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Parichatikanond W, Duangrat R, Nuamnaichati N, Mangmool S. Role of A 1 adenosine receptor in cardiovascular diseases: Bridging molecular mechanisms with therapeutic opportunities. Exp Mol Pathol 2025; 141:104952. [PMID: 39879680 DOI: 10.1016/j.yexmp.2025.104952] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/28/2024] [Revised: 01/12/2025] [Accepted: 01/20/2025] [Indexed: 01/31/2025]
Abstract
Adenosine serves as a critical homeostatic regulator, exerting influence over physiological and pathological conditions in the cardiovascular system. During cellular stress, increased extracellular adenosine levels have been implicated in conferring cardioprotective effects through the activation of adenosine receptors with the A1 adenosine receptor subtype showing the highest expression in the heart. A1 adenosine receptor stimulation inhibits adenylyl cyclase activity via heterotrimeric Gi proteins, leading to the activation of distinct downstream effectors involved in cardiovascular homeostasis. While the comprehensive characterization of the pharmacological functions and intracellular signaling pathways associated with the A1 adenosine receptor subtype is still ongoing, this receptor is widely recognized as a crucial pharmacological target for the treatment of various states of cardiovascular diseases (CVDs). In this review, we focus on elucidating signal transduction of A1 adenosine receptor, particularly Gi protein-dependent and -independent pathways, and their relevance to cardiovascular protective effects as well as pathological consequences during cellular and tissue stresses in the cardiovascular system. Additionally, we provide comprehensive updates and detailed insights into a range of A1 adenosine receptor agonists and antagonists, detailing their development and evaluation through preclinical and clinical studies with a specific focus on their potential for the management of CVDs, especially heart diseases.
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Affiliation(s)
| | - Ratchanee Duangrat
- Department of Pharmacology, Faculty of Science, Mahidol University, Bangkok 10400, Thailand
| | - Narawat Nuamnaichati
- Department of Pharmacology, Faculty of Medicine, Srinakharinwirot University, Bangkok 10110, Thailand
| | - Supachoke Mangmool
- Department of Pharmaceutical Care, Faculty of Pharmacy, Chiang Mai University, Chiang Mai 50200, Thailand.
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2
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Nguyen ATN, Tran QL, Baltos JA, McNeill SM, Nguyen DTN, May LT. Small molecule allosteric modulation of the adenosine A 1 receptor. Front Endocrinol (Lausanne) 2023; 14:1184360. [PMID: 37435481 PMCID: PMC10331460 DOI: 10.3389/fendo.2023.1184360] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/11/2023] [Accepted: 05/23/2023] [Indexed: 07/13/2023] Open
Abstract
G protein-coupled receptors (GPCRs) represent the target for approximately a third of FDA-approved small molecule drugs. The adenosine A1 receptor (A1R), one of four adenosine GPCR subtypes, has important (patho)physiological roles in humans. A1R has well-established roles in the regulation of the cardiovascular and nervous systems, where it has been identified as a potential therapeutic target for a number of conditions, including cardiac ischemia-reperfusion injury, cognition, epilepsy, and neuropathic pain. A1R small molecule drugs, typically orthosteric ligands, have undergone clinical trials. To date, none have progressed into the clinic, predominantly due to dose-limiting unwanted effects. The development of A1R allosteric modulators that target a topographically distinct binding site represent a promising approach to overcome current limitations. Pharmacological parameters of allosteric ligands, including affinity, efficacy and cooperativity, can be optimized to regulate A1R activity with high subtype, spatial and temporal selectivity. This review aims to offer insights into the A1R as a potential therapeutic target and highlight recent advances in the structural understanding of A1R allosteric modulation.
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Affiliation(s)
- Anh T. N. Nguyen
- Drug Discovery Biology, Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, VIC, Australia
| | - Quan L. Tran
- Drug Discovery Biology, Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, VIC, Australia
| | - Jo-Anne Baltos
- Drug Discovery Biology, Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, VIC, Australia
| | - Samantha M. McNeill
- Drug Discovery Biology, Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, VIC, Australia
| | - Diep T. N. Nguyen
- Department of Information Technology, Faculty of Engineering and Technology, Vietnam National University, Hanoi, Vietnam
| | - Lauren T. May
- Drug Discovery Biology, Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, VIC, Australia
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Zhuang Y, Yu ML, Lu SF. Purinergic signaling in myocardial ischemia-reperfusion injury. Purinergic Signal 2023; 19:229-243. [PMID: 35254594 PMCID: PMC9984618 DOI: 10.1007/s11302-022-09856-4] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/02/2021] [Accepted: 02/18/2022] [Indexed: 10/18/2022] Open
Abstract
Purines and their derivatives, extensively distributed in the body, act as a class of extracellular signaling molecules via a rich array of receptors, also known as purinoceptors (P1, P2X, and P2Y). They mediate multiple intracellular signal transduction pathways and participate in various physiological and pathological cell behaviors. Since the function in myocardial ischemia-reperfusion injury (MIRI), this review summarized the involvement of purinergic signal transduction in diversified pathological processes, including energy metabolism disorder, oxidative stress injury, calcium overload, inflammatory immune response, platelet aggregation, coronary vascular dysfunction, and cell necrosis and apoptosis. Moreover, increasing evidence suggests that purinergic signaling also mediates the prevention and treatment of MIRI, such as ischemic conditioning, pharmacological intervention, and some other therapies. In conclusion, this review exhibited that purinergic signaling mediates the complex processes of MIRI which shows its promising application and prospecting in the future.
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Affiliation(s)
- Yi Zhuang
- College of Acupuncture and Tuina, Nanjing University of Chinese Medicine, 138 Xian-lin Avenue, Qixia District, Nanjing, 210023, Jiangsu Province, China
| | - Mei-Ling Yu
- College of Acupuncture and Tuina, Nanjing University of Chinese Medicine, 138 Xian-lin Avenue, Qixia District, Nanjing, 210023, Jiangsu Province, China
| | - Sheng-Feng Lu
- College of Acupuncture and Tuina, Nanjing University of Chinese Medicine, 138 Xian-lin Avenue, Qixia District, Nanjing, 210023, Jiangsu Province, China. .,Key Laboratory of Acupuncture and Medicine Research of Ministry of Education, Nanjing University of Chinese Medicine, Nanjing, 210023, China.
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Xia Y, He F, Moukeila Yacouba MB, Zhou H, Li J, Xiong Y, Zhang J, Li H, Wang Y, Ke J. Adenosine A2a Receptor Regulates Autophagy Flux and Apoptosis to Alleviate Ischemia-Reperfusion Injury via the cAMP/PKA Signaling Pathway. Front Cardiovasc Med 2022; 9:755619. [PMID: 35571159 PMCID: PMC9099415 DOI: 10.3389/fcvm.2022.755619] [Citation(s) in RCA: 12] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/09/2021] [Accepted: 03/23/2022] [Indexed: 12/12/2022] Open
Abstract
Exploring effective methods to lessen myocardial ischemia-reperfusion injury still has positive significance. The adenosine A2a receptor (A2aR) has played a crucial part in cardiac ischemia-reperfusion injury. Previous studies revealed that the adenosine A2a receptor regulated autophagy, but the specific mechanism in myocardial ischemia-reperfusion injury was still unclear. We established an ischemia-reperfusion model (30 min of ischemia and 2 h of reperfusion) in vivo and a model with oxygen-glucose deprivation for 6 h and reoxygenation for 18 h (OGDR) in vitro. The ischemia-reperfusion injury resulted in prolonged QTc interval, left ventricular systolic dysfunction, and myocardial infarction. In vitro model, we found that the OGDR-induced autophagosomes and apoptosis caused myocardial cell death, as evidenced by a significant increase in the generation of lactate dehydrogenase and creatine kinase-MB. Furthermore, overactivated autophagy with rapamycin showed an anti-apoptotic effect. The interaction between autophagy and apoptosis in myocardial ischemia-reperfusion injury was complex and variable. We discovered that the activation of adenosine A2a receptor could promote the expression of Bcl-2 to inhibit the levels of Beclin-1 and LC3II. The number of autophagosomes exceeded that of autolysosomes under OGDR, but the result reversed after A2aR activation. Activated A2aR with its agonist CGS21680 before reperfusion saved cellular survival through anti-apoptosis and anti-autophagy effect, thus improving ventricular contraction disorders, and visibly reducing myocardial infarction size. The myocardial protection of adenosine A2a receptor after ischemia may involve the cAMP-PKA signaling pathway and the interaction of Bcl-2-Beclin-1.
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Cardoso AM, Silvério MNO, de Oliveira Maciel SFV. Purinergic signaling as a new mechanism underlying physical exercise benefits: a narrative review. Purinergic Signal 2021; 17:649-679. [PMID: 34590239 PMCID: PMC8677870 DOI: 10.1007/s11302-021-09816-4] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/08/2021] [Accepted: 07/21/2021] [Indexed: 11/27/2022] Open
Abstract
In the last years, it has become evident that both acute and chronic physical exercise trigger responses/adaptations in the purinergic signaling and these adaptations can be considered one important mechanism related to the exercise benefits for health improvement. Purinergic system is composed of enzymes (ectonucleotidases), receptors (P1 and P2 families), and molecules (ATP, ADP, adenosine) that are able to activate these receptors. These components are widely distributed in almost all cell types, and they respond/act in a specific manner depending on the exercise types and/or intensities as well as the cell type (organ/tissue analyzed). For example, while acute intense exercise can be associated with tissue damage, inflammation, and platelet aggregation, chronic exercise exerts anti-inflammatory and anti-aggregant effects, promoting health and/or treating diseases. All of these effects are dependent on the purinergic signaling. Thus, this review was designed to cover the aspects related to the relationship between physical exercise and purinergic signaling, with emphasis on the modulation of ectonucleotidases and receptors. Here, we discuss the impact of different exercise protocols as well as the differences between acute and chronic effects of exercise on the extracellular signaling exerted by purinergic system components. We also reinforce the concept that purinergic signaling must be understood/considered as a mechanism by which exercise exerts its effects.
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Affiliation(s)
- Andréia Machado Cardoso
- Graduate Program in Biomedical Sciences and Medicine Course, Federal University of Fronteira Sul - UFFS, Campus Chapecó, Rodovia SC 484 - Km 02, Fronteira Sul, 89815-899, Brazil.
- Graduate Program in Physical Education, Federal University of Santa Maria (UFSM), Santa Maria, RS, Brazil.
| | - Mauro Nicollas Oliveira Silvério
- Medicine Course, Federal University of Fronteira Sul - UFFS, Campus Chapecó, Rodovia SC 484 - Km 02, Fronteira Sul, 89815-899, Brazil
| | - Sarah Franco Vieira de Oliveira Maciel
- Graduate Program in Biomedical Sciences and Medicine Course, Federal University of Fronteira Sul - UFFS, Campus Chapecó, Rodovia SC 484 - Km 02, Fronteira Sul, 89815-899, Brazil
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Torregroza C, Glashoerster CO, Feige K, Stroethoff M, Raupach A, Heinen A, Hollmann MW, Huhn R. Mediation of the Cardioprotective Effects of Mannitol Discovered, with Refutation of Common Protein Kinases. Int J Mol Sci 2021; 22:ijms222212471. [PMID: 34830353 PMCID: PMC8625521 DOI: 10.3390/ijms222212471] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/29/2021] [Revised: 11/13/2021] [Accepted: 11/16/2021] [Indexed: 02/04/2023] Open
Abstract
The osmodiuretic agent Mannitol exerts cardioprotection against ischemia and reperfusion (I/R) injury when applied as a pre- and/or postconditioning stimulus. Previously, we demonstrated that these properties are mediated via the activation of mitochondrial ATP-sensitive potassium (mKATP) channels. However, considering Mannitol remains in the extracellular compartment, the question arises as to which receptor and intracellular signaling cascades are involved in myocardial protection by the osmodiuretic substance. Protein kinase B (Akt) and G (PKG), as part of the reperfusion injury salvage kinase (RISK) and/or endothelial nitric oxide (eNOS)/PKG pathway, are two well-investigated intracellular targets conferring myocardial protection upstream of mitochondrial potassium channels. Adenosine receptor subtypes have been shown to trigger different cardioprotective pathways, for example, the reperfusion injury. Further, Mannitol induces an increased activation of the adenosine 1 receptor (A1R) in renal cells conferring its nephroprotective properties. Therefore, we investigated whether (1) Akt and PKG are possible signaling targets involved in Mannitol-induced conditioning upstream of the mKATP channel and/or whether (2) cardioprotection by Mannitol is mediated via activation of the A1R. All experiments were performed on male Wistar rats in vitro employing the Langendorff isolated heart perfusion technique with infarct size determination as the primary endpoint. To unravel possible protein kinase activation, Mannitol was applied in combination with the Akt (MK2206) or PKG (KT5823) inhibitor. In further groups, an A1R blocker (DPCPX) was given with or without Mannitol. Preconditioning with Mannitol (Man) significantly reduced the infarct size compared to the control group. Co-administration of the A1R blocker DPXPC fully abolished myocardial protection of Mannitol. Interestingly and in contrast to the initial hypothesis, neither administration of the Akt nor the PKG blocker had any impact on the cardioprotective properties of Mannitol-induced preconditioning. These results are quite unexpected and show that the protein kinases Akt and PKG—as possible targets of known protective signaling cascades—are not involved in Mannitol-induced preconditioning. However, the cardioprotective effects of Mannitol are mediated via the A1R.
