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Saha P, Sharma SS. RNA Interference Unleashed: Current Perspective of Small Interfering RNA (siRNA) Therapeutics in the Treatment of Neuropathic Pain. ACS Pharmacol Transl Sci 2024; 7:2951-2970. [PMID: 39416962 PMCID: PMC11475279 DOI: 10.1021/acsptsci.4c00329] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/01/2024] [Revised: 08/12/2024] [Accepted: 09/09/2024] [Indexed: 10/19/2024]
Abstract
Neuropathic pain (NP) is one of the debilitating pain phenotypes that leads to the progressive degeneration of the central as well as peripheral nervous system. NP is often associated with hyperalgesia, allodynia, paresthesia, tingling, and burning sensations leading to disability, motor dysfunction, and compromised psychological state of the patients. Most of the conventional pharmacological agents are unable to improve the devastating conditions of pain because of their limited efficacy, undesirable side effects, and multifaceted pathophysiology of the diseased condition. A rapid rise in new cases of NP warrants further research for identifying the potential novel therapeutic modalities for treating NP. Recently, small interfering RNA (siRNA) approach has shown therapeutic potential in many disease conditions including NP. Delivery of siRNAs led to potential and selective downregulation of target mRNA and abolished the pain-related behaviors/pathophysiological pain response. The crucial role of siRNA in the treatment of NP by considering all of the pathways associated with NP that could be managed by siRNA therapeutics has been discussed. However, their therapeutic use is limited by several hurdles such as instability in systemic circulation due to their negative charge and membrane impermeability, off-target effects, immunogenicity, and inability to reach the intended site of action. This review also emphasizes several strategies and techniques to overcome these hurdles for translating these therapeutic siRNAs from bench to bedside by opening a new avenue for obtaining a potential therapeutic approach for treating NP.
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Affiliation(s)
- Priya Saha
- Department
of Pharmacology and Toxicology, National
Institute of Pharmaceutical Education and Research, S.A.S. Nagar, Mohali, Punjab 160062, India
| | - Shyam S. Sharma
- Department
of Pharmacology and Toxicology, National
Institute of Pharmaceutical Education and Research, S.A.S. Nagar, Mohali, Punjab 160062, India
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2
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Fu Q, Wang Y, Yan C, Xiang YK. Phosphodiesterase in heart and vessels: from physiology to diseases. Physiol Rev 2024; 104:765-834. [PMID: 37971403 PMCID: PMC11281825 DOI: 10.1152/physrev.00015.2023] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/03/2023] [Revised: 10/17/2023] [Accepted: 11/08/2023] [Indexed: 11/19/2023] Open
Abstract
Phosphodiesterases (PDEs) are a superfamily of enzymes that hydrolyze cyclic nucleotides, including cyclic adenosine monophosphate (cAMP) and cyclic guanosine monophosphate (cGMP). Both cyclic nucleotides are critical secondary messengers in the neurohormonal regulation in the cardiovascular system. PDEs precisely control spatiotemporal subcellular distribution of cyclic nucleotides in a cell- and tissue-specific manner, playing critical roles in physiological responses to hormone stimulation in the heart and vessels. Dysregulation of PDEs has been linked to the development of several cardiovascular diseases, such as hypertension, aneurysm, atherosclerosis, arrhythmia, and heart failure. Targeting these enzymes has been proven effective in treating cardiovascular diseases and is an attractive and promising strategy for the development of new drugs. In this review, we discuss the current understanding of the complex regulation of PDE isoforms in cardiovascular function, highlighting the divergent and even opposing roles of PDE isoforms in different pathogenesis.
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Affiliation(s)
- Qin Fu
- Department of Pharmacology, School of Basic Medicine, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
- The Key Laboratory for Drug Target Research and Pharmacodynamic Evaluation of Hubei Province, Wuhan, China
| | - Ying Wang
- Department of Pharmacology, School of Medicine, Southern University of Science and Technology, Shenzhen, China
| | - Chen Yan
- Aab Cardiovascular Research Institute, University of Rochester Medical Center, Rochester, New York, United States
| | - Yang K Xiang
- Department of Pharmacology, University of California at Davis, Davis, California, United States
- Department of Veterans Affairs Northern California Healthcare System, Mather, California, United States
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Gallo G, Savoia C. New Insights into Endothelial Dysfunction in Cardiometabolic Diseases: Potential Mechanisms and Clinical Implications. Int J Mol Sci 2024; 25:2973. [PMID: 38474219 DOI: 10.3390/ijms25052973] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/30/2024] [Revised: 02/27/2024] [Accepted: 03/01/2024] [Indexed: 03/14/2024] Open
Abstract
The endothelium is a monocellular layer covering the inner surface of blood vessels. It maintains vascular homeostasis regulating vascular tone and permeability and exerts anti-inflammatory, antioxidant, anti-proliferative, and anti-thrombotic functions. When the endothelium is exposed to detrimental stimuli including hyperglycemia, hyperlipidemia, and neurohormonal imbalance, different biological pathways are activated leading to oxidative stress, endothelial dysfunction, increased secretion of adipokines, cytokines, endothelin-1, and fibroblast growth factor, and reduced nitric oxide production, leading eventually to a loss of integrity. Endothelial dysfunction has emerged as a hallmark of dysmetabolic vascular impairment and contributes to detrimental effects on cardiac metabolism and diastolic dysfunction, and to the development of cardiovascular diseases including heart failure. Different biomarkers of endothelial dysfunction have been proposed to predict cardiovascular diseases in order to identify microvascular and macrovascular damage and the development of atherosclerosis, particularly in metabolic disorders. Endothelial dysfunction also plays an important role in the development of severe COVID-19 and cardiovascular complications in dysmetabolic patients after SARS-CoV-2 infection. In this review, we will discuss the biological mechanisms involved in endothelial dysregulation in the context of cardiometabolic diseases as well as the available and promising biomarkers of endothelial dysfunction in clinical practice.
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Affiliation(s)
- Giovanna Gallo
- Clinical and Molecular Medicine Department, Faculty of Medicine and Psychology, Sant'Andrea Hospital, Sapienza University of Rome, Via di Grottarossa 1035-1039, 00189 Rome, Italy
| | - Carmine Savoia
- Clinical and Molecular Medicine Department, Faculty of Medicine and Psychology, Sant'Andrea Hospital, Sapienza University of Rome, Via di Grottarossa 1035-1039, 00189 Rome, Italy
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Garcia-Rubio VG, Cabrera-Becerra SE, Ocampo-Ortega SA, Blancas-Napoles CM, Sierra-Sánchez VM, Romero-Nava R, Gutiérrez-Rojas RA, Huang F, Hong E, Villafaña S. siRNA Targeting PDE5A Partially Restores Vascular Damage Due to Type 1 Diabetes in a Streptozotocin-Induced Rat Model. Sci Pharm 2023; 91:52. [DOI: 10.3390/scipharm91040052] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/04/2025] Open
Abstract
Diabetes mellitus is a metabolic disease that can produce different alterations such as endothelial dysfunction, which is defined as a decrease in the vasodilator responses of the mechanisms involved such as the nitric oxide (NO) pathway. The overexpression of PDE5A has been reported in diabetes, which causes an increase in the hydrolysis of cGMP and a decrease in the NO pathway. For this reason, the aim of this study was to evaluate whether siRNAs targeting PDE5A can reduce the endothelial dysfunction associated with diabetes. We used male Wistar rats (200–250 g) that were administered streptozotocin (STZ) (60 mg/kg i.p) to induce diabetes. Two weeks after STZ administration, the siRNAs or vehicle were administered and then, at 4 weeks, dose–response curves to acetylcholine were performed and PDE5A mRNA levels were measured by RT-PCR. siRNAs were designed by the bioinformatic analysis of human–rat FASTA sequences and synthesised in the Mermade-8 equipment. Our results showed that 4 weeks of diabetes produces a decrease in the vasodilator responses to acetylcholine and an increase in the expression of PDE5A mRNA, while the administration of siRNAs partially restores the vasodilator response and decreases PDE5A expression. We conclude that the administration of siRNAs targeting PDE5A partially reverts the endothelial impairment associated with diabetes.
