. The relation between PAI-1 and inflammation is of particular interest, but current knowledge regarding regulation of PAI-1 in adipose tissue is mainly based on animal studies or ex vivo experiments on human cultured adipocytes. So far, no study has described stimulated gene expression and protein synthesis of PAI-1 in vivo in human adipose tissue. We used open heart surgery as a model of acute systemic inflammation. Twenty-two male patients underwent blood sampling and omental and subcutaneous adipose tissue biopsies for gene expression studies before and after surgery. Expression and localisation of PAI-1 antigen was evaluated by immunohistochemistry. After surgery gene expression of PAI-1 increased 27-fold in omental adipose tissue and three-fold in subcutaneous adipose tissue, but no differences were found in tissue-type plasminogen activator (t-PA) mRNA. PAI-1 antigen was localised within endothelial cells and in the adipose tissue interstitium close to vessels. The upregulated gene expression and protein synthesis in adipose tissue was followed by increased concentrations of PAI-1 antigen in plasma. In conclusion, we present for the first time that an acute systemic inflammation in humans increased gene expression and protein synthesis of PAI-1 in adipose tissue and that this increase was most prominent in omental adipose tissue. PAI-1 synthesis in adipose tissue due to acute systemic inflammation may be a link between inflammation and impaired endogenous fibrinolysis.
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Affiliation(s)
- Mattias Ekström
- Cardiology Unit, Department of Medicine, Karolinska University Hospital, Solna, Karolinska Institutet, Stockholm, Sweden.
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Than A, Tee WT, Chen P. Apelin secretion and expression of apelin receptors in 3T3-L1 adipocytes are differentially regulated by angiotensin type 1 and type 2 receptors. Mol Cell Endocrinol 2012; 351:296-305. [PMID: 22249006 DOI: 10.1016/j.mce.2012.01.005] [Citation(s) in RCA: 20] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/03/2011] [Revised: 12/27/2011] [Accepted: 01/04/2012] [Indexed: 12/28/2022]
Abstract
Adipocytes play pivotal roles in regulating metabolism through secretion of a variety of adipokines, which in turn is regulated by other metabolic factors (e.g., insulin). Understanding the regulations of adipokine secretion is important because adipokines are implicated with metabolic disorders, such as, obesity and diabetes mellitus. Here, we investigated the regulatory roles of angiotensin II (AngII) on the secretion of apelin in 3T3-L1 adipocytes, and distinct signaling pathways mediated by AngII receptor type 1 (AT₁) and type 2 (AT₂) were revealed. It was found that activation of AT₁ receptors stimulates apelin secretion in Ca²⁺, protein kinase C, and MAPK kinase dependent ways while activation of AT₂ receptors inhibits apelin secretion through cAMP and cGMP dependent pathways. Furthermore, we demonstrate that the expression of apelin receptor (APJ) is also similarly regulated by AT₁ and AT₂ receptors. Finally, a detailed AngII signaling map is proposed.
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Affiliation(s)
- Aung Than
- Division of Bioengineering, Nanyang Technological University, 70 Nanyang Drive, Singapore 637457, Singapore
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Fogari R, Zoppi A, Mugellini A, Maffioli P, Lazzari P, Derosa G. Role of angiotensin II in plasma PAI-1 changes induced by imidapril or candesartan in hypertensive patients with metabolic syndrome. Hypertens Res 2011; 34:1321-6. [PMID: 21814211 DOI: 10.1038/hr.2011.137] [Citation(s) in RCA: 21] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/09/2022]
Abstract
To evaluate the relationship between plasma plasminogen activator inhibitor-1 (PAI-1) and angiotensin II (Ang II) changes during treatment with imidapril and candesartan in hypertensive patients with metabolic syndrome. A total of 84 hypertensive patients with metabolic syndrome were randomized to imidapril 10 mg or candesartan 16 mg for 16 weeks. At weeks 4 and 8, there was a dose titration to imidapril 20 mg and candesartan 32 mg in nonresponders (systolic blood pressure (SBP) >140 and/or diastolic blood pressure (DBP) >90 mm Hg). We evaluated, at baseline and after 2, 4, 8, 12 and 16 weeks, clinic blood pressure, Ang II and PAI-1 antigen. Both imidapril and candesartan induced a similar SBP/DBP reduction (-19.4/16.8 and -19.5/16.3 mm Hg, respectively, P<0.001 vs. baseline). Both drugs decreased PAI-1 antigen after 4 weeks of treatment, but only the PAI-1 lowering effect of imidapril was sustained throughout the 16 weeks (-9.3 ng ml(-1), P<0.01 vs. baseline), whereas candesartan increased PAI-1 (+6.5 ng ml(-1), P<0.05 vs. baseline and P<0.01 vs. imidapril). Imidapril significantly decreased Ang II levels (-14.6 pg ml(-1) at week 16, P<0.05 vs. baseline), whereas candesartan increased them (+24.2 pg ml(-1), P<0.01 vs. baseline and vs. imidapril). In both groups there was a positive correlation between Ang II and PAI-1 changes (r=0.61, P<0.001 at week 16 for imidapril, and r=0.37, P<0.005 at week 16 for candesartan). Imidapril reduced plasma PAI-1 and Ang II levels, whereas candesartan increased them. This suggests that the different effect of angiotensin-converting enzyme inhibitors and Ang II blockers on Ang II production has a role in their different influence on fibrinolysis.
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Affiliation(s)
- Roberto Fogari
- Department of Internal Medicine and Therapeutics, Centro Ipertensione e Fisiopatologia Cardiovascolare, University of Pavia, Pavia, Italy.
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The Angiotensin Receptor Blocker, Azilsartan Medoxomil (TAK-491), Suppresses Vascular Wall Expression of Plasminogen Activator Inhibitor Type-I Protein Potentially Facilitating the Stabilization of Atherosclerotic Plaques. J Cardiovasc Pharmacol 2011; 58:143-8. [DOI: 10.1097/fjc.0b013e31821dcbea] [Citation(s) in RCA: 26] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/25/2022]
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Coffey CS, Asselbergs FW, Hebert PR, Hillege HL, Li Q, Moore JH, van Gilst WH. The Association of the Metabolic Syndrome with PAI-1 and t-PA Levels. Cardiol Res Pract 2011; 2011:541467. [PMID: 21559217 PMCID: PMC3087975 DOI: 10.4061/2011/541467] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/16/2010] [Revised: 01/12/2011] [Accepted: 02/09/2011] [Indexed: 11/23/2022] Open
Abstract
Background. We used a random sample (n = 2, 495) from the population-based Prevention of Renal and Vascular End-stage Disease (PREVEND) study population to examine the association of the metabolic syndrome (Met S) with plasminogen activator inhibitor type 1 (PAI-1) and tissue plasminogen activator (t-PA) antigen levels. Results. The overall prevalence of the Met S was 18%, was dependent on age and gender, and was positively associated with higher antigen levels of both PAI-1 and t-PA. These significant effects were maintained after adjustment for age, gender, BMI, elevated C-reactive protein, smoking status, urinary albumin excretion, and insulin levels. We found no significant interactions between the Met S and other covariates on PAI-1 and t-PA levels. Conclusions. Our study demonstrates that those with the Met S have significantly higher levels of PAI-1 and t-PA antigen, factors known to increase the risk of cardiovascular disease.
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Affiliation(s)
- Christopher S Coffey
- Department of Biostatistics, College of Public Health, University of Iowa, Iowa City, IA 52242, USA
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