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Affiliation(s)
- Carolin Torregroza
- Department of Anesthesiology, Medical Faculty and University Hospital Duesseldorf, Heinrich-Heine-University Duesseldorf, Moorenstr. 5, 40225 Duesseldorf, Germany; (C.T.); (C.O.G.); (M.S.); (A.R.); (R.H.)
| | - Chiara O. Glashoerster
- Department of Anesthesiology, Medical Faculty and University Hospital Duesseldorf, Heinrich-Heine-University Duesseldorf, Moorenstr. 5, 40225 Duesseldorf, Germany; (C.T.); (C.O.G.); (M.S.); (A.R.); (R.H.)
| | - Katharina Feige
- Department of Anesthesiology, Medical Faculty and University Hospital Duesseldorf, Heinrich-Heine-University Duesseldorf, Moorenstr. 5, 40225 Duesseldorf, Germany; (C.T.); (C.O.G.); (M.S.); (A.R.); (R.H.)
- Correspondence:
| | - Martin Stroethoff
- Department of Anesthesiology, Medical Faculty and University Hospital Duesseldorf, Heinrich-Heine-University Duesseldorf, Moorenstr. 5, 40225 Duesseldorf, Germany; (C.T.); (C.O.G.); (M.S.); (A.R.); (R.H.)
| | - Annika Raupach
- Department of Anesthesiology, Medical Faculty and University Hospital Duesseldorf, Heinrich-Heine-University Duesseldorf, Moorenstr. 5, 40225 Duesseldorf, Germany; (C.T.); (C.O.G.); (M.S.); (A.R.); (R.H.)
| | - André Heinen
- Institute of Cardiovascular Physiology, Medical Faculty and University Hospital Duesseldorf, Heinrich-Heine-University Duesseldorf, Universitaetsstr. 1, 40225 Duesseldorf, Germany;
| | - Markus W. Hollmann
- Department of Anesthesiology, Amsterdam University Medical Center (AUMC), Location AMC, Meiberdreef 9, 1105 AZ Amsterdam, The Netherlands;
| | - Ragnar Huhn
- Department of Anesthesiology, Medical Faculty and University Hospital Duesseldorf, Heinrich-Heine-University Duesseldorf, Moorenstr. 5, 40225 Duesseldorf, Germany; (C.T.); (C.O.G.); (M.S.); (A.R.); (R.H.)
- Department of Anesthesiology, Kerckhoff-Clinic GmbH, Benekestr. 2-8, 61231 Bad Nauheim, Germany
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Abstract
Nucleosides play central roles in all facets of life, from metabolism to cellular signaling. Because of their physiochemical properties, nucleosides are lipid bilayer impermeable and thus rely on dedicated transport systems to cross biological membranes. In humans, two unrelated protein families mediate nucleoside membrane transport: the concentrative and equilibrative nucleoside transporter families. The objective of this review is to provide a broad outlook on the current status of nucleoside transport research. We will discuss the role played by nucleoside transporters in human health and disease, with emphasis placed on recent structural advancements that have revealed detailed molecular principles of these important cellular transport systems and exploitable pharmacological features.
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Affiliation(s)
- Nicholas J. Wright
- Department of Biochemistry, Duke University Medical Center, 303 Research Drive, Durham, North Carolina, 27710, USA
| | - Seok-Yong Lee
- Department of Biochemistry, Duke University Medical Center, 303 Research Drive, Durham, North Carolina, 27710, USA
- Correspondence and requests for materials should be addressed to: S.-Y. Lee., , tel: 919-684-1005, fax: 919-684-8885
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Paganelli F, Gaudry M, Ruf J, Guieu R. Recent advances in the role of the adenosinergic system in coronary artery disease. Cardiovasc Res 2020; 117:1284-1294. [PMID: 32991685 DOI: 10.1093/cvr/cvaa275] [Citation(s) in RCA: 22] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/06/2020] [Revised: 08/14/2020] [Accepted: 09/15/2020] [Indexed: 12/18/2022] Open
Abstract
Adenosine is an endogenous nucleoside that plays a major role in the physiology and physiopathology of the coronary artery system, mainly by activating its A2A receptors (A2AR). Adenosine is released by myocardial, endothelial, and immune cells during hypoxia, ischaemia, or inflammation, each condition being present in coronary artery disease (CAD). While activation of A2AR improves coronary blood circulation and leads to anti-inflammatory effects, down-regulation of A2AR has many deleterious effects during CAD. A decrease in the level and/or activity of A2AR leads to: (i) lack of vasodilation, which decreases blood flow, leading to a decrease in myocardial oxygenation and tissue hypoxia; (ii) an increase in the immune response, favouring inflammation; and (iii) platelet aggregation, which therefore participates, in part, in the formation of a fibrin-platelet thrombus after the rupture or erosion of the plaque, leading to the occurrence of acute coronary syndrome. Inflammation contributes to the development of atherosclerosis, leading to myocardial ischaemia, which in turn leads to tissue hypoxia. Therefore, a vicious circle is created that maintains and aggravates CAD. In some cases, studying the adenosinergic profile can help assess the severity of CAD. In fact, inducible ischaemia in CAD patients, as assessed by exercise stress test or fractional flow reserve, is associated with the presence of a reserve of A2AR called spare receptors. The purpose of this review is to present emerging experimental evidence supporting the existence of this adaptive adenosinergic response to ischaemia or inflammation in CAD. We believe that we have achieved a breakthrough in the understanding and modelling of spare A2AR, based upon a new concept allowing for a new and non-invasive CAD management.
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Affiliation(s)
- Franck Paganelli
- C2VN, INSERM, INRAE, Aix-Marseille University, Campus Santé Timone, Faculté de Pharmacie, 27 Bd Jean Moulin, F-13005 Marseille, France.,Department of Cardiology, North Hospital, Chemin des Bourrely, F-13015 Marseille, France
| | - Marine Gaudry
- Department of Vascular Surgery, Timone Hospital, 278 Rue Saint Pierre, F-13005 Marseille, France
| | - Jean Ruf
- C2VN, INSERM, INRAE, Aix-Marseille University, Campus Santé Timone, Faculté de Pharmacie, 27 Bd Jean Moulin, F-13005 Marseille, France
| | - Régis Guieu
- C2VN, INSERM, INRAE, Aix-Marseille University, Campus Santé Timone, Faculté de Pharmacie, 27 Bd Jean Moulin, F-13005 Marseille, France.,Laboratory of Biochemistry, Timone Hospital, 278 Rue Saint Pierre, F-13005 Marseille, France
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9
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Adenosine and the Cardiovascular System: The Good and the Bad. J Clin Med 2020; 9:jcm9051366. [PMID: 32384746 PMCID: PMC7290927 DOI: 10.3390/jcm9051366] [Citation(s) in RCA: 67] [Impact Index Per Article: 13.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/05/2020] [Revised: 04/27/2020] [Accepted: 04/29/2020] [Indexed: 12/18/2022] Open
Abstract
Adenosine is a nucleoside that impacts the cardiovascular system via the activation of its membrane receptors, named A1R, A2AR, A2BR and A3R. Adenosine is released during hypoxia, ischemia, beta-adrenergic stimulation or inflammation and impacts heart rhythm and produces strong vasodilation in the systemic, coronary or pulmonary vascular system. This review summarizes the main role of adenosine on the cardiovascular system in several diseases and conditions. Adenosine release participates directly in the pathophysiology of atrial fibrillation and neurohumoral syncope. Adenosine has a key role in the adaptive response in pulmonary hypertension and heart failure, with the most relevant effects being slowing of heart rhythm, coronary vasodilation and decreasing blood pressure. In other conditions, such as altitude or apnea-induced hypoxia, obstructive sleep apnea, or systemic hypertension, the adenosinergic system activation appears in a context of an adaptive response. Due to its short half-life, adenosine allows very rapid adaptation of the cardiovascular system. Finally, the effects of adenosine on the cardiovascular system are sometimes beneficial and other times harmful. Future research should aim to develop modulating agents of adenosine receptors to slow down or conversely amplify the adenosinergic response according to the occurrence of different pathologic conditions.
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Calker D, Biber K, Domschke K, Serchov T. The role of adenosine receptors in mood and anxiety disorders. J Neurochem 2019; 151:11-27. [DOI: 10.1111/jnc.14841] [Citation(s) in RCA: 50] [Impact Index Per Article: 8.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/29/2019] [Revised: 07/15/2019] [Accepted: 07/18/2019] [Indexed: 12/25/2022]
Affiliation(s)
- Dietrich Calker
- Department for Psychiatry and Psychotherapy, Medical Center ‐ University of Freiburg, Faculty of Medicine University of Freiburg Freiburg Germany
| | - Knut Biber
- Section Medical Physiology, Department of Neuroscience University Medical Center Groningen, University of Groningen Groningen The Netherlands
| | - Katharina Domschke
- Department for Psychiatry and Psychotherapy, Medical Center ‐ University of Freiburg, Faculty of Medicine University of Freiburg Freiburg Germany
- Centre for Basics in Neuromodulation, Faculty of Medicine University of Freiburg Freiburg Germany
| | - Tsvetan Serchov
- Department of Stereotactic and Functional Neurosurgery, Faculty of Medicine, Medical Center ‐ University Freiburg University of Freiburg Freiburg Germany
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Bonyanian Z, Walker M, Du Toit E, Rose'Meyer RB. Multiple adenosine receptor subtypes stimulate wound healing in human EA.hy926 endothelial cells. Purinergic Signal 2019; 15:357-366. [PMID: 31254200 DOI: 10.1007/s11302-019-09668-z] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/11/2018] [Accepted: 06/20/2019] [Indexed: 10/26/2022] Open
Abstract
Wound healing is an important outcome of tissue damage and can be stimulated by adenosine released from cells during events such as tissue injury, ischaemia or tumour growth. The aim of this research was to determine the potency and efficacy of adenosine A1, A2A and A2B receptor agonists on the rate of wound healing and cell proliferation in human EA.hy926 endothelial cells. Real-time PCR data showed that only adenosine A1, A2A and A2B receptor mRNA were expressed in this cell line. All three adenosine receptor agonists, CPA, CGS21680 and NECA, significantly increased the rate of wound healing in human EAhy926 endothelial cells with the following order of potency CGS21680>CPA>NECA and efficacy CPA>NECA>CGS21680. The selective adenosine A1, A2A and A2B receptor antagonists, DPCPX, ZM241385 and MRS1754 (all at 10 nM), reversed the effects of their respective agonists. EAhy926 endothelial cell proliferation was also significantly increased with the adenosine A1 and A2B receptor agonists, CPA and NECA. Western blot analysis demonstrated that adenosine A2A and A1 receptor protein levels were highly expressed compared with the adenosine A2B receptors in the EAhy926 endothelial cell lines. While all three adenosine A1, A2A and A2B receptor subtypes contribute to cell proliferation and wound healing in human EAhy926 endothelial cells, treatments selectively targeting receptor subtypes may further enhance wound healing.