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Affiliation(s)
- Vanessa Giselle Garcia-Rubio
- Laboratorio de Señalización Intracelular, Sección de Estudios de Posgrado e Investigación, Escuela Superior de Medicina, Instituto Politécnico Nacional, Plan de San Luis y Salvador Díaz Mirón, Ciudad de México 11340, Mexico
| | - Sandra Edith Cabrera-Becerra
- Laboratorio de Señalización Intracelular, Sección de Estudios de Posgrado e Investigación, Escuela Superior de Medicina, Instituto Politécnico Nacional, Plan de San Luis y Salvador Díaz Mirón, Ciudad de México 11340, Mexico
| | - Sergio Adrian Ocampo-Ortega
- Laboratorio de Señalización Intracelular, Sección de Estudios de Posgrado e Investigación, Escuela Superior de Medicina, Instituto Politécnico Nacional, Plan de San Luis y Salvador Díaz Mirón, Ciudad de México 11340, Mexico
| | - Citlali Margarita Blancas-Napoles
- Laboratorio de Señalización Intracelular, Sección de Estudios de Posgrado e Investigación, Escuela Superior de Medicina, Instituto Politécnico Nacional, Plan de San Luis y Salvador Díaz Mirón, Ciudad de México 11340, Mexico
| | - Vivany Maydel Sierra-Sánchez
- Laboratorio de Señalización Intracelular, Sección de Estudios de Posgrado e Investigación, Escuela Superior de Medicina, Instituto Politécnico Nacional, Plan de San Luis y Salvador Díaz Mirón, Ciudad de México 11340, Mexico
| | - Rodrigo Romero-Nava
- Laboratorio de Señalización Intracelular, Sección de Estudios de Posgrado e Investigación, Escuela Superior de Medicina, Instituto Politécnico Nacional, Plan de San Luis y Salvador Díaz Mirón, Ciudad de México 11340, Mexico
| | | | - Fengyang Huang
- Departamento de Farmacología y Toxicología, “Hospital Infantil de México Federico Gómez” (HIMFG), Ciudad de México 06720, Mexico
| | - Enrique Hong
- Departamento de Neurofarmacobiología, Centro de Investigación y de Estudios Avanzados, Ciudad de México 07360, Mexico
| | - Santiago Villafaña
- Laboratorio de Señalización Intracelular, Sección de Estudios de Posgrado e Investigación, Escuela Superior de Medicina, Instituto Politécnico Nacional, Plan de San Luis y Salvador Díaz Mirón, Ciudad de México 11340, Mexico
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Coronary Microvascular Dysfunction in Diabetes Mellitus: Pathogenetic Mechanisms and Potential Therapeutic Options. Biomedicines 2022; 10:biomedicines10092274. [PMID: 36140374 PMCID: PMC9496134 DOI: 10.3390/biomedicines10092274] [Citation(s) in RCA: 47] [Impact Index Per Article: 15.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/05/2022] [Revised: 09/04/2022] [Accepted: 09/09/2022] [Indexed: 11/16/2022] Open
Abstract
Diabetic patients are frequently affected by coronary microvascular dysfunction (CMD), a condition consisting of a combination of altered vasomotion and long-term structural change to coronary arterioles leading to impaired regulation of blood flow in response to changing cardiomyocyte oxygen requirements. The pathogenesis of this microvascular complication is complex and not completely known, involving several alterations among which hyperglycemia and insulin resistance play particularly central roles leading to oxidative stress, inflammatory activation and altered barrier function of endothelium. CMD significantly contributes to cardiac events such as angina or infarction without obstructive coronary artery disease, as well as heart failure, especially the phenotype associated with preserved ejection fraction, which greatly impact cardiovascular (CV) prognosis. To date, no treatments specifically target this vascular damage, but recent experimental studies and some clinical investigations have produced data in favor of potential beneficial effects on coronary micro vessels caused by two classes of glucose-lowering drugs: glucagon-like peptide 1 (GLP-1)-based therapy and inhibitors of sodium-glucose cotransporter-2 (SGLT2). The purpose of this review is to describe pathophysiological mechanisms, clinical manifestations of CMD with particular reference to diabetes, and to summarize the protective effects of antidiabetic drugs on the myocardial microvascular compartment.
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Kataoka T, Kawaki Y, Kito Y, Suzuki J, Mori T, Hotta Y, Sanagawa A, Kawade Y, Maeda Y, Furukawa-Hibi Y, Kimura K. Gosha-Jinki-Gan Improved Erectile Dysfunction Caused by Anti-Cancer Agent Oxaliplatin by Decreasing Transcriptional Expression of Phosphodiesterase-5 in Rats. Sex Med 2022; 10:100484. [PMID: 35065470 PMCID: PMC9023251 DOI: 10.1016/j.esxm.2021.100484] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/14/2021] [Revised: 12/16/2021] [Accepted: 12/19/2021] [Indexed: 12/28/2022] Open
Abstract
Background A platinum-containing anti-cancer agent, oxaliplatin (L-OHP), is known to induce peripheral neuropathy, including erectile dysfunction (ED) as a side effect, while Gosha-jinki-gan (GJG) is a traditional Japanese herbal medicine mainly used for peripheral neuropathy. Aim To investigate the effect of GJG on L-OHP-induced ED in rats. Methods Twelve-week-old male Wister/ST rats were categorized into the following groups: Sham, Sham+GJG, L-OHP, and L-OHP+GJG (each n = 10). The L-OHP and L-OHP+GJG groups were injected intravenously with L-OHP (4 mg/kg) for 2 consecutive days in the first week. Statistical significance was determined using Bonferroni's multiple comparison test. Outcomes At the end of the study period, erectile function was evaluated by measuring intracavernosal pressure (ICP) and mean arterial pressure (MAP) after cavernous nerve stimulation. Western blot analysis was used to assess the neuronal nitric oxide synthase (nNOS) and endothelial nitric oxide synthase (eNOS) levels, and quantitative polymerase chain reaction was used to assess the expression of phosphodiesterase-5 (PDE-5) and nicotinamide adenine dinucleotide phosphate (NADPH) oxidase-1. Results The ICP/MAP ratio of L-OHP rats (0.34 ± 0.06) was significantly lower than that of Sham rats (0.67 ± 0.03, P < .01), however, the ICP/MAP ratio of L-OHP+GJG rats (0.55 ± 0.01) was significantly higher than that of L-OHP rats (P < .01). There were no significant differences in the nNOS and eNOS protein expression between both groups (P > .05). GJG administration significantly decreased PDE-5 and NADPH oxidase-1 messenger RNA expressions in the L-OHP+GJG group. Clinical Translation This animal model study suggests that GJG might be effective for erectile function in cancer survivors. Strengths & limitations Our study identified that GJG had no notable side effects in the treated group. Further investigation of the cavernous nerve would also help elucidate the mechanism of GJG effect, which is a limitation of this study. Conclusion We found that GJG administration improved L-OHP-induced ED by improving transcriptional PDE-5 expression. Kataoka T, Kawaki Y, Kito Y, et al. Gosha-Jinki-Gan Improved Erectile Dysfunction Caused by Anti-Cancer Agent Oxaliplatin by Decreasing Transcriptional Expression of Phosphodiesterase-5 in Rats. Sex Med 2022;10:100484.
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Aslan R, Taken K, Erbin A, Alp HH, Eryilmaz R, Sarilar O, Huyut Z. The synergistic effects of testosterone and phophodiesterase-5 inhibitor combination on oxidative stress markers, matrix metalloproteinases and oxidative DNA damage: A randomized controlled experimental study. Rev Int Androl 2022; 20:73-79. [PMID: 35115255 DOI: 10.1016/j.androl.2020.10.011] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/24/2020] [Accepted: 10/17/2020] [Indexed: 10/19/2022]
Abstract
PURPOSE To investigate the effects of combined tadalafil and testosterone usage on oxidative stress, DNA damage and MMPs in testosterone deficiency. METHODS Fifty rats were randomly divided into 5 groups (group-1: sham group-placebo, group-2: bilateral orchiectomy (ORX), group-3: bilateral ORX+tadalafil, group-4: bilateral ORX+testosterone, group-5: bilateral ORX+tadalafil+testosterone). Group-3 received tadalafil (5mg/kg/day, oral). Group-4 was administered testosterone undecanoate (100mg/kg i.m., single dose). Group-5 was administered a combination of tadalafil and testosterone undecanoate. All groups were compared with regard to serum nicotinamide adenine dinucleotide phosphate oxidase-4 (NOX-4), total thiol, matrix metalloproteinase-2 (MMP-2), MMP-3 and MMP-9, tissue inhibitor of metalloproteinases-1 (TIMP-1) and TIMP-2 and 8-hydroxy-2-deoxy guanosine (8-OHdG) levels. RESULTS Total thiol levels of group-2 were significantly lower than the other groups and thiol levels were higher in group-1 and group-5 than in the other groups. NOX4, MMP2 and 9 levels in group-2 were higher than in the other groups. MMP-9 levels in group-5 were lower than in groups 3 and 4 (p=.001). The level of 8-OHdG in groups 2 and 3 was higher than in the other groups (p=.001). In correlation analysis, 8-OHdG, MMP2, and 9 levels were negatively correlated with total thiol, whereas NOX4 and 8-OHdG levels were positively correlated with MMPs values. CONCLUSIONS The combination of testosterone with PDE-5 inhibitor suppresses MMP-9 levels and increases total thiol levels better than testosterone alone and tadalafil alone. Therefore, testosterone can be considered for use with PDE-5 inhibitor from the initial stage in case of testosterone deficiency.
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Affiliation(s)
- Rahmi Aslan
- Department of Urology, Faculty of Medicine, Van Yuzuncu Yıl University, Van, Turkey
| | - Kerem Taken
- Department of Urology, Faculty of Medicine, Van Yuzuncu Yıl University, Van, Turkey
| | - Akif Erbin
- Department of Urology, Haseki Training and Research Hospital, Istanbul, Turkey.
| | - Hamit Hakan Alp
- Department of Biochemistry, Faculty of Medicine, Van Yuzuncu Yıl University, Van, Turkey
| | - Recep Eryilmaz
- Department of Urology, Faculty of Medicine, Van Yuzuncu Yıl University, Van, Turkey
| | - Omer Sarilar
- Department of Urology, Haseki Training and Research Hospital, Istanbul, Turkey
| | - Zubeyir Huyut
- Department of Biochemistry, Faculty of Medicine, Van Yuzuncu Yıl University, Van, Turkey
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van de Wouw J, Steenhorst JJ, Sorop O, van Drie RWA, Wielopolski PA, Kleinjan A, Hirsch A, Duncker DJ, Merkus D. Impaired pulmonary vasomotor control in exercising swine with multiple comorbidities. Basic Res Cardiol 2021; 116:51. [PMID: 34510273 PMCID: PMC8435524 DOI: 10.1007/s00395-021-00891-7] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/02/2020] [Accepted: 07/29/2021] [Indexed: 12/15/2022]
Abstract
Pulmonary hypertension is common in heart failure with preserved ejection fraction (HFpEF). Here, we tested the hypothesis that comorbidities [diabetes mellitus (DM, streptozotocin), hypercholesterolemia (HC, high-fat diet) and chronic kidney disease (CKD, renal microembolization)] directly impair pulmonary vasomotor control in a DM + HC + CKD swine model. 6 months after induction of DM + HC + CKD, pulmonary arterial pressure was similar in chronically instrumented female DM + HC + CKD (n = 19) and Healthy swine (n = 18). However, cardiac output was lower both at rest and during exercise, implying an elevated pulmonary vascular resistance (PVR) in DM + HC + CKD swine (153 ± 10 vs. 122 ± 9 mmHg∙L-1∙min∙kg). Phosphodiesterase 5 inhibition and endothelin receptor antagonism decreased PVR in DM + HC + CKD (- 12 ± 12 and - 22 ± 7 mmHg∙L-1∙min∙kg) but not in Healthy swine (- 1 ± 12 and 2 ± 14 mmHg∙L-1∙min∙kg), indicating increased vasoconstrictor influences of phosphodiesterase 5 and endothelin. Inhibition of nitric oxide synthase produced pulmonary vasoconstriction that was similar in Healthy and DM + HC + CKD swine, but unmasked a pulmonary vasodilator effect of endothelin receptor antagonism in Healthy (- 56 ± 26 mmHg∙L-1∙min∙kg), whereas it failed to significantly decrease PVR in DM + HC + CKD, indicating loss of nitric oxide mediated inhibition of endothelin in DM + HC + CKD. Scavenging of reactive oxygen species (ROS) had no effect on PVR in either Healthy or DM + HC + CKD swine. Cardiovascular magnetic resonance imaging, under anesthesia, showed no right ventricular changes. Finally, despite an increased contribution of endogenous nitric oxide to vasomotor tone regulation in the systemic vasculature, systemic vascular resistance at rest was higher in DM + HC + CKD compared to Healthy swine (824 ± 41 vs. 698 ± 35 mmHg∙L-1∙min∙kg). ROS scavenging induced systemic vasodilation in DM + HC + CKD, but not Healthy swine. In conclusion, common comorbidities directly alter pulmonary vascular control, by enhanced PDE5 and endothelin-mediated vasoconstrictor influences, well before overt left ventricular backward failure or pulmonary hypertension develop.