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Affiliation(s)
- Zeinab Bonyanian
- School of Medical Sciences, Griffith University, Gold Coast Campus Southport, Queensland, 4122, Australia
| | - Matthew Walker
- School of Medical Sciences, Griffith University, Gold Coast Campus Southport, Queensland, 4122, Australia
| | - Eugene Du Toit
- School of Medical Sciences, Griffith University, Gold Coast Campus Southport, Queensland, 4122, Australia
| | - Roselyn B Rose'Meyer
- School of Medical Sciences, Griffith University, Gold Coast Campus Southport, Queensland, 4122, Australia.
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12
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Structures of human ENT1 in complex with adenosine reuptake inhibitors. Nat Struct Mol Biol 2019; 26:599-606. [PMID: 31235912 PMCID: PMC6705415 DOI: 10.1038/s41594-019-0245-7] [Citation(s) in RCA: 77] [Impact Index Per Article: 12.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/26/2019] [Accepted: 05/08/2019] [Indexed: 02/06/2023]
Abstract
The human Equilibrative Nucleoside Transporter 1 (hENT1), a member of the SLC29 family, plays crucial roles in adenosine signaling, cellular uptake of nucleoside for DNA and RNA synthesis, and nucleoside-derived anticancer and antiviral drug transport in human. Because of its central role in adenosine signaling, it is the target of adenosine reuptake inhibitors (AdoRI), several of which are clinically used. Despite its importance in human physiology and pharmacology, the molecular basis of hENT1-mediated adenosine transport and its inhibition by AdoRIs are limited due to the absence of structural information on hENT1. Here we present crystal structures of hENT1 in complex with two chemically distinct AdoRIs: dilazep and S-(4-Nitrobenzyl)-6-thioinosine (NBMPR). Combined with mutagenesis study, our structural analyses elucidate two distinct inhibitory mechanisms exhibited on hENT1, while giving insight into adenosine recognition and transport. Our studies provide the platform for improved pharmacological intervention of adenosine and nucleoside analog drug transport by hENT1.
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13
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Yadav VR, Teng B, Mustafa SJ. Enhanced A 1 adenosine receptor-induced vascular contractions in mesenteric artery and aorta of in L-NAME mouse model of hypertension. Eur J Pharmacol 2018; 842:111-117. [PMID: 30347181 DOI: 10.1016/j.ejphar.2018.10.024] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/24/2018] [Revised: 10/13/2018] [Accepted: 10/17/2018] [Indexed: 01/28/2023]
Abstract
L-NAME-induced hypertension is commonly used to study endothelial dysfunction and related vascular effects. It has been reported that genetic deletion of A1 adenosine receptor (AR) reduces blood pressure (BP) increases in mice and thus, suggesting the involvement of A1AR. Thus, we sought to determine whether A1AR-induced vascular responses were altered in this mouse model of hypertension. L-NAME (1 mg/ml) was given in the drinking water for 28 days to mice. The BP was monitored using non-invasive tail-cuff system. Muscle tension studies were performed using DMT for mesenteric arteries (MAs) and organ bath for aorta. Protein expression was analyzed by western blot. Significantly, higher systolic and mean arterial blood pressure was noted in L-NAME mice. In MAs, higher 2-Chloro-N6-cyclopentyladenosine (CCPA, selective A1AR agonist) induced contractions in hypertensive mice were observed. This enhanced contraction was inhibited by HET0016 (Cytochrome 450 4A inhibitor, 10 µM, 15 min). Contrary, 5'-(N-Ethylcarboxamido) adenosine (NECA, non-selective AR agonist) induced vascular responses were comparable in both groups. Pinacidil (KATP channel opener) induced relaxation was significantly increased in hypertensive mice. In aorta, CCPA-induced contractions were enhanced and inhibited by HET0016 in hypertensive mice. Notably, NECA-induced contractions in aorta were enhanced in hypertensive mice. Higher expressions of A1AR and Cyp4A were noted in MAs of hypertensive mice. In addition, in aorta, higher A1AR and comparable Cyp4A levels were observed in hypertensive mice. A1AR-induced vascular contractions were enhanced in hypertensive mice aorta and MAs. Cyp4A plays a role in altered vascular responses in MAs.
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Affiliation(s)
- Vishal R Yadav
- Department of Physiology and Pharmacology, West Virginia University, Morgantown, WV, USA
| | - Bunyen Teng
- Coagulation and Blood Research Task Area, US Army Institute of Surgical Research, San Antonio, TX, USA
| | - S Jamal Mustafa
- Department of Physiology and Pharmacology, West Virginia University, Morgantown, WV, USA; Center for Translational Science Institute, West Virginia University, Morgantown, WV, USA.
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14
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Alencar AKN, Montes GC, Barreiro EJ, Sudo RT, Zapata-Sudo G. Adenosine Receptors As Drug Targets for Treatment of Pulmonary Arterial Hypertension. Front Pharmacol 2017; 8:858. [PMID: 29255415 PMCID: PMC5722832 DOI: 10.3389/fphar.2017.00858] [Citation(s) in RCA: 25] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/12/2017] [Accepted: 11/09/2017] [Indexed: 01/05/2023] Open
Abstract
Pulmonary arterial hypertension (PAH) is a clinical condition characterized by pulmonary arterial remodeling and vasoconstriction, which promote chronic vessel obstruction and elevation of pulmonary vascular resistance. Long-term right ventricular (RV) overload leads to RV dysfunction and failure, which are the main determinants of life expectancy in PAH subjects. Therapeutic options for PAH remain limited, despite the introduction of prostacyclin analogs, endothelin receptor antagonists, phosphodiesterase type 5 inhibitors, and soluble guanylyl cyclase stimulators within the last 15 years. Through addressing the pulmonary endothelial and smooth muscle cell dysfunctions associated with PAH, these interventions delay disease progression but do not offer a cure. Emerging approaches to improve treatment efficacy have focused on beneficial actions to both the pulmonary vasculature and myocardium, and several new targets have been investigated and validated in experimental PAH models. Herein, we review the effects of adenosine and adenosine receptors (A1, A2A, A2B, and A3) on the cardiovascular system, focusing on the A2A receptor as a pharmacological target. This receptor induces pulmonary vascular and heart protection in experimental models, specifically models of PAH. Targeting the A2A receptor could potentially serve as a novel and efficient approach for treating PAH and concomitant RV failure. A2A receptor activation induces pulmonary endothelial nitric oxide synthesis, smooth muscle cell hyperpolarization, and vasodilation, with important antiproliferative activities through the inhibition of collagen deposition and vessel wall remodeling in the pulmonary arterioles. The pleiotropic potential of A2A receptor activation is highlighted by its additional expression in the heart tissue, where it participates in the regulation of intracellular calcium handling and maintenance of heart chamber structure and function. In this way, the activation of A2A receptor could prevent the production of a hypertrophic and dysfunctional phenotype in animal models of cardiovascular diseases.
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Affiliation(s)
- Allan K N Alencar
- Programa de Pesquisa em Desenvolvimento de Fármacos, Instituto de Ciências Biomédicas, Universidade Federal do Rio de Janeiro, Rio de Janeiro, Brazil
| | - Guilherme C Montes
- Programa de Pesquisa em Desenvolvimento de Fármacos, Instituto de Ciências Biomédicas, Universidade Federal do Rio de Janeiro, Rio de Janeiro, Brazil
| | - Eliezer J Barreiro
- Programa de Pesquisa em Desenvolvimento de Fármacos, Instituto de Ciências Biomédicas, Universidade Federal do Rio de Janeiro, Rio de Janeiro, Brazil
| | - Roberto T Sudo
- Programa de Pesquisa em Desenvolvimento de Fármacos, Instituto de Ciências Biomédicas, Universidade Federal do Rio de Janeiro, Rio de Janeiro, Brazil
| | - Gisele Zapata-Sudo
- Programa de Pesquisa em Desenvolvimento de Fármacos, Instituto de Ciências Biomédicas, Universidade Federal do Rio de Janeiro, Rio de Janeiro, Brazil
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15
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Zukowska P, Kutryb-Zajac B, Jasztal A, Toczek M, Zabielska M, Borkowski T, Khalpey Z, Smolenski RT, Slominska EM. Deletion of CD73 in mice leads to aortic valve dysfunction. Biochim Biophys Acta Mol Basis Dis 2017; 1863:1464-1472. [PMID: 28192180 DOI: 10.1016/j.bbadis.2017.02.008] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/01/2016] [Revised: 02/06/2017] [Accepted: 02/08/2017] [Indexed: 01/11/2023]
Abstract
Aortic stenosis is known to involve inflammation and thrombosis. Changes in activity of extracellular enzyme - ecto-5'-nucleotidase (referred also as CD73) can alter inflammatory and thrombotic responses. This study aimed to evaluate the effect of CD73 deletion in mice on development of aortic valve dysfunction and to compare it to the effect of high-fat diet. Four groups of mice (normal-diet Wild Type (WT), high-fat diet WT, normal diet CD73-/-, high-fat diet CD73-/-) were maintained for 15weeks followed by echocardiographic analysis of aortic valve function, measurement of aortic surface activities of nucleotide catabolism enzymes as well as alkaline phosphatase activity, mineral composition and histology of aortic valve leaflets. CD73-/- knock out led to an increase in peak aortic flow (1.06±0.26m/s) compared to WT (0.79±0.26m/s) indicating obstruction. Highest values of peak aortic flow (1.26±0.31m/s) were observed in high-fat diet CD73-/- mice. Histological analysis showed morphological changes in CD73-/- including thickening and accumulation of dark deposits, proved to be melanin. Concentrations of Ca2+, Mg2+ and PO43- in valve leaflets were elevated in CD73-/- mice. Alkaline phosphatase (ALP) activity was enhanced after ATP treatment and reduced after adenosine treatment in aortas incubated in osteogenic medium. AMP hydrolysis in CD73-/- was below 10% of WT. Activity of ecto-adenosine deaminase (eADA), responsible for adenosine deamination, in the CD73-/- was 40% lower when compared to WT. Deletion of CD73 in mice leads to aortic valve dysfunction similar to that induced by high-fat diet suggesting important role of this surface protein in maintaining heart valve integrity.
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Affiliation(s)
- P Zukowska
- Department of Biochemistry, Medical University of Gdansk, Poland
| | - B Kutryb-Zajac
- Department of Biochemistry, Medical University of Gdansk, Poland
| | - A Jasztal
- Jagiellonian Center for Experimental Therapeutics, Jagiellonian University, Krakow, Poland
| | - M Toczek
- Department of Biochemistry, Medical University of Gdansk, Poland
| | - M Zabielska
- Department of Biochemistry, Medical University of Gdansk, Poland
| | - T Borkowski
- Department of Biochemistry, Medical University of Gdansk, Poland
| | - Z Khalpey
- Department of Surgery, Division of Cardiothoracic Surgery, University of Arizona, College of Medicine, Tuscon, United States
| | - R T Smolenski
- Department of Biochemistry, Medical University of Gdansk, Poland
| | - E M Slominska
- Department of Biochemistry, Medical University of Gdansk, Poland.
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16
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Oyarzún C, Garrido W, Alarcón S, Yáñez A, Sobrevia L, Quezada C, San Martín R. Adenosine contribution to normal renal physiology and chronic kidney disease. Mol Aspects Med 2017; 55:75-89. [PMID: 28109856 DOI: 10.1016/j.mam.2017.01.004] [Citation(s) in RCA: 25] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/02/2016] [Revised: 01/11/2017] [Accepted: 01/13/2017] [Indexed: 12/12/2022]
Abstract
Adenosine is a nucleoside that is particularly interesting to many scientific and clinical communities as it has important physiological and pathophysiological roles in the kidney. The distribution of adenosine receptors has only recently been elucidated; therefore it is likely that more biological roles of this nucleoside will be unveiled in the near future. Since the discovery of the involvement of adenosine in renal vasoconstriction and regulation of local renin production, further evidence has shown that adenosine signaling is also involved in the tubuloglomerular feedback mechanism, sodium reabsorption and the adaptive response to acute insults, such as ischemia. However, the most interesting finding was the increased adenosine levels in chronic kidney diseases such as diabetic nephropathy and also in non-diabetic animal models of renal fibrosis. When adenosine is chronically increased its signaling via the adenosine receptors may change, switching to a state that induces renal damage and produces phenotypic changes in resident cells. This review discusses the physiological and pathophysiological roles of adenosine and pays special attention to the mechanisms associated with switching homeostatic nucleoside levels to increased adenosine production in kidneys affected by CKD.
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Affiliation(s)
- Carlos Oyarzún
- Institute of Biochemistry and Microbiology, Science Faculty, Universidad Austral de Chile, Valdivia, Chile
| | - Wallys Garrido
- Institute of Biochemistry and Microbiology, Science Faculty, Universidad Austral de Chile, Valdivia, Chile
| | - Sebastián Alarcón
- Institute of Biochemistry and Microbiology, Science Faculty, Universidad Austral de Chile, Valdivia, Chile
| | - Alejandro Yáñez
- Institute of Biochemistry and Microbiology, Science Faculty, Universidad Austral de Chile, Valdivia, Chile
| | - Luis Sobrevia
- Cellular and Molecular Physiology Laboratory (CMPL), Division of Obstetrics and Gynaecology, School of Medicine, Faculty of Medicine, Pontificia Universidad Católica de Chile, Santiago 8330024, Chile; Department of Physiology, Faculty of Pharmacy, Universidad de Sevilla, Seville E-41012, Spain; University of Queensland Centre for Clinical Research (UQCCR), Faculty of Medicine and Biomedical Sciences, University of Queensland, Herston QLD 4029, Queensland, Australia
| | - Claudia Quezada
- Institute of Biochemistry and Microbiology, Science Faculty, Universidad Austral de Chile, Valdivia, Chile
| | - Rody San Martín
- Institute of Biochemistry and Microbiology, Science Faculty, Universidad Austral de Chile, Valdivia, Chile.
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17
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Prasanna G, Li B, Mogi M, Rice DS. Pharmacology of novel intraocular pressure-lowering targets that enhance conventional outflow facility: Pitfalls, promises and what lies ahead? Eur J Pharmacol 2016; 787:47-56. [DOI: 10.1016/j.ejphar.2016.03.003] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/05/2016] [Revised: 02/15/2016] [Accepted: 03/01/2016] [Indexed: 12/18/2022]
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18
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Bravo CA, Vatner DE, Pachon R, Zhang J, Vatner SF. A Food and Drug Administration-Approved Antiviral Agent that Inhibits Adenylyl Cyclase Type 5 Protects the Ischemic Heart Even When Administered after Reperfusion. J Pharmacol Exp Ther 2016; 357:331-6. [PMID: 26941173 PMCID: PMC4851318 DOI: 10.1124/jpet.116.232538] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/28/2016] [Accepted: 02/24/2016] [Indexed: 01/28/2023] Open
Abstract
A Food and Drug Administration-approved antiviral agent, known as vidarabine or adenine 9-β-D-arabinofuranoside (AraA), has features of inhibiting adenylyl cyclase type 5 (AC5) and protects against chronic coronary artery occlusion (CAO). The goal of this investigation was to determine whether AraA protects against myocardial ischemia, even when delivered after coronary artery reperfusion (CAR). AraA, delivered after CAR in wild-type mice, reduced infarct size by 55% compared with vehicle-treated controls, whereas an equal dose of adenosine reduced infarct size only when administered before CAR. A 5-fold greater dose of adenosine was required to reduce infarct size when delivered after CAR, which also reduced arterial pressure by 15%, whereas AraA did not affect pressure. The reduction in infarct size with AraA was prevented by a MEK/extracellular signal-regulated kinase blocker, a pathway also involved in the mechanism of protection of the AC5 knockout (KO) model. Infarct size was also reduced in cardiac-specific AC5 KO mice similarly in the presence and absence of AraA, further suggesting that AraA protection involves the AC5 pathway. AraA reduced infarct size in chronically instrumented conscious pigs when delivered after CAR, and in this model, it also reduced post-CAR coronary hyperemia, which could be another mechanism for cardioprotection (i.e., by reducing oxidative stress during CAR). Thus, AraA inhibits AC5 and exhibits unique cardioprotection when delivered after CAR, which is critical for clinical translation.
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Affiliation(s)
- Claudio A Bravo
- Department of Cell Biology and Molecular Medicine, Rutgers, New Jersey Medical School, Newark, New Jersey
| | - Dorothy E Vatner
- Department of Cell Biology and Molecular Medicine, Rutgers, New Jersey Medical School, Newark, New Jersey
| | - Ronald Pachon
- Department of Cell Biology and Molecular Medicine, Rutgers, New Jersey Medical School, Newark, New Jersey
| | - Jie Zhang
- Department of Cell Biology and Molecular Medicine, Rutgers, New Jersey Medical School, Newark, New Jersey
| | - Stephen F Vatner
- Department of Cell Biology and Molecular Medicine, Rutgers, New Jersey Medical School, Newark, New Jersey
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19
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Bragança B, Oliveira-Monteiro N, Ferreirinha F, Lima PA, Faria M, Fontes-Sousa AP, Correia-de-Sá P. Ion Fluxes through KCa2 (SK) and Cav1 (L-type) Channels Contribute to Chronoselectivity of Adenosine A1 Receptor-Mediated Actions in Spontaneously Beating Rat Atria. Front Pharmacol 2016; 7:45. [PMID: 27014060 PMCID: PMC4780064 DOI: 10.3389/fphar.2016.00045] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/25/2015] [Accepted: 02/18/2016] [Indexed: 11/24/2022] Open
Abstract
Impulse generation in supraventricular tissue is inhibited by adenosine and acetylcholine via the activation of A1 and M2 receptors coupled to inwardly rectifying GIRK/KIR3.1/3.4 channels, respectively. Unlike M2 receptors, bradycardia produced by A1 receptors activation predominates over negative inotropy. Such difference suggests that other ion currents may contribute to adenosine chronoselectivity. In isolated spontaneously beating rat atria, blockade of KCa2/SK channels with apamin and Cav1 (L-type) channels with nifedipine or verapamil, sensitized atria to the negative inotropic action of the A1 agonist, R-PIA, without affecting the nucleoside negative chronotropy. Patch-clamp experiments in the whole-cell configuration mode demonstrate that adenosine, via A1 receptors, activates the inwardly-rectifying GIRK/KIR3.1/KIR3.4 current resulting in hyperpolarization of atrial cardiomyocytes, which may slow down heart rate. Conversely, the nucleoside inactivates a small conductance Ca2+-activated KCa2/SK outward current, which eventually reduces the repolarizing force and thereby prolong action potentials duration and Ca2+ influx into cardiomyocytes. Immunolocalization studies showed that differences in A1 receptors distribution between the sinoatrial node and surrounding cardiomyocytes do not afford a rationale for adenosine chronoselectivity. Immunolabelling of KIR3.1, KCa2.2, KCa2.3, and Cav1 was also observed throughout the right atrium. Functional data indicate that while both A1 and M2 receptors favor the opening of GIRK/KIR3.1/3.4 channels modulating atrial chronotropy, A1 receptors may additionally restrain KCa2/SK activation thereby compensating atrial inotropic depression by increasing the time available for Ca2+ influx through Cav1 (L-type) channels.
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Affiliation(s)
- Bruno Bragança
- Laboratório de Farmacologia e Neurobiologia - Center for Drug Discovery and Innovative Medicines (MedInUP), Instituto de Ciências Biomédicas Abel Salazar (ICBAS), Universidade do Porto (UP) Porto, Portugal
| | - Nádia Oliveira-Monteiro
- Laboratório de Farmacologia e Neurobiologia - Center for Drug Discovery and Innovative Medicines (MedInUP), Instituto de Ciências Biomédicas Abel Salazar (ICBAS), Universidade do Porto (UP) Porto, Portugal
| | - Fátima Ferreirinha
- Laboratório de Farmacologia e Neurobiologia - Center for Drug Discovery and Innovative Medicines (MedInUP), Instituto de Ciências Biomédicas Abel Salazar (ICBAS), Universidade do Porto (UP) Porto, Portugal
| | - Pedro A Lima
- Departamento de Química e Bioquímica, Faculdade de Ciências, Centro de Química e Bioquímica, Universidade de Lisboa Lisboa, Portugal
| | - Miguel Faria
- Laboratório de Farmacologia e Neurobiologia - Center for Drug Discovery and Innovative Medicines (MedInUP), Instituto de Ciências Biomédicas Abel Salazar (ICBAS), Universidade do Porto (UP) Porto, Portugal
| | - Ana P Fontes-Sousa
- Laboratório de Farmacologia e Neurobiologia - Center for Drug Discovery and Innovative Medicines (MedInUP), Instituto de Ciências Biomédicas Abel Salazar (ICBAS), Universidade do Porto (UP) Porto, Portugal
| | - Paulo Correia-de-Sá
- Laboratório de Farmacologia e Neurobiologia - Center for Drug Discovery and Innovative Medicines (MedInUP), Instituto de Ciências Biomédicas Abel Salazar (ICBAS), Universidade do Porto (UP) Porto, Portugal
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20
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Lougiakis N, Papapetropoulos A, Gikas E, Toumpas S, Efentakis P, Wedmann R, Zoga A, Zhou Z, Iliodromitis EK, Skaltsounis AL, Filipovic MR, Pouli N, Marakos P, Andreadou I. Synthesis and Pharmacological Evaluation of Novel Adenine–Hydrogen Sulfide Slow Release Hybrids Designed as Multitarget Cardioprotective Agents. J Med Chem 2016; 59:1776-90. [DOI: 10.1021/acs.jmedchem.5b01223] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/22/2022]
Affiliation(s)
- Nikolaos Lougiakis
- Department
of Pharmaceutical Chemistry, Faculty of Pharmacy, National and Kapodistrian University of Athens, 15771, Athens, Greece
| | - Andreas Papapetropoulos
- Department
of Pharmaceutical Chemistry, Faculty of Pharmacy, National and Kapodistrian University of Athens, 15771, Athens, Greece
| | - Evangelos Gikas
- Department
of Pharmaceutical Chemistry, Faculty of Pharmacy, National and Kapodistrian University of Athens, 15771, Athens, Greece
| | - Spyridon Toumpas
- Department
of Pharmaceutical Chemistry, Faculty of Pharmacy, National and Kapodistrian University of Athens, 15771, Athens, Greece
| | - Panagiotis Efentakis
- Department
of Pharmaceutical Chemistry, Faculty of Pharmacy, National and Kapodistrian University of Athens, 15771, Athens, Greece
| | - Rudolf Wedmann
- Department
of Chemistry and Pharmacy, Friedrich-Alexander University of Erlangen-Nuremberg, 91054 Erlangen, Germany
| | - Anastasia Zoga
- Department
of Pharmaceutical Chemistry, Faculty of Pharmacy, National and Kapodistrian University of Athens, 15771, Athens, Greece
- Second University
Department of Cardiology, Medical School, Attikon General Hospital,
National and Kapodistrian University of Athens, 12462, Athens, Greece
| | - Zhongmin Zhou
- Department
of Pharmaceutical Chemistry, Faculty of Pharmacy, National and Kapodistrian University of Athens, 15771, Athens, Greece
| | - Efstathios K. Iliodromitis
- Second University
Department of Cardiology, Medical School, Attikon General Hospital,
National and Kapodistrian University of Athens, 12462, Athens, Greece
| | - Alexios-Leandros Skaltsounis
- Department
of Pharmacognosy and Natural Products Chemistry, Faculty of Pharmacy, National and Kapodistrian University of Athens, 15771, Athens, Greece
| | - Milos R. Filipovic
- Department
of Chemistry and Pharmacy, Friedrich-Alexander University of Erlangen-Nuremberg, 91054 Erlangen, Germany
| | - Nicole Pouli
- Department
of Pharmaceutical Chemistry, Faculty of Pharmacy, National and Kapodistrian University of Athens, 15771, Athens, Greece
| | - Panagiotis Marakos
- Department
of Pharmaceutical Chemistry, Faculty of Pharmacy, National and Kapodistrian University of Athens, 15771, Athens, Greece
| | - Ioanna Andreadou
- Department
of Pharmaceutical Chemistry, Faculty of Pharmacy, National and Kapodistrian University of Athens, 15771, Athens, Greece
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21
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Kretschmar C, Oyarzún C, Villablanca C, Jaramillo C, Alarcón S, Perez G, Díaz-Encarnación MM, Pastor-Anglada M, Garrido W, Quezada C, San Martín R. Reduced Adenosine Uptake and Its Contribution to Signaling that Mediates Profibrotic Activation in Renal Tubular Epithelial Cells: Implication in Diabetic Nephropathy. PLoS One 2016; 11:e0147430. [PMID: 26808537 PMCID: PMC4726618 DOI: 10.1371/journal.pone.0147430] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/23/2015] [Accepted: 01/03/2016] [Indexed: 11/18/2022] Open
Abstract
Altered nucleoside levels may be linked to pathogenic signaling through adenosine receptors. We hypothesized that adenosine dysregulation contributes to fibrosis in diabetic kidney disease. Our findings indicate that high glucose levels and experimental diabetes decreased uptake activity through the equilibrative nucleoside transporter 1 (ENT1) in proximal tubule cells. In addition, a correlation between increased plasma content of adenosine and a marker of renal fibrosis in diabetic rats was evidenced. At the cellular level, exposure of HK2 cells to high glucose, TGF-β and the general adenosine receptor agonist NECA, induced the expression of profibrotic cell activation markers α-SMA and fibronectin. These effects can be avoided by using a selective antagonist of the adenosine A3 receptor subtype in vitro. Furthermore, induction of fibrosis marker α-SMA was prevented by the A3 receptor antagonist in diabetic rat kidneys. In conclusion, we evidenced the contribution of purinergic signaling to renal fibrosis in experimental diabetic nephropathy.