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Affiliation(s)
- Jens van de Wouw
- Division of Experimental Cardiology, Department of Cardiology, Erasmus MC, University Medical Center Rotterdam, PO Box 2040, 3000 CA, Rotterdam, The Netherlands
| | - Jarno J Steenhorst
- Division of Experimental Cardiology, Department of Cardiology, Erasmus MC, University Medical Center Rotterdam, PO Box 2040, 3000 CA, Rotterdam, The Netherlands
| | - Oana Sorop
- Division of Experimental Cardiology, Department of Cardiology, Erasmus MC, University Medical Center Rotterdam, PO Box 2040, 3000 CA, Rotterdam, The Netherlands
| | - Ruben W A van Drie
- Division of Experimental Cardiology, Department of Cardiology, Erasmus MC, University Medical Center Rotterdam, PO Box 2040, 3000 CA, Rotterdam, The Netherlands
| | - Piotr A Wielopolski
- Department of Radiology and Nuclear Medicine, Erasmus MC, University Medical Center Rotterdam, Rotterdam, The Netherlands
| | - Alex Kleinjan
- Department of Pulmonary Medicine, Erasmus MC, University Medical Center Rotterdam, Rotterdam, The Netherlands
| | - Alexander Hirsch
- Department of Radiology and Nuclear Medicine, Erasmus MC, University Medical Center Rotterdam, Rotterdam, The Netherlands
- Department of Cardiology, Erasmus MC, University Medical Center Rotterdam, Rotterdam, The Netherlands
| | - Dirk J Duncker
- Division of Experimental Cardiology, Department of Cardiology, Erasmus MC, University Medical Center Rotterdam, PO Box 2040, 3000 CA, Rotterdam, The Netherlands
| | - Daphne Merkus
- Division of Experimental Cardiology, Department of Cardiology, Erasmus MC, University Medical Center Rotterdam, PO Box 2040, 3000 CA, Rotterdam, The Netherlands.
- Institute for Surgical Research, Walter Brendel Center of Experimental Medicine (WBex), University Clinic Munich, LMU Munich, Munich, Germany.
- German Center for Cardiovascular Research, Partner Site Munich, Munich Heart Alliance, Munich, Germany.
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Mukherjee D, Konduri GG. Pediatric Pulmonary Hypertension: Definitions, Mechanisms, Diagnosis, and Treatment. Compr Physiol 2021; 11:2135-2190. [PMID: 34190343 PMCID: PMC8289457 DOI: 10.1002/cphy.c200023] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
Abstract
Pediatric pulmonary hypertension (PPH) is a multifactorial disease with diverse etiologies and presenting features. Pulmonary hypertension (PH), defined as elevated pulmonary artery pressure, is the presenting feature for several pulmonary vascular diseases. It is often a hidden component of other lung diseases, such as cystic fibrosis and bronchopulmonary dysplasia. Alterations in lung development and genetic conditions are an important contributor to pediatric pulmonary hypertensive disease, which is a distinct entity from adult PH. Many of the causes of pediatric PH have prenatal onset with altered lung development due to maternal and fetal conditions. Since lung growth is altered in several conditions that lead to PPH, therapy for PPH includes both pulmonary vasodilators and strategies to restore lung growth. These strategies include optimal alveolar recruitment, maintaining physiologic blood gas tension, nutritional support, and addressing contributing factors, such as airway disease and gastroesophageal reflux. The outcome for infants and children with PH is highly variable and largely dependent on the underlying cause. The best outcomes are for neonates with persistent pulmonary hypertension (PPHN) and reversible lung diseases, while some genetic conditions such as alveolar capillary dysplasia are lethal. © 2021 American Physiological Society. Compr Physiol 11:2135-2190, 2021.
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Affiliation(s)
- Devashis Mukherjee
- Division of Neonatology, Department of Pediatrics, Medical College of Wisconsin, Children’s Research Institute, Children’s Wisconsin, Milwaukee, Wisconsin, 53226 USA
| | - Girija G. Konduri
- Division of Neonatology, Department of Pediatrics, Medical College of Wisconsin, Children’s Research Institute, Children’s Wisconsin, Milwaukee, Wisconsin, 53226 USA
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10
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Ozen G, Aljesri K, Celik Z, Turkyılmaz G, Turkyılmaz S, Teskin O, Norel X, Topal G. Mechanism of thromboxane receptor-induced vasoconstriction in human saphenous vein. Prostaglandins Other Lipid Mediat 2020; 151:106476. [PMID: 32721526 DOI: 10.1016/j.prostaglandins.2020.106476] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/29/2020] [Revised: 06/29/2020] [Accepted: 07/16/2020] [Indexed: 12/18/2022]
Abstract
Saphenous vein (SV) is one of the most widely used graft material in patients undergoing coronary artery bypass graft surgery (CABG). Thromboxane A2 (TXA2) is implicated in graft failure by inducing vasoconstriction and platelet aggregation. The aim of this study is to investigate the mechanism involved in TXA2-induced vasoconstriction in human SV. The role of different inhibitors and blockers on U46619 (TXA2-mimetic)-induced vasoconstriction is investigated by using an isolated organ bath system. Relaxation responses to several mediators are evaluated in SV pre-contracted with U46619 and compared with those pre-contracted with phenylephrine. Our results demonstrate that U46619-induced contraction is completely blocked by myosin light chain kinase inhibitor ML-9 or TP receptor antagonist BAY u3405. Furthermore, U46619-induced contraction is partially inhibited by phospholipase C inhibitor U73122, protein kinase C inhibitor calphostin C, Rho-kinase inhibitor Y-27632, L-type calcium channel blocker nifedipine, store-operated channel inhibitor SKF96365 or removal of extracellular calcium. Relaxation responses to NO donor (sodium nitroprusside), guanylate cyclase (GC) stimulator (riociguat), phosphodiesterase (PDE) inhibitors (sildenafil, IBMX), adenylate cyclase (AC) activator (forskolin) and acetylcholine (ACh) are markedly reduced when U46619 is used as a pre-contraction agent. Our results demonstrate that influx of extracellular Ca2+ (through L-type calcium channels and store-operated calcium channels) and intracellular Ca2+ release together with Ca2+ sensitization (through Rho-kinase activation) are necessary components for TXA2-induced vasoconstriction in SV. Moreover, more pronounced decrease in vasorelaxation induced by several mediators (SNP, riociguat, sildenafil, IBMX, forskolin, and ACh) in the presence of U46619 when compared with phenylephrine suggests that there is a crosstalk between the TP receptor signaling pathway and PDE, AC, GC enzymes. We believe that the investigation of mechanism of the TXA2-induced vasoconstriction in SV will provide additional information for the prevention of SV graft failure.
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Affiliation(s)
- Gulsev Ozen
- Department of Pharmacology, Faculty of Pharmacy, Istanbul University, Istanbul 34116, Turkey.
| | - Khadija Aljesri
- Department of Pharmacology, Faculty of Pharmacy, Istanbul University, Istanbul 34116, Turkey
| | - Zeynep Celik
- Department of Pharmacology, Faculty of Pharmacy, Istanbul University, Istanbul 34116, Turkey
| | - Gulsum Turkyılmaz
- Department of Cardiovascular Surgery, Bakirkoy Dr Sadi Konuk Education and Research Hospital Bakırkoy, Istanbul, Turkey
| | - Saygın Turkyılmaz
- Department of Cardiovascular Surgery, Bakirkoy Dr Sadi Konuk Education and Research Hospital Bakırkoy, Istanbul, Turkey
| | - Onder Teskin
- Department of Cardiovascular Surgery, Biruni University, Istanbul, Turkey
| | - Xavier Norel
- Université de Paris, INSERM, UMR-S 1148, CHU X. Bichat, 75018 Paris, France
| | - Gokce Topal
- Department of Pharmacology, Faculty of Pharmacy, Istanbul University, Istanbul 34116, Turkey
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Li B, Ming Y, Liu Y, Xing H, Fu R, Li Z, Ni R, Li L, Duan D, Xu J, Li C, Xiang M, Song H, Chen J. Recent Developments in Pharmacological Effect, Mechanism and Application Prospect of Diazeniumdiolates. Front Pharmacol 2020; 11:923. [PMID: 32655397 PMCID: PMC7324472 DOI: 10.3389/fphar.2020.00923] [Citation(s) in RCA: 24] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/19/2020] [Accepted: 06/08/2020] [Indexed: 12/20/2022] Open
Abstract
Nitric oxide (NO) is a simple structured and unstable free radical molecule, which participates in the regulation of many pathophysiological processes. It functions both as a second messenger and as an endogenous neurotransmitter. Diazeniumdiolates (NONOates) are a series of compounds containing the functional parent nuclear structure of [N(O)NO]-, which are the most widely studied NO donors. NONOates are unstable and easy to release NO in physiological conditions. The biomedical applications and drug development of NO donor have attracted the scientists' attention in recent years. In this review, recent advances in NONOates research are highlighted in terms of chemical structures, molecular characteristics, pharmacological effects, and biomedical application prospects.