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Affiliation(s)
- Catalina Kretschmar
- Institute of Biochemistry and Microbiology, Science Faculty, Universidad Austral de Chile, Valdivia, Chile
| | - Carlos Oyarzún
- Institute of Biochemistry and Microbiology, Science Faculty, Universidad Austral de Chile, Valdivia, Chile
| | - Cristopher Villablanca
- Institute of Biochemistry and Microbiology, Science Faculty, Universidad Austral de Chile, Valdivia, Chile
| | - Catherinne Jaramillo
- Institute of Biochemistry and Microbiology, Science Faculty, Universidad Austral de Chile, Valdivia, Chile
| | - Sebastián Alarcón
- Institute of Biochemistry and Microbiology, Science Faculty, Universidad Austral de Chile, Valdivia, Chile
| | - Gustavo Perez
- Institute of Biochemistry and Microbiology, Science Faculty, Universidad Austral de Chile, Valdivia, Chile
| | | | - Marçal Pastor-Anglada
- Institute of Biomedicine and Oncology Programme, National Biomedical Research Institute of Liver and Gastrointestinal Diseases (CIBER EHD), Department of Biochemistry and Molecular Biology, University of Barcelona, Barcelona, Spain
| | - Wallys Garrido
- Institute of Biochemistry and Microbiology, Science Faculty, Universidad Austral de Chile, Valdivia, Chile
| | - Claudia Quezada
- Institute of Biochemistry and Microbiology, Science Faculty, Universidad Austral de Chile, Valdivia, Chile
| | - Rody San Martín
- Institute of Biochemistry and Microbiology, Science Faculty, Universidad Austral de Chile, Valdivia, Chile
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22
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Quantification of adenosine A 1 receptor biased agonism: Implications for drug discovery. Biochem Pharmacol 2016; 99:101-12. [DOI: 10.1016/j.bcp.2015.11.013] [Citation(s) in RCA: 50] [Impact Index Per Article: 5.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/15/2015] [Accepted: 11/09/2015] [Indexed: 12/20/2022]
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23
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Abstract
Adenosine exerts a variety of physiological effects by binding to cell surface G-protein-coupled receptor subtypes, namely, A1, A2a, A2b, and A3. The central physiological role of adenosine is to preclude tissue injury and promote repair in response to stress. In the heart, adenosine acts as a cytoprotective modulator, linking cardiac function to metabolic demand predominantly via activation of adenosine A1 receptors (A1Rs), which leads to inhibition of adenylate cyclase activity, modulation of protein kinase C, and opening of ATP-sensitive potassium channels. Activation of myocardial adenosine A1Rs has been shown to modulate a variety of pathologies associated with ischemic cardiac injury, including arrhythmogenesis, coronary and ventricular dysfunction, apoptosis, mitochondrial dysfunction, and ventricular remodeling. Partial A1R agonists are agents that are likely to elicit favorable pharmacological responses in heart failure (HF) without giving rise to the undesirable cardiac and extra-cardiac effects observed with full A1R agonism. Preclinical data have shown that partial adenosine A1R agonists protect and improve cardiac function at doses that do not result in undesirable effects on heart rate, atrioventricular conduction, and blood pressure, suggesting that these compounds may constitute a valuable new therapy for chronic HF. Neladenoson bialanate (BAY1067197) is the first oral partial and highly selective A1R agonist that has entered clinical development for the treatment of HF. This review provides an overview of adenosine A1R-mediated signaling in the heart, summarizes the results from preclinical and clinical studies of partial A1R agonists in HF, and discusses the potential benefits of these drugs in the clinical setting.
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24
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Bonyanian Z, Rose'Meyer RB. Caffeine and its Potential Role in Attenuating Impaired Wound Healing in Diabetes. JOURNAL OF CAFFEINE RESEARCH 2015. [DOI: 10.1089/jcr.2015.0011] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/29/2022]
Affiliation(s)
- Zeinab Bonyanian
- School of Medical Sciences, Griffith University, Gold Coast, Australia
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25
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Yadav VR, Nayeem MA, Tilley SL, Mustafa SJ. Angiotensin II stimulation alters vasomotor response to adenosine in mouse mesenteric artery: role for A1 and A2B adenosine receptors. Br J Pharmacol 2015; 172:4959-69. [PMID: 26227882 DOI: 10.1111/bph.13265] [Citation(s) in RCA: 21] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/23/2015] [Revised: 07/16/2015] [Accepted: 07/26/2015] [Indexed: 12/20/2022] Open
Abstract
BACKGROUND AND PURPOSE Stimulation of the A1 adenosine receptor and angiotensin II receptor type-1 (AT1 receptor) causes vasoconstriction through activation of cytochrome P450 4A (CYP4A) and ERK1/2. Thus, we hypothesized that acute angiotensin II activation alters the vasomotor response induced by the non-selective adenosine receptor agonist, NECA, in mouse mesenteric arteries (MAs). EXPERIMENTAL APPROACH We used a Danish Myo Technology wire myograph to measure muscle tension in isolated MAs from wild type (WT), A1 receptor and A2B receptor knockout (KO) mice. Western blots were performed to determine the expression of AT1 receptors and CYP4A. KEY RESULTS Acute exposure (15 min) to angiotensin II attenuated the NECA-dependent vasodilatation and enhanced vasoconstriction. This vasoconstrictor effect of angiotensin II in NECA-treated MAs was abolished in A1 receptor KO mice and in WT mice treated with the A1 receptor antagonist DPCPX, CYP4A inhibitor HET0016 and ERK1/2 inhibitor PD98059. In MAs from A2B receptor KO mice, the vasoconstrictor effect of angiotensin II on the NECA-induced response was shown to be dependent on A1 receptors. Furthermore, in A2B receptor KO mice, the expression of AT1 receptors and CYP4A was increased and the angiotensin II-induced vasoconstriction enhanced. In addition, inhibition of KATP channels with glibenclamide significantly reduced NECA-induced vasodilatation in WT mice. CONCLUSIONS AND IMPLICATIONS Acute angiotensin II stimulation enhanced A1 receptor-dependent vasoconstriction and inhibited A2B receptor-dependent vasodilatation, leading to a net vasoconstriction and altered vasomotor response to NECA in MAs. This interaction may be important in the regulation of BP.
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Affiliation(s)
- Vishal R Yadav
- Department of Physiology and Pharmacology, School of Medicine, Morgantown, WV, USA
| | - Mohammed A Nayeem
- Department of Pharmaceutical Sciences, School of Pharmacy, West Virginia University, Morgantown, WV, USA
| | - Stephen L Tilley
- Department of Medicine, University of North Carolina, Chapel Hill, NC, USA
| | - S Jamal Mustafa
- Department of Physiology and Pharmacology, School of Medicine, Morgantown, WV, USA.,West Virginia Center for Translational Science Institute, Morgantown, WV, USA
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26
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Yu M, Jie X, Xu L, Chen C, Shen W, Cao Y, Lian G, Qi R. Recent Advances in Dendrimer Research for Cardiovascular Diseases. Biomacromolecules 2015; 16:2588-98. [DOI: 10.1021/acs.biomac.5b00979] [Citation(s) in RCA: 39] [Impact Index Per Article: 3.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/25/2022]
Affiliation(s)
- Maomao Yu
- Peking
University Institute of Cardiovascular Sciences, Peking University Health Science Center, Beijing 100191, China
| | - Xu Jie
- School
of Pharmacy, Shihezi University, Shihezi 832000, China
| | - Lu Xu
- Peking
University Institute of Cardiovascular Sciences, Peking University Health Science Center, Beijing 100191, China
| | - Cong Chen
- Peking
University Institute of Cardiovascular Sciences, Peking University Health Science Center, Beijing 100191, China
| | - Wanli Shen
- School
of Pharmacy, Shihezi University, Shihezi 832000, China
| | - Yini Cao
- Peking
University Institute of Cardiovascular Sciences, Peking University Health Science Center, Beijing 100191, China
| | - Guan Lian
- School
of Pharmacy, Shihezi University, Shihezi 832000, China
| | - Rong Qi
- Peking
University Institute of Cardiovascular Sciences, Peking University Health Science Center, Beijing 100191, China
- School
of Pharmacy, Shihezi University, Shihezi 832000, China
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27
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Yang ZJ, Zhong YS. Effect of adenosine on GLAST expression in the retina of a chronic ocular hypertension rat model. Exp Ther Med 2015; 10:991-994. [PMID: 26622427 DOI: 10.3892/etm.2015.2607] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/28/2014] [Accepted: 04/02/2015] [Indexed: 11/06/2022] Open
Abstract
This study was performed to evaluate the effect of adenosine and an adenosine receptor antagonist on the expression of the L-glutamate/L-aspartate transporter (GLAST) in the retina of a chronic ocular hypertension (COH) rat model. COH models were established via the cauterization of three episcleral veins. Measurements of the intraocular pressure of the right eye (COH eye) were taken weekly by a handheld digital tonometer. A total of 10 µM adenosine or 10 µM adenosine + 100 nM SCH442416 solution (2 µl) was injected into the rat vitreous space. The reverse transcription-quantitative polymerase chain reaction, western blotting and immunohistochemistry were used to detect GLAST expression. Compared with the COH group, GLAST mRNA expression was decreased by 33.6% in the group treated with adenosine (n=6, P=0.020) and was increased by 159.6% in the group treated with SCH442416 (n=6, P=0.001). Administration of adenosine decreased GLAST protein expression by 34.7% (n=6, P<0.001), while treatment with the adenosine A2A receptor antagonist SCH442416 increased GLAST protein expression by 48.3% compared with the control COH group (n=6, P<0.001). Immunohistochemical experiments showed that administration of adenosine decreased GLAST protein expression, as compared with expression in the control COH rat retina. Administration of SCH442416 markedly increased GLAST protein expression. The results of the present study may provide a novel method for retinal neuron protection.
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Affiliation(s)
- Zi-Jian Yang
- Department of Ophthalmology, Ruijin Hospital Affiliated Medical School, Shanghai Jiaotong University, Shanghai 200025, P.R. China
| | - Yi-Sheng Zhong
- Department of Ophthalmology, Ruijin Hospital Affiliated Medical School, Shanghai Jiaotong University, Shanghai 200025, P.R. China
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28
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Adenosine 2B Receptor Activation Reduces Myocardial Reperfusion Injury by Promoting Anti-Inflammatory Macrophages Differentiation via PI3K/Akt Pathway. OXIDATIVE MEDICINE AND CELLULAR LONGEVITY 2015; 2015:585297. [PMID: 26161239 PMCID: PMC4486757 DOI: 10.1155/2015/585297] [Citation(s) in RCA: 43] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 09/18/2014] [Revised: 12/09/2014] [Accepted: 12/11/2014] [Indexed: 11/17/2022]
Abstract
BACKGROUND Activation of the adenosine A2B receptor (A2BR) can reduce myocardial ischemia/reperfusion (IR) injury. However, the mechanism underlying the A2BR-mediated cardioprotection is less clear. The present study was designed to investigate the potential mechanisms of cardioprotection mediated by A2BR. METHODS AND RESULTS C57BL/6 mice underwent 40-minute ischemia and 60-minute reperfusion. ATL-801, a potent selective A2BR antagonist, could not block ischemic preconditioning induced protection. BAY 60-6583, a highly selective A2BR agonist, significantly reduced myocardial infarct size, and its protective effect could be blocked by either ATL-801 or wortmannin. BAY 60-6583 increased phosphorylated Akt (p-Akt) levels in the heart at 10 min of reperfusion, and this phosphorylation could also be blocked by ATL-801 or wortmannin. Furthermore, BAY 60-6583 significantly increased M2 macrophages and decreased M1 macrophage and neutrophils infiltration in reperfused hearts, which also could be blocked by wortmannin. Meanwhile, confocal imaging studies showed that the majority of Akt phosphorylation in the heart was colocalized to CD206+ cells in both control and BAY 60-6583 pretreated hearts. CONCLUSION Our results indicated that pretreatment with BAY 60-6583 protects the heart against myocardial IR injury by its anti-inflammatory effects, probably by modulating macrophages phenotype switching via a PI3K/Akt pathway.