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Affiliation(s)
| | | | | | | | | | | | | | | | | | | | | | | | | | - Jianhong Chen
- Department of Pharmacy, Daping Hospital, Army Medical University, Chongqing, China
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12
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Luo E, Wang D, Yan G, Qiao Y, Zhu B, Liu B, Hou J, Tang C. The NF-κB/miR-425-5p/MCT4 axis: A novel insight into diabetes-induced endothelial dysfunction. Mol Cell Endocrinol 2020; 500:110641. [PMID: 31711985 DOI: 10.1016/j.mce.2019.110641] [Citation(s) in RCA: 24] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/21/2019] [Revised: 11/05/2019] [Accepted: 11/06/2019] [Indexed: 12/21/2022]
Abstract
Endothelial cells (ECs) primarily rely on glycolysis for their energy metabolism, and the final product of glycolysis-lactate-is transferred out of cells via monocarboxylate transporter 4 (MCT4). We previously showed that MCT4 downregulation is involved in diabetic endothelial injury. However, the underlying regulatory mechanisms of MCT4 in diabetes remain unclear. This study showed that miR-425-5p was significantly upregulated in diabetic patients and human umbilical vein endothelial cells (HUVECs) treated with high glucose (HG) and interleukin-1β (IL-1β). MCT4 was shown to be a direct target gene of miR-425-5p, and miR-425-5p expression led to MCT4 downregulation, lactate accumulation and increased apoptosis in HUVECs. Furthermore, the results indicated that NF-κB signaling activation increased miR-425-5p levels and induced MCT4 downregulation, lactate accumulation and apoptosis in HUVECs. In conclusion, NF-κB/miR-425-5p/MCT4 axis activation plays a crucial role in the EC injury induced by HG and IL-1β.
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Affiliation(s)
- Erfei Luo
- School of Medicine, Southeast University, Nanjing, 210009, China.
| | - Dong Wang
- Department of Cardiology, Zhongda Hospital, Southeast University, Nanjing, 210009, China.
| | - Gaoliang Yan
- Department of Cardiology, Zhongda Hospital, Southeast University, Nanjing, 210009, China.
| | - Yong Qiao
- Department of Cardiology, Zhongda Hospital, Southeast University, Nanjing, 210009, China.
| | - Boqian Zhu
- School of Medicine, Southeast University, Nanjing, 210009, China.
| | - Bo Liu
- School of Medicine, Southeast University, Nanjing, 210009, China.
| | - Jiantong Hou
- School of Medicine, Southeast University, Nanjing, 210009, China.
| | - Chengchun Tang
- Department of Cardiology, Zhongda Hospital, Southeast University, Nanjing, 210009, China.
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13
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Teixeira-da-Silva JJ, Nunes-Moreira HS, Silva CO, Lahlou S, Naro F, Xavier FE, Duarte GP. Chronic administration of sildenafil improves endothelial function in spontaneously hypertensive rats by decreasing COX-2 expression and oxidative stress. Life Sci 2019; 225:29-38. [DOI: 10.1016/j.lfs.2019.03.074] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/05/2019] [Revised: 03/20/2019] [Accepted: 03/29/2019] [Indexed: 11/28/2022]
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Knapp M, Tu X, Wu R. Vascular endothelial dysfunction, a major mediator in diabetic cardiomyopathy. Acta Pharmacol Sin 2019; 40:1-8. [PMID: 29867137 PMCID: PMC6318313 DOI: 10.1038/s41401-018-0042-6] [Citation(s) in RCA: 206] [Impact Index Per Article: 34.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/03/2018] [Accepted: 04/06/2018] [Indexed: 12/23/2022]
Abstract
Diabetes mellitus is currently a major public health problem. A common complication of diabetes is cardiac dysfunction, which is recognized as a microvascular disease that leads to morbidity and mortality in diabetic patients. While ischemic events are commonly observed in diabetic patients, the risk for developing heart failure is also increased, independent of the severity of coronary artery disease and hypertension. This diabetes-associated clinical entity is considered a distinct disease process referred to as "diabetic cardiomyopathy". However, it is not clear how diabetes promotes cardiac dysfunction. Vascular endothelial dysfunction is thought to be one of the key risk factors. The impact of diabetes on the endothelium involves several alterations, including hyperglycemia, fatty acid oxidation, reduced nitric oxide (NO), oxidative stress, inflammatory activation, and altered barrier function. The current review provides an update on mechanisms that specifically target endothelial dysfunction, which may lead to diabetic cardiomyopathy.
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Affiliation(s)
- Maura Knapp
- Department of Medicine, Section of Cardiology, University of Chicago, Chicago, USA
| | - Xin Tu
- Department of Medicine, Section of Cardiology, University of Chicago, Chicago, USA
| | - Rongxue Wu
- Department of Medicine, Section of Cardiology, University of Chicago, Chicago, USA.
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15
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Su JB. Vascular endothelial dysfunction and pharmacological treatment. World J Cardiol 2015; 7:719-741. [PMID: 26635921 PMCID: PMC4660468 DOI: 10.4330/wjc.v7.i11.719] [Citation(s) in RCA: 127] [Impact Index Per Article: 12.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/05/2015] [Revised: 06/23/2015] [Accepted: 09/18/2015] [Indexed: 02/06/2023] Open
Abstract
The endothelium exerts multiple actions involving regulation of vascular permeability and tone, coagulation and fibrinolysis, inflammatory and immunological reactions and cell growth. Alterations of one or more such actions may cause vascular endothelial dysfunction. Different risk factors such as hypercholesterolemia, homocystinemia, hyperglycemia, hypertension, smoking, inflammation, and aging contribute to the development of endothelial dysfunction. Mechanisms underlying endothelial dysfunction are multiple, including impaired endothelium-derived vasodilators, enhanced endothelium-derived vasoconstrictors, over production of reactive oxygen species and reactive nitrogen species, activation of inflammatory and immune reactions, and imbalance of coagulation and fibrinolysis. Endothelial dysfunction occurs in many cardiovascular diseases, which involves different mechanisms, depending on specific risk factors affecting the disease. Among these mechanisms, a reduction in nitric oxide (NO) bioavailability plays a central role in the development of endothelial dysfunction because NO exerts diverse physiological actions, including vasodilation, anti-inflammation, antiplatelet, antiproliferation and antimigration. Experimental and clinical studies have demonstrated that a variety of currently used or investigational drugs, such as angiotensin-converting enzyme inhibitors, angiotensin AT1 receptors blockers, angiotensin-(1-7), antioxidants, beta-blockers, calcium channel blockers, endothelial NO synthase enhancers, phosphodiesterase 5 inhibitors, sphingosine-1-phosphate and statins, exert endothelial protective effects. Due to the difference in mechanisms of action, these drugs need to be used according to specific mechanisms underlying endothelial dysfunction of the disease.
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16
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Dani C, Poggi C. The role of genetic polymorphisms in antioxidant enzymes and potential antioxidant therapies in neonatal lung disease. Antioxid Redox Signal 2014; 21:1863-80. [PMID: 24382101 PMCID: PMC4203110 DOI: 10.1089/ars.2013.5811] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/12/2022]
Abstract
SIGNIFICANCE Oxidative stress is involved in the development of newborn lung diseases, such as bronchopulmonary dysplasia and persistent pulmonary hypertension of the newborn. The activity of antioxidant enzymes (AOEs), which is impaired as a result of prematurity and oxidative injury, may be further affected by specific genetic polymorphisms or an unfavorable combination of more of them. RECENT ADVANCES Genetic polymorphisms of superoxide dismutase and catalase were recently demonstrated to be protective or risk factors for the main complications of prematurity. A lot of research focused on the potential of different antioxidant strategies in the prevention and treatment of lung diseases of the newborn, providing promising results in experimental models. CRITICAL ISSUES The effect of different genetic polymorphisms on protein synthesis and activity has been poorly detailed in the newborn, hindering to derive conclusive results from the observed associations with adverse outcomes. Therapeutic strategies that aimed at enhancing the activity of AOEs were poorly studied in clinical settings and partially failed to produce clinical benefits. FUTURE DIRECTIONS The clarification of the effects of genetic polymorphisms on the proteomics of the newborn is mandatory, as well as the assessment of a larger number of polymorphisms with a possible correlation with adverse outcome. Moreover, antioxidant treatments should be carefully translated to clinical settings, after further details on optimal doses, administration techniques, and adverse effects are provided. Finally, the study of genetic polymorphisms could help select a specific high-risk population, who may particularly benefit from targeted antioxidant strategies.
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Affiliation(s)
- Carlo Dani
- Section of Neonatology, Department of Neurosciences, Psychology, Drug Research and Child Health, Careggi University Hospital , Florence, Italy
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17
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Brandes RP, Weissmann N, Schröder K. Redox-mediated signal transduction by cardiovascular Nox NADPH oxidases. J Mol Cell Cardiol 2014; 73:70-9. [PMID: 24560815 DOI: 10.1016/j.yjmcc.2014.02.006] [Citation(s) in RCA: 71] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/02/2014] [Revised: 02/06/2014] [Accepted: 02/07/2014] [Indexed: 11/30/2022]
Abstract
The only known function of the Nox family of NADPH oxidases is the production of reactive oxygen species (ROS). Some Nox enzymes show high tissue-specific expression and the ROS locally produced are required for synthesis of hormones or tissue components. In the cardiovascular system, Nox enzymes are low abundant and function as redox-modulators. By reacting with thiols, nitric oxide (NO) or trace metals, Nox-derived ROS elicit a plethora of cellular responses required for physiological growth factor signaling and the induction and adaptation to pathological processes. The interactions of Nox-derived ROS with signaling elements in the cardiovascular system are highly diverse and will be detailed in this article, which is part of a Special Issue entitled "Redox Signalling in the Cardiovascular System".
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Affiliation(s)
- Ralf P Brandes
- Institut für Kardiovaskuläre Physiologie, Goethe-Universität Frankfurt, Germany.
| | - Norbert Weissmann
- Giessen University Lung Center, Justus-Liebig-Universität, Gießen, Germany
| | - Katrin Schröder
- Institut für Kardiovaskuläre Physiologie, Goethe-Universität Frankfurt, Germany
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18
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Ellinsworth DC, Shukla N, Fleming I, Jeremy JY. Interactions between thromboxane A₂, thromboxane/prostaglandin (TP) receptors, and endothelium-derived hyperpolarization. Cardiovasc Res 2014; 102:9-16. [PMID: 24469536 DOI: 10.1093/cvr/cvu015] [Citation(s) in RCA: 54] [Impact Index Per Article: 4.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/15/2022] Open
Abstract
Endothelium-dependent smooth muscle hyperpolarization (EDH) increasingly predominates over endothelium-derived nitric oxide (NO) as a participant in vasodilation as vessel size decreases. Its underlying nature is highly variable between vessel types, species, disease states, and exact experimental conditions, and is variably mediated by one or more transferable endothelium-derived hyperpolarizing factors and/or the electrotonic spread of endothelial hyperpolarization into the media via gap junctions. Although generally regarded (and studied) as a mechanism that is independent of NO and prostanoids, evidence has emerged that the endothelium-derived contracting factor and prostanoid thromboxane A2 can modulate several signalling components central to EDH, and therefore potentially curtail vasodilation through mechanisms that are distinct from those putatively involved in direct smooth muscle contraction. Notably, vascular production of thromboxane A2 is elevated in a number of cardiovascular disease states that promote endothelial dysfunction. This review will therefore discuss the mechanisms through which thromboxane A2 interacts with and modulates EDH, and will also consider the implications of such cross-talk in vasodilator control in health and disease.
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Affiliation(s)
- David C Ellinsworth
- Bristol Heart Institute, University of Bristol, Queens Building Level 7, Upper Maudlin St, Bristol Royal Infirmary, Upper Maudlin Street, Bristol BS2 8HW, UK
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19
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New roles for old pathways? A circuitous relationship between reactive oxygen species and cyclo-oxygenase in hypertension. Clin Sci (Lond) 2013; 126:111-21. [PMID: 24059588 DOI: 10.1042/cs20120651] [Citation(s) in RCA: 65] [Impact Index Per Article: 5.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
Elevated production of prostanoids from the constitutive (COX-1) or inducible (COX-2) cyclo-oxygenases has been involved in the alterations in vascular function, structure and mechanical properties observed in cardiovascular diseases, including hypertension. In addition, it is well known that production of ROS (reactive oxygen species) plays an important role in the impaired contractile and vasodilator responses, vascular remodelling and altered vascular mechanics of hypertension. Of particular interest is the cross-talk between NADPH oxidase and mitochondria, the main ROS sources in hypertension, which may represent a vicious feed-forward cycle of ROS production. In recent years, there is experimental evidence showing a relationship between ROS and COX-derived products. Thus ROS can activate COX and the COX/PG (prostaglandin) synthase pathways can induce ROS production through effects on different ROS generating enzymes. Additionally, recent evidence suggests that the COX-ROS axis might constitute a vicious circle of self-perpetuating vasoactive products that have a pathophysiological role in altered vascular contractile and dilator responses and hypertension development. The present review discusses the current knowledge on the role of oxidative stress and COX-derived prostanoids in the vascular alterations observed in hypertension, highlighting new findings indicating that these two pathways act in concert to induce vascular dysfunction.
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20
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Chen T, Song D, Shan G, Wang K, Wang Y, Ma J, Zhong Y. The association between diabetes mellitus and nonarteritic anterior ischemic optic neuropathy: a systematic review and meta-analysis. PLoS One 2013; 8:e76653. [PMID: 24098798 PMCID: PMC3786911 DOI: 10.1371/journal.pone.0076653] [Citation(s) in RCA: 40] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/06/2013] [Accepted: 08/25/2013] [Indexed: 11/20/2022] Open
Abstract
Background The association of diabetes mellitus (DM) with nonarteritic anterior ischemic optic neuropathy (NAION) has been inconclusive. Purpose To determine whether DM is associated with an increased risk of NAION. Methods A comprehensive literature search was performed for published studies reporting both DM and NAION based on PubMed and EMBASE. After reviewing characteristics of all the included studies systematically, meta-analytical method was employed to calculate the pooled odds ratio (OR) and associated 95% confidence interval (CI) from random-effects models. Heterogeneity was assessed by Q-statistic test. Funnel Plot, Begg's and Egger's linear regression test were applied to evaluate publication bias. A sensitivity analysis and meta-regression analysis were also performed to assess the robustness of results. Results 2,096 participants from 12 case-control studies were pooled for a meta-analysis. The result of meta-analysis of these studies indicated that DM is associated with increased risk of NAION (pooled OR = 1.64, 95% CI = 1.17–2.30; P = 0.004). Sensitivity analysis indicated our findings are robust, and meta-regression analysis revealed no significant effect in terms of geographical area, gender, age of patients with NAION, the year of the publication, source of the controls, and sample size (all p>0.05). Evidence of publication bias was not observed in our study. Conclusion Meta-analysis suggests that DM might be associated with increased risk of NAION.
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Affiliation(s)
- Ting Chen
- Department of Ophthalmology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Delu Song
- Scheie Eye Institute, University of Pennsylvania Perelman School of Medicine, Philadelphia, Pennsylvania, United States of America
| | - Guangliang Shan
- Department of Epidemiology and Statistics, Institute of Basic Medical Science, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Ke Wang
- Department of Epidemiology and Statistics, Institute of Basic Medical Science, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Yiwei Wang
- Department of Ophthalmology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Jin Ma
- Department of Ophthalmology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
- * E-mail: (JM); (YZ)
| | - Yong Zhong
- Department of Ophthalmology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
- * E-mail: (JM); (YZ)
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21
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Low nanomolar thapsigargin inhibits the replication of vascular smooth muscle cells through reversible endoplasmic reticular stress. Eur J Pharmacol 2013; 714:210-7. [PMID: 23751510 DOI: 10.1016/j.ejphar.2013.05.036] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/07/2013] [Revised: 05/13/2013] [Accepted: 05/29/2013] [Indexed: 01/23/2023]
Abstract
Thapsigargin (TG), an inhibitor of Ca(2+) ATPase pumps in the endoplasmic reticulum (ER), inhibits replication of human vascular smooth muscle cell (hVSMC) at low nM concentrations. TG blocks replication of other cell types through promotion of ER stress (ERS). In order to determine whether ERS may mediate the cytostatic effect of TG in hVSMCs, the effect of TG on ERS in hVSMCs was studied by assessing markers of ERS: Immunoglobulin Heavy Chain Binding Protein (BiP), growth inhibitory transcription factor, GADD153, phosphorlylated eukaryotic initiation factor 2α (p-eIF2α) and phosphorlylated protein kinase R (p-PKR). hVSMCs derived from saphenous veins were rendered quiescent with serum-free medium for 96 h incubated with 10 nM TG at 37 °C for 24 h, then washed free of TG and incubated with 10% foetal calf serum (FCS) for a further 24 h. At selected times, BiP, GADD153, p-eIF2α, p-PKR and cyclin D1 expression was assessed. TG promoted a marked increase in BiP and GADD153, but suppressed cyclin D1 mRNA and protein expression. Under serum-free conditions p-eIF2α and p-PKR expression was not enhanced by TG. 15-24 h After removal of TG all these factors returned to levels seen in control cells. These data demonstrate that the inhibitory effect of 10nM TG on hVSMC replication is mediated through induction of ERS and associated factors that cessate replication and is reversible. These observations have implications in the aetiology and treatment of diseases that include atherogenesis, vein graft failure and restenosis.
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22
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Radovits T, Arif R, Bömicke T, Korkmaz S, Barnucz E, Karck M, Merkely B, Szabó G. Vascular dysfunction induced by hypochlorite is improved by the selective phosphodiesterase-5-inhibitor vardenafil. Eur J Pharmacol 2013; 710:110-9. [PMID: 23623933 DOI: 10.1016/j.ejphar.2013.04.012] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/24/2012] [Revised: 04/10/2013] [Accepted: 04/12/2013] [Indexed: 11/27/2022]
Abstract
Reactive oxygen species, such as hypochlorite induce oxidative stress, which impairs nitric oxide (NO)-cyclic guanosine monophosphate (cGMP) signalling and leads to vascular dysfunction. It has been proposed, that elevated cGMP-levels may contribute to an effective cytoprotection against oxidative stress. We investigated the effects of vardenafil, a selective inhibitor of the cGMP-degrading phosphodiesterase-5 enzyme on vascular dysfunction induced by hypochlorite. In organ bath experiments for isometric tension, we investigated the endothelium-dependent and endothelium-independent vasorelaxation of isolated rat aortic rings using cumulative concentrations of acetylcholine and sodium nitroprusside (SNP). Vascular dysfunction was induced by exposing rings to hypochlorite (100-400 µM). In the treatment groups, rats were pretreated with vardenafil (30 and 300 µg/kg i.v.). Immunohistochemical analysis was performed for the oxidative stress markers nitrotyrosine, poly(ADP-ribose) and for apoptosis inducing factor (AIF). Exposure to hypochlorite resulted in a marked impairment of acetylcholine-induced endothelium-dependent vasorelaxation of aortic rings. Pretreatment with vardenafil led to improved endothelial function as reflected by the higher maximal vasorelaxation (Rmax) to acetylcholine. Regarding endothelium-independent vasorelaxation, hypochlorite exposure led to a left-shift of SNP concentration-response curves in the vardenafil groups without any alterations of the Rmax. In the hypochlorite groups immunohistochemical analysis showed enhanced poly(ADP-ribose)-formation and nuclear translocation of AIF, which were prevented by vardenafil-pretreatment. Our results support the view that cytoprotective effects of PDE-5-inhibitors on the endothelium may underlie the improved endothelial function, however, a slight sensitisation of vascular smooth muscle to NO was also confirmed. PDE-5-inhibition may represent a potential therapy approach for treating vascular dysfunction induced by oxidative stress.
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Affiliation(s)
- Tamás Radovits
- Department of Cardiac Surgery, University of Heidelberg, 2. OG. INF 326, 69120 Heidelberg, Germany.