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29
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Yang C, Leung GPH. Equilibrative Nucleoside Transporters 1 and 4: Which One Is a Better Target for Cardioprotection Against Ischemia-Reperfusion Injury? J Cardiovasc Pharmacol 2015; 65:517-21. [PMID: 26070128 PMCID: PMC4461397 DOI: 10.1097/fjc.0000000000000194] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/07/2014] [Accepted: 11/14/2014] [Indexed: 01/04/2023]
Abstract
The cardioprotective effects of adenosine and adenosine receptor agonists have been studied extensively. However, their therapeutic outcomes in ischemic heart disease are limited by systemic side effects such as hypotension, bradycardia, and sedation. Equilibrative nucleoside transporter (ENT) inhibitors may be an alternative. By reducing the uptake of extracellular adenosine, ENT1 inhibitors potentiate the cardioprotective effect of endogenous adenosine. They have fewer systemic side effects because they selectively increase the extracellular adenosine levels in ischemic tissues undergoing accelerated adenosine formation. Nonetheless, long-term inhibition of ENT1 may adversely affect tissues that have low capacity for de novo nucleotide biosynthesis. ENT1 inhibitors may also affect the cellular transport, and hence the efficacy, of anticancer and antiviral nucleoside analogs used in chemotherapy. It has been proposed that ENT4 may also contribute to the regulation of extracellular adenosine in the heart, especially under the acidotic conditions associated with ischemia. Like ENT1 inhibitors, ENT4 inhibitors should work specifically on ischemic tissues. Theoretically, ENT4 inhibitors do not affect tissues that rely on ENT1 for de novo nucleotide synthesis. They also have no interaction with anticancer and antiviral nucleosides. Development of specific ENT4 inhibitors may open a new avenue in research on ischemic heart disease therapy.
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Affiliation(s)
- Cui Yang
- Ethnic Drug Screening & Pharmacology Center, Key Laboratory of Chemistry in Ethnic Medicinal Resources, State Ethnic Affairs Commission & Ministry of Education, Yunnan Minzu University, Kunming, China; and
| | - George P. H. Leung
- Department of Pharmacology and Pharmacy, The University of Hong Kong, Hong Kong, China
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30
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Boros D, Thompson J, Larson DF. Adenosine regulation of the immune response initiated by ischemia reperfusion injury. Perfusion 2015; 31:103-10. [PMID: 25987550 DOI: 10.1177/0267659115586579] [Citation(s) in RCA: 28] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/18/2022]
Abstract
It is clinically established that adenosine has negative chronotropic, antiarrhythmic effects and reduces arterial blood pressure. Adenosine addition to cardioplegic solutions used in cardiac operations is clinically well tolerated and has been shown to improve myocardial protection in several studies. However, the mechanism of action remains unclear. Therefore, it is important to define the effect of adenosine on the inflammatory cascade as immune cell activation occurs early during ischemia reperfusion injury. Adenosine appears to mediate the initial steps of the inflammatory cascade via its four G-coupled protein receptors: A1, A2A, A2B, and A3, expressed on neutrophils, lymphocytes and macrophages. The adenosine receptor isotype dictates the immune response. More specifically, the A1 and A3 receptors stimulate a pro-inflammatory immune response whereas the A2A and A2B are immunosuppressive. As the adenosine receptors are important for cardiac pre-conditioning and post-conditioning, adenosine may regulate the inflammatory responses initiated during ischemia-mediated immune injury related to myocardial protection.
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Affiliation(s)
- D Boros
- Sarver Heart Center, College of Medicine, The University of Arizona, Tucson, AZ, USA
| | - J Thompson
- Sarver Heart Center, College of Medicine, The University of Arizona, Tucson, AZ, USA
| | - D F Larson
- Sarver Heart Center, College of Medicine, The University of Arizona, Tucson, AZ, USA
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31
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Burnstock G, Pelleg A. Cardiac purinergic signalling in health and disease. Purinergic Signal 2015; 11:1-46. [PMID: 25527177 PMCID: PMC4336308 DOI: 10.1007/s11302-014-9436-1] [Citation(s) in RCA: 104] [Impact Index Per Article: 10.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/24/2014] [Accepted: 11/25/2014] [Indexed: 01/09/2023] Open
Abstract
This review is a historical account about purinergic signalling in the heart, for readers to see how ideas and understanding have changed as new experimental results were published. Initially, the focus is on the nervous control of the heart by ATP as a cotransmitter in sympathetic, parasympathetic, and sensory nerves, as well as in intracardiac neurons. Control of the heart by centers in the brain and vagal cardiovascular reflexes involving purines are also discussed. The actions of adenine nucleotides and nucleosides on cardiomyocytes, atrioventricular and sinoatrial nodes, cardiac fibroblasts, and coronary blood vessels are described. Cardiac release and degradation of ATP are also described. Finally, the involvement of purinergic signalling and its therapeutic potential in cardiac pathophysiology is reviewed, including acute and chronic heart failure, ischemia, infarction, arrhythmias, cardiomyopathy, syncope, hypertrophy, coronary artery disease, angina, diabetic cardiomyopathy, as well as heart transplantation and coronary bypass grafts.
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Affiliation(s)
- Geoffrey Burnstock
- Autonomic Neuroscience Centre, University College Medical School, Rowland Hill Street, London, NW3 2PF, UK,
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32
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Tang J, Jiang X, Zhou Y, Dai Y. Effects of A2BR on the biological behavior of mouse renal fibroblasts during hypoxia. Mol Med Rep 2015; 11:4397-402. [PMID: 25672943 DOI: 10.3892/mmr.2015.3320] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/30/2014] [Accepted: 01/21/2015] [Indexed: 11/06/2022] Open
Abstract
Fibroblasts are the effector cells of collagen secretion in renal interstitial fibrosis (RIF), and their proliferation and activation are essential for the development of RIF. Hypoxic ischemia in local tissues has been identified in chronic kidney diseases (CKDs), with adenosine (ADO) as a key signaling molecule. The current study investigated the association between ADO and the biological behavior of renal fibroblasts by establishing an in vitro hypoxia cell model. This aimed to provide experimental evidence for the prevention and treatment of RIF. NIH3T3 fibroblasts were exposed to hypoxia, and the subtypes of the ADO receptor (AR) on the cell surface were identified by a TaqMan probe‑based assay. Cells were divided into the following four groups: i) Control; ii) 5'‑N‑ethylcarboxamidoadenosine (NECA); iii) PT, NECA + 8‑phenyltheophylline (PT); and iv) MRS, NECA + N‑(4‑cyanophenyl)‑2‑[4‑(2,3,6,7‑tetrahydro‑2,6‑dioxo‑1,3‑dipropyl‑1H‑purin‑8‑yl)phenoxy]‑acetamide (MRS1754). The mRNA levels of transforming growth factor‑β1 (TGF‑β1), procollagen α1 (I) and α‑smooth muscle actin (α‑SMA) were measured following 24, 48, and 72 h of hypoxia. Cell proliferation was evaluated by a 3‑(4,5‑dimethylthiazol‑2‑yl)‑2,5‑diphenyltetrazolium bromide assay at 0, 12, 24, 48 and 72 h. The results demonstrated that A2BR was the predominant AR subtype present in hypoxia‑stimulated fibroblasts. NECA significantly induced fibroblast proliferation and upregulated the expression of TGF‑β1, procollagen α1 (I) and α‑SMA mRNA, while 8‑PT and MRS1754 inhibited fibroblast proliferation and downregulated the expression of TGF‑β1, procollagen α1 (I) and α‑SMA mRNA. The blockage of A2BR in hypoxia significantly inhibited the proliferation and activation of fibroblasts, and reduced the production of profibrotic cytokines, thus preventing the generation and development of fibrosis.
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Affiliation(s)
- Jin Tang
- Department of Urology, The Third Xiangya Hospital of Central South University, Changsha, Hunan 410013, P.R. China
| | - Xianzhen Jiang
- Department of Urology, The Third Xiangya Hospital of Central South University, Changsha, Hunan 410013, P.R. China
| | - Yihong Zhou
- Department of Urology, The Third Xiangya Hospital of Central South University, Changsha, Hunan 410013, P.R. China
| | - Yingbo Dai
- Department of Urology, The Third Xiangya Hospital of Central South University, Changsha, Hunan 410013, P.R. China
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33
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Romagnoli R, Baraldi PG, IJzerman AP, Massink A, Cruz-Lopez O, Lopez-Cara LC, Saponaro G, Preti D, Aghazadeh Tabrizi M, Baraldi S, Moorman AR, Vincenzi F, Borea PA, Varani K. Synthesis and Biological Evaluation of Novel Allosteric Enhancers of the A1 Adenosine Receptor Based on 2-Amino-3-(4′-Chlorobenzoyl)-4-Substituted-5-Arylethynyl Thiophene. J Med Chem 2014; 57:7673-86. [DOI: 10.1021/jm5008853] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/29/2022]
Affiliation(s)
- Romeo Romagnoli
- Dipartimento
di Scienze Chimiche e Farmaceutiche, Università di Ferrara, Via Fossato
di Mortara 17-19, 44121 Ferrara, Italy
| | - Pier Giovanni Baraldi
- Dipartimento
di Scienze Chimiche e Farmaceutiche, Università di Ferrara, Via Fossato
di Mortara 17-19, 44121 Ferrara, Italy
| | - Adriaan P. IJzerman
- Leiden Academic
Centre for Drug Research, Division of Medicinal Chemistry, P.O. Box 9502, 2300 RA Leiden, The Netherlands
| | - Arnault Massink
- Leiden Academic
Centre for Drug Research, Division of Medicinal Chemistry, P.O. Box 9502, 2300 RA Leiden, The Netherlands
| | - Olga Cruz-Lopez
- Dipartimento
di Scienze Chimiche e Farmaceutiche, Università di Ferrara, Via Fossato
di Mortara 17-19, 44121 Ferrara, Italy
| | - Luisa Carlota Lopez-Cara
- Dipartimento
di Scienze Chimiche e Farmaceutiche, Università di Ferrara, Via Fossato
di Mortara 17-19, 44121 Ferrara, Italy
| | - Giulia Saponaro
- Dipartimento
di Scienze Chimiche e Farmaceutiche, Università di Ferrara, Via Fossato
di Mortara 17-19, 44121 Ferrara, Italy
| | - Delia Preti
- Dipartimento
di Scienze Chimiche e Farmaceutiche, Università di Ferrara, Via Fossato
di Mortara 17-19, 44121 Ferrara, Italy
| | - Mojgan Aghazadeh Tabrizi
- Dipartimento
di Scienze Chimiche e Farmaceutiche, Università di Ferrara, Via Fossato
di Mortara 17-19, 44121 Ferrara, Italy
| | - Stefania Baraldi
- Dipartimento
di Scienze Chimiche e Farmaceutiche, Università di Ferrara, Via Fossato
di Mortara 17-19, 44121 Ferrara, Italy
| | - Allan R. Moorman
- King Pharmaceuticals
Inc., Research and Development, 4000
CentreGreen Way, Suite 300, Cary, North Carolina 27513
| | - Fabrizio Vincenzi
- Dipartimento
di Scienze Mediche, Sezione di Farmacologia, Università di Ferrara, Via Savonarola 9, 44121 Ferrara, Italy
| | - Pier Andrea Borea
- Dipartimento
di Scienze Mediche, Sezione di Farmacologia, Università di Ferrara, Via Savonarola 9, 44121 Ferrara, Italy
| | - Katia Varani
- Dipartimento
di Scienze Mediche, Sezione di Farmacologia, Università di Ferrara, Via Savonarola 9, 44121 Ferrara, Italy
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El-Ani D, Philipchik I, Stav H, Levi M, Zerbib J, Shainberg A. Tumor necrosis factor alpha protects heart cultures against hypoxic damage via activation of PKA and phospholamban to prevent calcium overload. Can J Physiol Pharmacol 2014; 92:917-25. [PMID: 25349921 DOI: 10.1139/cjpp-2014-0092] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/22/2023]
Abstract
This study aims to elucidate the mechanisms by which tumor necrosis factor alpha (TNFα) provides protection from hypoxic damage to neonatal rat cardiomyocyte cultures. We show that when intracellular Ca(2+) ([Ca(2+)]i) levels are elevated by extracellular Ca(2+) ([Ca(2+)]o) or by hypoxia, then TNFα decreased [Ca(2+)]i in individual cardiomyocytes. However, TNFα did not reduce [Ca(2+)]i after its increase by thapsigargin, (a SERCA2a inhibitor), indicating that TNFα attenuates Ca(2+) overload through Ca(2+) uptake by SERCA2a. TNFα did not reduce [Ca(2+)]i, following its elevation when [Ca(2+)]o levels were elevated in TNFα receptor knock-out mice. H-89, a protein kinase A (PKA) inhibitor, attenuated the protective effect of TNFα when the cardiomyoctyes were subjected to hypoxia, as determined by lactate dehydrogenase (LDH) and creatine kinase (CK) released and from the cardiomyocytes. Moreover, when the levels of [Ca(2+)]i were increased by hypoxia, H-89, but not KN93, (a calmodulin kinase II inhibitor), prevented the reduction in [Ca(2+)]i by TNFα. TNFα increased the phosphorylation of PKA in normoxic and hypoxic cardiomyoctes, indicating that the cardioprotective effect of TNFα against hypoxic damage was via PKA activation. Hypoxia decreased phosphorylated phospholamban levels; however, TNFα attenuated this decrease following hypoxia. It is suggested that TNFα activates phospholamban phosphorylation in hypoxic heart cultures via PKA to stimulate SERCA2a activity to limit Ca(2+) overload.