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23
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Farrow KN, Lee KJ, Perez M, Schriewer JM, Wedgwood S, Lakshminrusimha S, Smith CL, Steinhorn RH, Schumacker PT. Brief hyperoxia increases mitochondrial oxidation and increases phosphodiesterase 5 activity in fetal pulmonary artery smooth muscle cells. Antioxid Redox Signal 2012; 17:460-70. [PMID: 22229392 PMCID: PMC3365357 DOI: 10.1089/ars.2011.4184] [Citation(s) in RCA: 49] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
AIMS Oxygen is a pulmonary vasodilator, but data suggest high O(2) concentrations impede that response. We previously reported 24 h of 100% O(2) increased phosphodiesterase 5 (PDE5) activity in fetal pulmonary artery smooth muscle cells (FPASMC) and in ventilated neonatal lambs. PDE5 degrades cyclic GMP (cGMP) and inhibits nitric oxide (NO)-mediated cGMP-dependent vasorelaxation. We sought to determine the mechanism by which hyperoxia initiates reactive oxygen species (ROS) production and regulates PDE5. RESULTS Thirty minutes of hyperoxia increased mitochondrial ROS versus normoxia (30.3±1.7% vs. 21.1±2.8%), but had no effect on cytosolic ROS, measured by roGFP, a ratiometric protein thiol redox sensor. Hyperoxia increased PDE5 activity (220±39%) and decreased cGMP responsiveness to NO (37±17%). Mitochondrial catalase overexpression attenuated hyperoxia-induced mitochondrial roGFP oxidation, compared to FPASMC infected with empty adenoviral vector (50±3% of control) or mitochondrial superoxide dismutase. MitoTEMPO, mitochondrial catalase, and DT-3, a cGMP-dependent protein kinase I alpha inhibitor, decreased PDE5 activity (32±13%, 26±21%, and 63±10% of control, respectively), and restored cGMP responsiveness to NO (147±16%,172±29%, and 189±43% of control, respectively). C57Bl6 mice exposed to 90%-100% O(2) for 45 min±mechanical ventilation had increased PA PDE5 activity (206±39% and 235±75%, respectively). INNOVATION This is the first description that hyperoxia induces ROS in the mitochondrial matrix prior to the cytosol. Our results indicate that short hyperoxia exposures can produce significant changes in critical cellular signaling pathways. CONCLUSIONS These results indicate that mitochondrial matrix oxidant signals generated during hyperoxia, specifically H(2)O(2), activate PDE5 in a cGMP-dependent protein kinase-dependent manner in pulmonary vascular smooth muscle cells.
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Affiliation(s)
- Kathryn N Farrow
- Department of Pediatrics, Northwestern University, Chicago, IL 60611, USA.
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24
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Muzaffar S, Jeremy JY, Angelini GD, Shukla N. NADPH oxidase 4 mediates upregulation of type 4 phosphodiesterases in human endothelial cells. J Cell Physiol 2012; 227:1941-50. [PMID: 21732365 DOI: 10.1002/jcp.22922] [Citation(s) in RCA: 26] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/29/2022]
Abstract
The protective actions of prostacyclin (PGI(2) ) are mediated by cyclic AMP (cAMP) which is reduced by type 4 phosphodiesterases (PDE4) which hydrolyze cAMP. Superoxide (O2(-)) from NADPH oxidase (Nox) is associated with impaired PGI(2) bioactivity. The objective of this study, therefore, was to study the relationship between Nox and PDE4 expression in human umbilical vein endothelial cells (HUVECs). HUVECs were incubated with the thromboxane A(2) analog, U46619, 8-isoprostane F(2α) (8IP), or tumor necrosing factor alpha (TNFα) [±iloprost (a PGI(2) analog)] and the expression of PDE4A, B, C, and D and splice variants thereof assessed using Western blotting and qPCR and mRNA silencing of Nox4 and Nox5. Effects on cell replication and angiogenesis were also studied. U46619, 8IP, and TNFα increased the expression of Nox 4 and Nox 5 and all PDE4 isoforms as well as cell replication and tubule formation (index of angiogenesis), effects inhibited by mRNA silencing of Nox4 (but not Nox5) and iloprost and rolipram. These data demonstrate that upregulation of Nox4 leads to an upregulation of PDE4A, B, and D and increased hydrolysis of cAMP which in turn augments cell replication and angiogenesis. This mechanism may be central to vasculopathies associated with endothelial dysfunction since the PGI(2)-cAMP signaling axis plays a key role in mediating functions that include hemostasis and angiogenesis.
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Affiliation(s)
- Saima Muzaffar
- Bristol Heart Institute, University of Bristol, Bristol, UK
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25
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Oxidative stress and vein graft failure: a focus on NADH oxidase, nitric oxide and eicosanoids. Curr Opin Pharmacol 2012; 12:160-5. [DOI: 10.1016/j.coph.2012.01.005] [Citation(s) in RCA: 25] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/26/2011] [Revised: 01/06/2012] [Accepted: 01/09/2012] [Indexed: 11/17/2022]
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Endothelin-1 (ET-1) and vein graft failure and the therapeutic potential of ET-1 receptor antagonists. Pharmacol Res 2011; 63:483-9. [DOI: 10.1016/j.phrs.2010.10.018] [Citation(s) in RCA: 13] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/15/2010] [Revised: 10/27/2010] [Accepted: 10/29/2010] [Indexed: 12/21/2022]
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27
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Markoula S, Giannopoulos S, Asproudis I, Kostoulas C, Nikas A, Bagli E, Kyritsis AP, Georgiou I. Renin-angiotensin-aldosterone system genes and nonarteritic anterior ischemic optic neuropathy. Mol Vis 2011; 17:1254-60. [PMID: 21633717 PMCID: PMC3103746] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/12/2010] [Accepted: 05/03/2011] [Indexed: 11/16/2022] Open
Abstract
PURPOSE Recent literature suggests a genetic component for non-arteritic anterior ischemic optic neuropathy (NAION). We examined the association of the insertion/deletion (I/D) polymorphism of the angiotensin-converting enzyme gene, of the M235T polymorphism of the angiotensinogen gene, and of the A1166C polymorphism of the angiotensin II type 1 receptor gene with NAION. METHODS Forty-seven patients with NAION and 76 controls, age- and gender-matched, were recruited and genotyped for renin-angiotensin-aldosterone system (RAAS) genes. Genotypes were determined by polymerase chain reaction and restriction enzyme analysis. NAION and control groups were compared in regard to the prevalence of renin-angiotensin-aldosterone system polymorphisms, and further stratified by age and gender. RESULTS NAION occurrence was not associated with the M235T polymorphism of the angiotensinogen gene and the A1166C polymorphism of the angiotensin II, type 1 receptor gene. Regarding the angiotensin-converting enzyme insertion/deletion polymorphism, our findings suggest that the II genotype could be a risk factor for NAION in younger male patients when compared to all cases and controls (p=0.033, odds ratio=5.71, confidence interval=1.152¨C28.35 and p=0.03, odds ratio=5.33, confidence interval=1.17¨C24.31 respectively). Furthermore I allele was present in all male patients younger than 55 years, making this allele a likely predisposing factor for NAION in young males. CONCLUSIONS Since NAION may occur when compromised watershed microcirculation is combined with insufficient autoregulation of systematic circulation, polymorphisms of genes involved in systematic circulation, such as the RAAS genes, may be associated with NAION occurrence. Large-scale, multicentered, controlled prospective studies are needed to further explore the effects of RAAS polymorphisms or other genetic factors on NAION susceptibility.
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Affiliation(s)
- Sofia Markoula
- Department of Neurology, University of Ioannina School of Medicine, Ioannina, Greece
| | - Sotirios Giannopoulos
- Department of Neurology, University of Ioannina School of Medicine, Ioannina, Greece
| | - Ioannis Asproudis
- Department of Ophthalmology, University of Ioannina School of Medicine, Ioannina, Greece
| | - Charilaos Kostoulas
- Laboratory of Medical Genetics, University Hospital of Ioannina, Ioannina, Greece
| | - Alexios Nikas
- Department of Ophthalmology, University of Ioannina School of Medicine, Ioannina, Greece
| | - Eleni Bagli
- Department of Ophthalmology, University of Ioannina School of Medicine, Ioannina, Greece
| | | | - Ioannis Georgiou
- Laboratory of Medical Genetics, University Hospital of Ioannina, Ioannina, Greece
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Muzaffar S, Shukla N, Massey Y, Angelini GD, Jeremy JY. NADPH oxidase 1 mediates upregulation of thromboxane A2 synthase in human vascular smooth muscle cells: Inhibition with iloprost. Eur J Pharmacol 2011; 658:187-92. [DOI: 10.1016/j.ejphar.2011.02.020] [Citation(s) in RCA: 20] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/18/2010] [Revised: 01/24/2011] [Accepted: 02/05/2011] [Indexed: 10/18/2022]
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Francis SH, Blount MA, Corbin JD. Mammalian Cyclic Nucleotide Phosphodiesterases: Molecular Mechanisms and Physiological Functions. Physiol Rev 2011; 91:651-90. [DOI: 10.1152/physrev.00030.2010] [Citation(s) in RCA: 451] [Impact Index Per Article: 32.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/20/2022] Open
Abstract
The superfamily of cyclic nucleotide (cN) phosphodiesterases (PDEs) is comprised of 11 families of enzymes. PDEs break down cAMP and/or cGMP and are major determinants of cellular cN levels and, consequently, the actions of cN-signaling pathways. PDEs exhibit a range of catalytic efficiencies for breakdown of cAMP and/or cGMP and are regulated by myriad processes including phosphorylation, cN binding to allosteric GAF domains, changes in expression levels, interaction with regulatory or anchoring proteins, and reversible translocation among subcellular compartments. Selective PDE inhibitors are currently in clinical use for treatment of erectile dysfunction, pulmonary hypertension, intermittent claudication, and chronic pulmonary obstructive disease; many new inhibitors are being developed for treatment of these and other maladies. Recently reported x-ray crystallographic structures have defined features that provide for specificity for cAMP or cGMP in PDE catalytic sites or their GAF domains, as well as mechanisms involved in catalysis, oligomerization, autoinhibition, and interactions with inhibitors. In addition, major advances have been made in understanding the physiological impact and the biochemical basis for selective localization and/or recruitment of specific PDE isoenzymes to particular subcellular compartments. The many recent advances in understanding PDE structures, functions, and physiological actions are discussed in this review.
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Affiliation(s)
- Sharron H. Francis
- Department of Molecular Physiology and Biophysics, Vanderbilt University School of Medicine, Nashville, Tennessee; and Department of Medicine-Renal Division, Emory University School of Medicine, Atlanta, Georgia
| | - Mitsi A. Blount
- Department of Molecular Physiology and Biophysics, Vanderbilt University School of Medicine, Nashville, Tennessee; and Department of Medicine-Renal Division, Emory University School of Medicine, Atlanta, Georgia
| | - Jackie D. Corbin
- Department of Molecular Physiology and Biophysics, Vanderbilt University School of Medicine, Nashville, Tennessee; and Department of Medicine-Renal Division, Emory University School of Medicine, Atlanta, Georgia
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Murray F, Maclean MR, Insel PA. Role of phosphodiesterases in adult-onset pulmonary arterial hypertension. Handb Exp Pharmacol 2011:279-305. [PMID: 21695645 DOI: 10.1007/978-3-642-17969-3_12] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 05/30/2023]
Abstract
Pulmonary arterial hypertension (PAH) is characterized by increased mean pulmonary artery pressure (mPAP) due to vasoconstriction and structural changes in the small pulmonary arteries (PAs); proliferation of pulmonary artery smooth muscle cells (PASMCs) contributes to the remodeling. The abnormal pathophysiology in the pulmonary vasculature relates to decreased cyclic nucleotide levels in PASMCs. Phosphodiesterases (PDEs) catalyze the hydrolysis of cAMP and cGMP, thereby PDE inhibitors are effective in vasodilating the PA and decreasing PASMC proliferation. Experimental studies support the use of PDE3, PDE5, and PDE1 inhibitors in PAH. PDE5 inhibitors such as sildenafil are clinically approved to treat different forms of PAH and lower mPAP, increase functional capacity, and decrease right ventricular hypertrophy, without decreasing systemic arterial pressure. New evidence suggests that the combination of PDE inhibitors with other therapies for PAH may be beneficial in treating the disease. Furthermore, inhibiting PDEs in the heart and the inflammatory cells that infiltrate the PA may offer new targets to reduce right ventricular hypertrophy and inhibit inflammation that is associated with and contributes to the development of PAH. This chapter summarizes the advances in the area and the future of PDEs in PAH.
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Affiliation(s)
- F Murray
- Department of Pharmacology and Department of Medicine, BSB 3073, University of California, 9500 Gilman Drive, La Jolla, San Diego, CA 92093-0636, USA.
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Endothelial nitric oxide synthase polymorphism (G894T) and nonarteritic anterior ischemic optic neuropathy. Vis Neurosci 2010; 27:183-5. [PMID: 21073768 DOI: 10.1017/s0952523810000350] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/06/2022]
Abstract
Nonarteritic anterior ischemic optic neuropathy (NAION) is associated with vascular risk factors and a genetic predisposition for NAION. In this study, we examined the potential association of endothelial nitric oxide synthase (eNOS) G894T polymorphism with NAION. For this, 45 patients (29 men and 16 women) and 193 controls (122 men and 71 women) were enrolled prospectively and genotyped for eNOS genes. Genotypes were determined by polymerase chain reaction and restriction enzyme analysis. The prevalence of eNOS polymorphisms was estimated in NAION patients and controls. Genotype frequencies were estimated with chi-square test, and odds ratios were calculated. We found that eNOS G894T polymorphism is not associated with NAION occurrence as the genotype and allele frequencies were not significantly different between the control and patient groups (TT vs. GG + GT: P = 0.646 and T vs. G: P = 0.86). The precise mechanism of NAION occurrence has not been elucidated yet; since NAION may occur when a compromised watershed microcirculation is combined with insufficient autoregulation of systematic circulation, other alterations in the eNOS gene or polymorphism of genes involved in systematic circulation may be associated with NAION occurrence.
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Farrow KN, Wedgwood S, Lee KJ, Czech L, Gugino SF, Lakshminrusimha S, Schumacker PT, Steinhorn RH. Mitochondrial oxidant stress increases PDE5 activity in persistent pulmonary hypertension of the newborn. Respir Physiol Neurobiol 2010; 174:272-81. [PMID: 20804862 DOI: 10.1016/j.resp.2010.08.018] [Citation(s) in RCA: 56] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/29/2010] [Revised: 08/21/2010] [Accepted: 08/23/2010] [Indexed: 12/29/2022]
Abstract
In the pulmonary vasculature, phosphodiesterase-5 (PDE5) degrades cGMP and inhibits nitric oxide-mediated, cGMP-dependent vasorelaxation. We previously reported that ventilation with 100% O2 increased PDE5 activity in pulmonary arteries (PAs) of pulmonary hypertension lambs (PPHN) more than in control lambs. In the present study, PA smooth muscle cells (PASMCs) from PPHN lambs had increased basal PDE5 activity, decreased cGMP-responsiveness to NO, and increased mitochondrial matrix oxidant stress compared to control PASMC. Hyperoxia (24 h) increased PDE5 activity and mitochondrial matrix oxidant stress above baseline to a similar degree in PPHN and control PASMC. Mitochondrially targeted catalase decreased PDE5 activity at baseline and after hyperoxia in PPHN PASMC. Similarly, catalase treatment of PPHN lambs ventilated with 100% O2 decreased PDE5 activity and increased cGMP in PA. We conclude that baseline PDE5 activity and oxidative stress is increased in PPHN PASMC, and scavenging H2O2 is sufficient to block oxidant-mediated increases in PDE5 activity in PPHN.
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Affiliation(s)
- Kathryn N Farrow
- Department of Pediatrics, Northwestern University, Chicago, IL 60611, United States.
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Francis SH, Busch JL, Corbin JD, Sibley D. cGMP-dependent protein kinases and cGMP phosphodiesterases in nitric oxide and cGMP action. Pharmacol Rev 2010; 62:525-63. [PMID: 20716671 PMCID: PMC2964902 DOI: 10.1124/pr.110.002907] [Citation(s) in RCA: 733] [Impact Index Per Article: 48.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
To date, studies suggest that biological signaling by nitric oxide (NO) is primarily mediated by cGMP, which is synthesized by NO-activated guanylyl cyclases and broken down by cyclic nucleotide phosphodiesterases (PDEs). Effects of cGMP occur through three main groups of cellular targets: cGMP-dependent protein kinases (PKGs), cGMP-gated cation channels, and PDEs. cGMP binding activates PKG, which phosphorylates serines and threonines on many cellular proteins, frequently resulting in changes in activity or function, subcellular localization, or regulatory features. The proteins that are so modified by PKG commonly regulate calcium homeostasis, calcium sensitivity of cellular proteins, platelet activation and adhesion, smooth muscle contraction, cardiac function, gene expression, feedback of the NO-signaling pathway, and other processes. Current therapies that have successfully targeted the NO-signaling pathway include nitrovasodilators (nitroglycerin), PDE5 inhibitors [sildenafil (Viagra and Revatio), vardenafil (Levitra), and tadalafil (Cialis and Adcirca)] for treatment of a number of vascular diseases including angina pectoris, erectile dysfunction, and pulmonary hypertension; the PDE3 inhibitors [cilostazol (Pletal) and milrinone (Primacor)] are used for treatment of intermittent claudication and acute heart failure, respectively. Potential for use of these medications in the treatment of other maladies continues to emerge.
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Affiliation(s)
- Sharron H Francis
- Department of Molecular Physiology & Biophysics, Vanderbilt University School of Medicine, 2215 Garland Avenue, Nashville, TN 37232-0615, USA.
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Farrow KN, Lakshminrusimha S, Czech L, Groh BS, Gugino SF, Davis JM, Russell JA, Steinhorn RH. SOD and inhaled nitric oxide normalize phosphodiesterase 5 expression and activity in neonatal lambs with persistent pulmonary hypertension. Am J Physiol Lung Cell Mol Physiol 2010; 299:L109-16. [PMID: 20400523 DOI: 10.1152/ajplung.00309.2009] [Citation(s) in RCA: 58] [Impact Index Per Article: 3.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/22/2022] Open
Abstract
Phosphodiesterase 5 (PDE5) and soluble guanylate cyclase (sGC) are key regulators of cGMP and pulmonary vascular tone. We sought to determine the impact of mechanical ventilation with O(2) with or without inhaled nitric oxide (iNO) or recombinant human Cu/Zn SOD (rhSOD) on sGC, PDE5, and cGMP in the ovine ductal ligation model of persistent pulmonary hypertension of the newborn (PPHN). PPHN lambs were ventilated with 100% O(2) for 24 h alone or combined with either inhalation of 20 parts per million (ppm) iNO continuously or a single intratracheal dose of rhSOD (5 mg/kg). Ventilated PPHN lambs were compared with PPHN fetuses, control fetuses, and 1-day-old spontaneously breathing lambs (1DSB). In the small pulmonary arteries of 1DSB lambs, sGC expression increased, PDE5 expression decreased, and cGMP concentrations increased relative to fetal levels. In PPHN lambs ventilated with 100% O(2), sGC activity increased to levels comparable with 1DSB levels. However, PDE5 expression and activity increased, and cGMP levels remained at fetal levels. Addition of either iNO or rhSOD decreased PDE5 expression and activity in PPHN lambs and increased cGMP levels to levels comparable with 1DSB lambs. These data suggest that ventilation of PPHN lambs with 100% O(2) impairs cGMP-mediated vasodilation in part due to increased PDE5 expression and activity. The addition of either iNO or rhSOD normalized PDE5 and cGMP levels. Thus therapies designed to decrease PDE5 and increase cGMP, such as iNO and rhSOD, may prove useful in the treatment of PPHN in newborn infants.
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Affiliation(s)
- Kathryn N Farrow
- Dept. of Pediatrics, Northwestern Univ. Feinberg School of Medicine, 310 E. Superior St., Morton 4-685D, Chicago, IL 60611, USA.