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Affiliation(s)
- Dalia El-Ani
- The Mina & Everard Goodman Faculty of Life Sciences, Bar-Ilan University, Ramat-Gan 5290002, Israel
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35
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Oral administration of inosine promotes recovery after experimental spinal cord injury in rat. Neurol Sci 2014; 35:1785-91. [DOI: 10.1007/s10072-014-1840-3] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/28/2014] [Accepted: 05/15/2014] [Indexed: 12/21/2022]
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36
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Maimon N, Titus PA, Sarelius IH. Pre-exposure to adenosine, acting via A(2A) receptors on endothelial cells, alters the protein kinase A dependence of adenosine-induced dilation in skeletal muscle resistance arterioles. J Physiol 2014; 592:2575-90. [PMID: 24687580 DOI: 10.1113/jphysiol.2013.265835] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022] Open
Abstract
Adenosine (ADO) is an endogenous vasodilatory purine widely recognized to be a significant contributor to functional hyperaemia. Despite this, many aspects of the mechanisms by which ADO induces dilation in small resistance arterioles are not established, or appear contradictory. These include: identification of the primary receptor subtype; its location on endothelial (EC) or vascular smooth muscle cells; whether ADO acts on KATP channels in these resistance vessels; and the contribution of cAMP/protein kinase A (PKA) signalling to the response. In intravital microscopy studies of intact or EC-denuded skeletal muscle arterioles, we show that ADO acts via A2A receptors located on ECs to produce vasodilation via activation of KATP channels located on vascular smooth muscle cells. Importantly, we found that the signalling pathway involves cAMP as expected, but that a requirement for PKA activation is demonstrable only if the vessel is not pre-exposed to ADO. That is, PKA-dependent signalling varies with pre-exposure to ADO. Further, we show that PKA activation alone is not sufficient to dilate these arterioles; an additional EC calcium-dependent signalling mechanism is required for vasodilation to ADO. The ability of arterioles in situ to respond to occupancy of a specific receptor by utilizing different cell signalling pathways under different conditions to produce the same response allows the arteriole to respond to key homeostatic requirements using more than a single signalling mechanism. Clearly, this is likely to be physiologically advantageous, but the role for this signalling flexibility in the integrated arteriolar response that underlies functional hyperaemia will require further exploration.
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Affiliation(s)
- Nir Maimon
- Department of Pharmacology and Physiology, University of Rochester, Rochester, NY, USA
| | - Patricia A Titus
- Department of Pharmacology and Physiology, University of Rochester, Rochester, NY, USA
| | - Ingrid H Sarelius
- Department of Pharmacology and Physiology, University of Rochester, Rochester, NY, USA
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37
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Vincenzi F, Targa M, Romagnoli R, Merighi S, Gessi S, Baraldi PG, Borea PA, Varani K. TRR469, a potent A(1) adenosine receptor allosteric modulator, exhibits anti-nociceptive properties in acute and neuropathic pain models in mice. Neuropharmacology 2014; 81:6-14. [PMID: 24486382 DOI: 10.1016/j.neuropharm.2014.01.028] [Citation(s) in RCA: 52] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/15/2013] [Revised: 01/14/2014] [Accepted: 01/20/2014] [Indexed: 01/21/2023]
Abstract
A(1) adenosine receptors (ARs) have been identified as a potential target for the development of anti-nociceptive compounds. The present study explores the analgesic effects of a novel A(1)AR positive allosteric modulator, TRR469, in different models of acute and chronic pain in mice. To evaluate the allosteric enhancement, in vitro binding experiments were performed. The anti-nociceptive properties were investigated in formalin and writhing tests, and in the streptozotocin-induced diabetic neuropathic pain model. Rotarod and catalepsy tests were used to identify potential side effects, while the functional effect of TRR469 was studied using [(3)H]-d-aspartate release from synaptosomes. TRR469 effectively inhibited nociceptive responses in the formalin and writhing tests, with effects comparable to those of the reference analgesic morphine. Isobolographic analysis of the combination of TRR469 and morphine revealed an additive interaction. TRR469 was anti-allodynic in the neuropathic pain model and did not display locomotor or cataleptic side effects. TRR469 enhanced the binding of the agonist radioligand [(3)H]-CCPA and induced a 33-fold increase of adenosine affinity in spinal cord membranes. In mouse spinal cord synaptosomes, TRR469 enhanced the inhibitory effect of A(1)AR activation on [(3)H]-d-aspartate release, a non-metabolizable analogue of glutamate. In conclusion, this research demonstrates the anti-nociceptive effect of the novel compound TRR469, one of the most potent and effective A(1)AR positive allosteric modulators so far synthesized. The use of TRR469 allows for the possibility of exploiting analgesic properties of endogenous adenosine, with a minor potential to develop the various side effects often associated with the use of direct receptor agonists.
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Affiliation(s)
- Fabrizio Vincenzi
- Department of Medical Sciences, Pharmacology Section, University of Ferrara, via Fossato di Mortara 17/19, 44121 Ferrara, Italy
| | - Martina Targa
- Department of Medical Sciences, Pharmacology Section, University of Ferrara, via Fossato di Mortara 17/19, 44121 Ferrara, Italy
| | - Romeo Romagnoli
- Department of Pharmaceutical Sciences, University of Ferrara, via Fossato di Mortara 17/19, 44121 Ferrara, Italy
| | - Stefania Merighi
- Department of Medical Sciences, Pharmacology Section, University of Ferrara, via Fossato di Mortara 17/19, 44121 Ferrara, Italy
| | - Stefania Gessi
- Department of Medical Sciences, Pharmacology Section, University of Ferrara, via Fossato di Mortara 17/19, 44121 Ferrara, Italy
| | - Pier Giovanni Baraldi
- Department of Pharmaceutical Sciences, University of Ferrara, via Fossato di Mortara 17/19, 44121 Ferrara, Italy
| | - Pier Andrea Borea
- Department of Medical Sciences, Pharmacology Section, University of Ferrara, via Fossato di Mortara 17/19, 44121 Ferrara, Italy
| | - Katia Varani
- Department of Medical Sciences, Pharmacology Section, University of Ferrara, via Fossato di Mortara 17/19, 44121 Ferrara, Italy.
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Li J, Xu JP, Zhao XZ, Sun XJ, Xu ZW, Song SJ. Protective Effect of Metformin on Myocardial Injury in Metabolic Syndrome Patients following Percutaneous Coronary Intervention. Cardiology 2013; 127:133-9. [DOI: 10.1159/000355574] [Citation(s) in RCA: 26] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/06/2013] [Accepted: 09/10/2013] [Indexed: 11/19/2022]
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Wang C, Lin W, Playa H, Sun S, Cameron K, Buolamwini J. Dipyridamole analogs as pharmacological inhibitors of equilibrative nucleoside transporters. Identification of novel potent and selective inhibitors of the adenosine transporter function of human equilibrative nucleoside transporter 4 (hENT4). Biochem Pharmacol 2013; 86:1531-40. [PMID: 24021350 PMCID: PMC3866046 DOI: 10.1016/j.bcp.2013.08.063] [Citation(s) in RCA: 37] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/03/2013] [Revised: 08/27/2013] [Accepted: 08/27/2013] [Indexed: 01/04/2023]
Abstract
To identify needed human equilibrative nucleoside transporter 4 (hENT4) inhibitors, we cloned and stably expressed the recombinant protein in PK15NTD (nucleoside transporter deficient) cells, and, investigated its interaction with a series of dipyridamole analogs synthesized in our laboratory. Compounds were tested in this newly established hENT4 expressing system as well in previous stably expressed hENT1 and hENT2 expressing systems. Of the dipyridamole analogs evaluated, about one fourth of the compounds inhibited hENT4 with higher potencies than dipyridamole. The most potent of them, Compound 30 displayed an IC₅₀ of 74.4 nM, making it about 38 times more potent than dipyridamole (IC₅₀=2.8 μM), and selectivities of about 80-fold and 20-fold relative to ENT1 and ENT2, respectively. Structure-activity relationship showed nitrogen-containing monocyclic rings and noncyclic substituents at the 4- and 8-positions of the pyrimido[5,4-d]pyrimidine were important for the inhibitory activity against hENT4. The most potent and selective hENT4 inhibitors tended to have a 2,6-di(N-monohydroxyethyl) substitution on the pyrimidopyrimidine ring system. The inhibitors of hENT4 identified in this study are the most selective and potent inhibitors of hENT4 adenosine transporter function to date, and should serve as useful pharmacological/biochemical tools and/or potential leads for ENT4-based therapeutics. Also, the new hENT4-expressing PK15 cell line established will serve as a useful screening tool for the discovery and design of hENT4 ligands.
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Affiliation(s)
- Chunmei Wang
- Department of Pharmaceutical Sciences, College of Pharmacy, University of Tennessee Health Science Center, Memphis, Tennessee 38163, USA
| | | | - Hilaire Playa
- Department of Pharmaceutical Sciences, College of Pharmacy, University of Tennessee Health Science Center, Memphis, Tennessee 38163, USA
| | - Shan Sun
- Department of Pharmaceutical Sciences, College of Pharmacy, University of Tennessee Health Science Center, Memphis, Tennessee 38163, USA
| | - Kenyuna Cameron
- Department of Pharmaceutical Sciences, College of Pharmacy, University of Tennessee Health Science Center, Memphis, Tennessee 38163, USA
| | - John Buolamwini
- Department of Pharmaceutical Sciences, College of Pharmacy, University of Tennessee Health Science Center, Memphis, Tennessee 38163, USA
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40
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Synthesis and biological evaluation of novel 2-amino-3-aroyl-4-neopentyl-5-substituted thiophene derivatives as allosteric enhancers of the A₁ adenosine receptor. Bioorg Med Chem 2013; 22:148-66. [PMID: 24332652 DOI: 10.1016/j.bmc.2013.11.043] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/20/2013] [Accepted: 11/21/2013] [Indexed: 11/23/2022]
Abstract
2-Amino-3-benzoyl thiophenes have been widely reported to act as allosteric enhancers at the A1 adenosine receptor. Their activity can be increased considerably by appropriate substitutions at the 4- and 5-positions of the thiophene ring. Substituent size at the thiophene C-4 position seemed to be a factor closely related to activity, with the 4-neopentyl (2,2-dimethylpropyl) substitution showing the greatest enhanced activity. A wide series of 2-amino-3-aroyl-4-neopentylthiophene derivatives with general structure 3, characterized by the presence of different substituents (bromine, aryl and heteroaryl) at the 5-position of the thiophene ring, have been identified as potent AEs at the A1AR. With only one exception, all of the synthesized compounds proved to be superior to the reference compound PD 81,723 in a functional assay. Derivatives 3p, 3u, 3am, 3ap and 3ar were the most active compounds in binding (saturation and competition) and functional cAMP studies, being able to potentiate agonist [(3)H]CCPA binding to the A1 receptor.