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Milara J, Juan G, Ortiz JL, Guijarro R, Losada M, Serrano A, Morcillo EJ, Cortijo J. Cigarette smoke-induced pulmonary endothelial dysfunction is partially suppressed by sildenafil. Eur J Pharm Sci 2010; 39:363-72. [PMID: 20093183 DOI: 10.1016/j.ejps.2010.01.005] [Citation(s) in RCA: 20] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/07/2009] [Accepted: 01/11/2010] [Indexed: 01/28/2023]
Abstract
Cigarette smoke mediated oxidative stress and endothelial dysfunction are important processes in the pathogenesis of several lung disorders. In this study we evaluated the effect of PDE5 inhibition on pulmonary artery endothelial dysfunction induced by cigarette smoke in vitro. Human pulmonary artery endothelial cells (HPAEC) were incubated in the absence or presence of PDE5 inhibitor sildenafil (10 nM-1 microM), PKG agonist 8-Br-cGMP (1mM), or the antioxidants dyphenyleneiodonium (DPI 1 microM) and N-acetylcysteine (NAC 1mM) for 30 min. Then, cigarette smoke extract (CSE) was added for 24h. CSE (2.5-10%)-induced ROS generation was suppressed by DPI, and partially reversed by sildenafil and 8-Br-cGMP. Decreases in intracellular levels of cGMP and extracellular NO induced by CSE were reversed by sildenafil and DPI. Furthermore, CSE-induced pg91(phox) and PDE5 mRNA overexpression were suppressed by both sildenafil and DPI. CSE (2.5-10%) induced upregulation of IL-6, IL-8 and Ang-2, and decreased Ang-1 expression in parallel to apoptosis which were partially suppressed by sildenafil, 8-Br-cGMP, DPI and NAC. This study demonstrates that PDE5 inhibition attenuates the oxidant burden and the inflammatory and remodeling effects of CSE in human HPAEC which may contribute to the therapeutic value of PDE5 inhibitors for pulmonary disorders coursing with endothelial dysfunction.
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Affiliation(s)
- Javier Milara
- Research Unit, University General Hospital Consortium, Valencia, Spain.
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Ziolkowski N, Grover AK. Functional linkage as a direction for studies in oxidative stress: α-adrenergic receptorsThis review is one of a selection of papers published in a Special Issue on Oxidative Stress in Health and Disease. Can J Physiol Pharmacol 2010; 88:220-32. [PMID: 20393587 DOI: 10.1139/y10-013] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/25/2023]
Abstract
The α-adrenergic receptors (adrenoceptors) are activated by the endogenous agonists epinephrine and norepinephrine. They are G protein-coupled receptors that may be broadly classified into α1 (subclasses α1A, α1B, α1D) and α2 (subclasses α2A, α2B, α2C). The α1-adrenoceptors act by binding to Gαq subunits of the G proteins, causing activation of phospholipase C (PLC). PLC converts phosphatidylinositol 4,5-bisphosphate into inositol trisphosphate (IP3) and diacylglycerol (DAG), which have downstream effects on cytosolic Ca2+ concentration. The α2-adrenoceptors bind to Gαi thus inhibiting adenylyl cyclase and decreasing cAMP levels. DAG alters protein kinase C activity and cAMP activates protein kinase A. The downstream pathways of the two receptors may also interact. Activation of α1- and α2-adrenoceptors in vascular smooth muscle results in vasoconstriction. However, the densities of individual receptor subclasses vary between vessel beds or between vessels of various sizes within the same bed. In vasculature, the densities of adrenoceptor subclasses differ between conduit arteries and arterioles. These differences, along with differences in coupling mechanisms, allow for fine regulation of arterial blood flow. This diversity is enhanced by interactions resulting from homo- and heterodimer formation of the receptors, metabolic pathways, and kinases. Reactive oxygen species generated in pathologies may alter α1- and α2-adrenoceptor cascades, change vascular contractility, or cause remodeling of blood vessels. This review emphasizes the need for understanding the functional linkage between α-adrenoceptor subtypes, coupling, cross talk, and oxidative stress in cardiovascular pathologies.
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Affiliation(s)
- Natalia Ziolkowski
- Departments of Medicine and Biology, McMaster University, 1200 Main Street West, Hamilton, ON L8N 3Z5, Canada
| | - Ashok K. Grover
- Departments of Medicine and Biology, McMaster University, 1200 Main Street West, Hamilton, ON L8N 3Z5, Canada
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Taibi G, Carruba G, Miceli V, Cocciadiferro L, Cucchiara A, Nicotra CMA. Sildenafil protects epithelial cell through the inhibition of xanthine oxidase and the impairment of ROS production. Free Radic Res 2010; 44:232-239. [PMID: 19968586 DOI: 10.3109/10715760903431426] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/05/2023]
Abstract
Xanthine oxidase (XO) plays an important role in various forms of ischemic and vascular injuries, inflammatory diseases and chronic heart failure. The XO inhibitors allopurinol and oxypurinol held considerable promise in the treatment of these conditions both in experimental animals and in human clinical trials. More recently, an endothelium-based protective effect of sildenafil has been reported in preconditioning prior to ischemia/reperfusion in healthy human subjects. Based on the structural similarities between allopurinol and oxypurinol with sildenafil and with zaprinast the authors have investigated the potential effects of these latter compounds on the buttermilk XO and on non-tumourigenic (HMEC) and malignant (MCF7) human mammary epithelial cells. Both sildenafil and zaprinast induced a significant and consistent decrease of XO expression and activity in either cell line. In MCF7 cells only, this effect was associated with the abrogation of xanthine-induced cytotoxicity. Overall, the data suggest that the protective effect of sildenafil on epithelial cells is a consequence of the inhibition of the XO and of the resulting decrease of free oxygen radical production that may influence the expression of NADPH oxidase and PDE-5.
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Affiliation(s)
- Gennaro Taibi
- Dipartimento di Oncologia Sperimentale e Applicazioni Cliniche, Sezione di Biochimica e Oncologia Clinica, AOUP Paolo Giaccone', Università di Palermo, Via Del Vespro 129, 90127 Palermo, Italy.
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Tazzeo T, Worek F, Janssen L. The NADPH oxidase inhibitor diphenyleneiodonium is also a potent inhibitor of cholinesterases and the internal Ca(2+) pump. Br J Pharmacol 2009; 158:790-6. [PMID: 19788497 DOI: 10.1111/j.1476-5381.2009.00394.x] [Citation(s) in RCA: 33] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/27/2022] Open
Abstract
BACKGROUND AND PURPOSE Diphenyleneiodonium (DPI) is often used as an NADPH oxidase inhibitor, but is increasingly being found to have unrelated side effects. We investigated its effects on smooth muscle contractions and the related mechanisms. EXPERIMENTAL APPROACH We studied isometric contractions in smooth muscle strips from bovine trachea. Cholinesterase activity was measured using a spectrophotometric assay; internal Ca(2+) pump activity was assessed by Ca(2+) uptake into smooth muscle microsomes. KEY RESULTS Contractions to acetylcholine were markedly enhanced by DPI (10(-4) M), whereas those to carbachol (CCh) were not, suggesting a possible inhibition of cholinesterase. DPI markedly suppressed contractions evoked by CCh, KCl and 5-HT, and also unmasked phasic activity in otherwise sustained responses. Direct biochemical assays confirmed that DPI was a potent inhibitor of acetylcholinesterase and butyrylcholinesterase (IC(50) approximately 8 x 10(-6) M and 6 x 10(-7) M, respectively), following a readily reversible, mixed non-competitive type of inhibition. The inhibitory effects of DPI on CCh contractions were not mimicked by another NADPH oxidase inhibitor (apocynin), nor the Src inhibitors PP1 or PP2, ruling out an action through the NADPH oxidase signalling pathway. Several features of the DPI-mediated suppression of agonist-evoked responses (i.e. suppression of peak magnitudes and unmasking of phasic activity) are similar to those of cyclopiazonic acid, an inhibitor of the internal Ca(2+) pump. Direct measurement of microsomal Ca(2+) uptake revealed that DPI modestly inhibits the internal Ca(2+) pump. CONCLUSIONS AND IMPLICATIONS DPI inhibits cholinesterase activity and the internal Ca(2+) pump in tracheal smooth muscle.
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Affiliation(s)
- T Tazzeo
- Firestone Institute for Respiratory Health, St. Joseph's Hospital, Hamilton, Ontario, Canada
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Abstract
INTRODUCTION Penile detumescence depends on the hydrolysis of cyclic guanosine monophosphate (cGMP) by phosphodiesterase type 5 (PDE5). It is hoped that a review of publications relevant to the regulation of PDE5 in the penis will be helpful to both scientists and clinicians who are interested in the sciences of erectile function/dysfunction. AIMS The aim of this article is to comprehensively review the mechanisms by which PDE5 activity and expression in the penis are regulated. All published studies relevant to PDE5 regulation in the penis or penile cells will be reviewed. METHODS Entrez (PubMed) was used to search for publications relevant to the topics of this review. Keywords used in the searches included vascular, cavernous, penis, smooth muscle, signaling molecules, erection, priapism, and PDE5. Articles that are dedicated to the study of erectile function/dysfunction were prioritized for citation. RESULTS Regulation of PDE5 can occur at both protein and gene levels. At protein level, PDE5 is activated by phosphorylation and/or allosteric cGMP binding. Deactivation is carried out by protein phosphatase 1 and thus linked to the Rho-kinase signaling pathway. Cleavage of PDE5 into an inactive form has been shown as carried out by caspase-3. At the gene level, PDE5 expression is regulated at two alternative promoters, PDE5A and PDE5A2, both of which are positively regulated by cyclic adenosine monophosphate and cGMP. Downregulation of PDE5 has been observed in the penis of castrated animals; however, proof of androgen regulation of PDE5 gene requires examination of the smooth muscle content. Hyperoxia and hypoxia, respectively, regulate PDE5 expression positively and negatively. Hypoxic downregulation of PDE5 is a possible mechanism for the development of priapism. CONCLUSIONS PDE5 can be regulated at protein and gene levels. In the penis, changes of PDE5 activity have been linked to its phosphorylation status, and downregulation of PDE5 expression has been associated with hypoxia.
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Affiliation(s)
- Ching-Shwun Lin
- Knuppe Molecular Urology Laboratory, University of California, Department of Urology, San Francisco, CA 94115, USA.
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