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Key Words
- 2-Amino-3-benzoylthiophene
- 2-chloro-N(6)-cyclopentyladenosine
- A(1) adenosine receptor
- AE(s)
- Allosteric modulation
- CCPA
- CHO
- CNS
- CsF
- ERG
- EWG
- G protein-coupled receptors
- GPCRs
- N-bromosuccinimide
- NBS
- PdCl(2)(DPPF)
- [(3)H](4-(2-[7-amino-2-(2-furil)[1,2.4]triazolo[2,3-a][1,3,5]triazin-5-ylamino]ethyl)phenol)
- [(3)H]1,3-dipropyl-8-cyclopentyl-xanthine
- [(3)H]2-chloro-N(6)-cyclopentyladenosine
- [(3)H]5-N-(4-methoxyphenylcarbamoyl)amino-8-propyl-2-(2-furyl)pyrazolo[4,3-e]-1,2,4-triazolo[1,5-c]pyrimidine
- [(3)H]CCPA
- [(3)H]DPCPX
- [(3)H]MRE-3008F20
- [(3)H]ZM 241385
- [1,1′-bis(diphenylphosphino)ferrocene] dichloropalladium(II) complex with dichloromethane
- allosteric enhancer(s)
- cAMP
- central nervous system
- cesium fluoride
- chinese hamster ovary
- cyclic adenosine monophosphate
- electron-releasing group
- electron-withdrawing group
- hA(1)AR
- human A(1) adenosine receptor
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GIRK Channel Activation Via Adenosine or Muscarinic Receptors Has Similar Effects on Rat Atrial Electrophysiology. J Cardiovasc Pharmacol 2013; 62:192-8. [DOI: 10.1097/fjc.0b013e3182965221] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/26/2022]
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Takahashi-Sato K, Murakawa M, Kimura J, Ito MA, Matsuoka I. Loss of ectonucleotidases from the coronary vascular bed after ischemia-reperfusion in isolated rat heart. BMC Cardiovasc Disord 2013; 13:53. [PMID: 23890190 PMCID: PMC3733877 DOI: 10.1186/1471-2261-13-53] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/26/2012] [Accepted: 07/25/2013] [Indexed: 11/30/2022] Open
Abstract
Background Ectonucleotidase plays an important role in the regulation of cardiac function by controlling extracellular levels of adenine nucleotides and adenosine. To determine the influence of ischemia-reperfusion injury on ectonucleotidase activity in coronary vascular bed, we compared the metabolic profile of adenine nucleotides during the coronary circulation in pre- and post-ischemic heart. Methods Langendorff-perfused rat hearts were used to assess the intracoronary metabolism of adenine nucleotides. The effects of ischemia on the adenine nucleotide metabolism were examined after 30 min of ischemia and 30 min of reperfusion. Adenine nucleotide metabolites were measured by high performance liquid chromatography. Results ATP, ADP and AMP were rapidly metabolized to adenosine and inosine during the coronary circulation. After ischemia, ectonucleotidase activity of the coronary vascular bed was significantly decreased. In addition, the perfusate from the ischemic heart contained a considerable amount of enzymes degrading ATP, AMP and adenosine. Immunoblot analysis revealed that the perfusate from the ischemic heart dominantly contained ectonucleoside triphosphate diphosphohydrolase 1, and, to a lesser extent, ecto-5’-nucleotidase. The leakage of nucleotide metabolizing enzymes from the coronary vascular bed by ischemia-reperfusion was more remarkable in aged rats, in which post-ischemic cardiac dysfunction was more serious. Conclusion Ectonucleotidases were liberated from the coronary vascular bed by ischemia-reperfusion, resulting in an overall decrease in ectonucleotidase activity in the post-ischemic coronary vascular bed. These results suggest that decreased ectonucleotidase activity by ischemia may exacerbate subsequent reperfusion injury, and that levels of circulating ectonucleotidase may reflect the severity of ischemic vascular injury.
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Abstract
Adenosine kinase (ADK; EC 2.7.1.20) is an evolutionarily conserved phosphotransferase that converts the purine ribonucleoside adenosine into 5'-adenosine-monophosphate. This enzymatic reaction plays a fundamental role in determining the tone of adenosine, which fulfills essential functions as a homeostatic and metabolic regulator in all living systems. Adenosine not only activates specific signaling pathways by activation of four types of adenosine receptors but it is also a primordial metabolite and regulator of biochemical enzyme reactions that couple to bioenergetic and epigenetic functions. By regulating adenosine, ADK can thus be identified as an upstream regulator of complex homeostatic and metabolic networks. Not surprisingly, ADK dysfunction is involved in several pathologies, including diabetes, epilepsy, and cancer. Consequently, ADK emerges as a rational therapeutic target, and adenosine-regulating drugs have been tested extensively. In recent attempts to improve specificity of treatment, localized therapies have been developed to augment adenosine signaling at sites of injury or pathology; those approaches include transplantation of stem cells with deletions of ADK or the use of gene therapy vectors to downregulate ADK expression. More recently, the first human mutations in ADK have been described, and novel findings suggest an unexpected role of ADK in a wider range of pathologies. ADK-regulating strategies thus represent innovative therapeutic opportunities to reconstruct network homeostasis in a multitude of conditions. This review will provide a comprehensive overview of the genetics, biochemistry, and pharmacology of ADK and will then focus on pathologies and therapeutic interventions. Challenges to translate ADK-based therapies into clinical use will be discussed critically.
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Affiliation(s)
- Detlev Boison
- Legacy Research Institute, 1225 NE 16th Ave, Portland, OR 97202, USA.
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An allosteric modulator of the adenosine A1 receptor improves cardiac function following ischaemia in murine isolated hearts. Pharmaceuticals (Basel) 2013; 6:546-56. [PMID: 24276124 PMCID: PMC3816699 DOI: 10.3390/ph6040546] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/04/2013] [Revised: 03/26/2013] [Accepted: 04/01/2013] [Indexed: 12/21/2022] Open
Abstract
The effect of an allosteric modulator of the adenosine A1 receptors was investigated using an ischaemia-reperfusion protocol in murine isolated hearts. Isolated hearts were perfused with Kreb-Henseleit solution gassed with carbogen gas (95% O2 and 5% CO2) in Langendorff mode and electrically paced at 480 bpm. Following 20 min equilibration and 20 min global normothermic ischaemia, the allosteric modulator VCP333 (1 μM) or the adenosine A1 receptor partial agonist VCP102 (10 μM) were infused after 5 min of reperfusion for 15 min. Upon termination of the drug treatment, reperfusion continued for a further 40 min. At the end of 60 min reperfusion, treatment with VCP333 or VCP102 improved the recovery of the left ventricular developed pressure when compared to control group responses (p < 0.05). Neither compound affected end diastolic pressure, coronary flow rates or dP/dtmax values when compared to control tissues during reperfusion (p > 0.05). The infusion of VCP102 or VCP333 during reperfusion reduced cardiac troponin I efflux to 6.7% and 25% respectively of control heart efflux (p < 0.05). This data indicates that the allosteric modulator of the adenosine A1 receptor (VCP333) has similar characteristics to the adenosine receptor partial agonist VCP102 as it improves cardiac function and reduces myocardial cell death following an ischaemic episode.
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Sharma AK, Munajjam A, Vaishnav B, Sharma R, Sharma A, Kishore K, Sharma A, Sharma D, Kumari R, Tiwari A, Singh SK, Gaur S, Jatav VS, Srinivasan BP, Agarwal SS. Involvement of adenosine and standardization of aqueous extract of garlic (Allium sativum Linn.) on cardioprotective and cardiodepressant properties in ischemic preconditioning and myocardial ischemia-reperfusion induced cardiac injury. J Biomed Res 2013; 26:24-36. [PMID: 23554727 PMCID: PMC3596077 DOI: 10.1016/s1674-8301(12)60004-9] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/30/2011] [Revised: 08/09/2011] [Accepted: 09/08/2011] [Indexed: 01/22/2023] Open
Abstract
The present study investigated the effect of garlic (Allium sativum Linn.) aqueous extracts on ischemic preconditioning and ischemia-reperfusion induced cardiac injury, as well as adenosine involvement in ischemic preconditioning and garlic extract induced cardioprotection. A model of ischemia-reperfusion injury was established using Langendorff apparatus. Aqueous extract of garlic dose was standardized (0.5%, 0.4%, 0.3%, 0.2%, 0.1%, 0.07%, 0.05%, 0.03%, 0.01%), and the 0.05% dose was found to be the most effective. Higher doses (more than 0.05%) were highly toxic, causing arrhythmia and cardiodepression, whereas the lower doses were ineffective. Garlic exaggerated the cardioprotective effect of ischemic preconditioning. The cardioprotective effect of ischemic preconditioning and garlic cardioprotection was significantly attenuated by theophylline (1,000 µmol/L) and 8-SPT (10 mg/kg, i.p.) and expressed by increased myocardial infarct size, increased LDH level, and reduced nitrite and adenosine levels. These findings suggest that adenosine is involved in the pharmacological and molecular mechanism of garlic induced cardioprotection and mediated by the modulation of nitric oxide.
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Affiliation(s)
- Ashish Kumar Sharma
- Department of Pharmacology, Gyan Vihar School of Pharmacy, Suresh Gyan Vihar University, Mahal, Jagatpura, Jaipur (Rajasthan) 302025, India
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Zhong Y, Yang Z, Huang WC, Luo X. Adenosine, adenosine receptors and glaucoma: An updated overview. Biochim Biophys Acta Gen Subj 2013; 1830:2882-90. [DOI: 10.1016/j.bbagen.2013.01.005] [Citation(s) in RCA: 56] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/19/2012] [Revised: 12/21/2012] [Accepted: 01/07/2013] [Indexed: 01/30/2023]
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El Messaoudi S, Rongen GA, Riksen NP. Metformin Therapy in Diabetes: The Role of Cardioprotection. Curr Atheroscler Rep 2013; 15:314. [DOI: 10.1007/s11883-013-0314-z] [Citation(s) in RCA: 50] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/18/2022]
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Abstract
Diabetic nephropathy ranks as the most devastating kidney disease worldwide. It characterizes in the early onset by glomerular hypertrophy, hyperfiltration and mesangial expansion. Experimental models show that overproduction of vascular endothelial growth factor (VEGF) is a pathogenic condition for podocytopathy; however the mechanisms that regulate this growth factor induction are not clearly identified. We determined that the adenosine A(2B) receptor (A(2B)AR) mediates VEGF overproduction in ex vivo glomeruli exposed to high glucose concentration, requiring PKCα and Erk1/2 activation. The glomerular content of A(2B)AR was concomitantly increased with VEGF at early stages of renal disease in streptozotocin-induced diabetic rats. Further, in vivo administration of an antagonist of A(2B)AR in diabetic rats blocked the glomerular overexpression of VEGF, mesangial cells activation and proteinuria. In addition, we also determined that the accumulation of extracellular adenosine occurs in glomeruli of diabetic rats. Correspondingly, raised urinary adenosine levels were found in diabetic rats. In conclusion, we evidenced that adenosine signaling at the onset of diabetic kidney disease is a pathogenic event that promotes VEGF induction.
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Lucarini N, Napolioni V, Magrini A, Gloria F. The Effect of ACP1-ADA1Genetic Interaction on Human Life Span. Hum Biol 2012; 84:725-33. [DOI: 10.3378/027.084.0606] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 07/15/2013] [Indexed: 11/05/2022]
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