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Liu Z, Wu X, Wang Q, Li Z, Liu X, Sheng X, Zhu H, Zhang M, Xu J, Feng X, Wu B, Lv X. CD73-Adenosine A 1R Axis Regulates the Activation and Apoptosis of Hepatic Stellate Cells Through the PLC-IP 3-Ca 2+/DAG-PKC Signaling Pathway. Front Pharmacol 2022; 13:922885. [PMID: 35784730 PMCID: PMC9245432 DOI: 10.3389/fphar.2022.922885] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/18/2022] [Accepted: 05/25/2022] [Indexed: 12/12/2022] Open
Abstract
Alcohol-related liver fibrosis (ALF) is a form of alcohol-related liver disease (ALD) that generally occurs in response to heavy long-term drinking. Ecto-5'-nucleotidase (NT5E), also known as CD73, is a cytomembrane protein linked to the cell membrane via a GPI anchor that regulates the conversion of extracellular ATP to adenosine. Adenosine and its receptors are important regulators of the cellular response. Previous studies showed that CD73 and adenosine A1 receptor (A1R) were important in alcohol-related liver disease, however the exact mechanism is unclear. The aim of this study was to elucidate the role and mechanism of the CD73-A1R axis in both a murine model of alcohol and carbon tetrachloride (CCl4) induced ALF and in an in vitro model of fibrosis induced by acetaldehyde. The degree of liver injury was determined by measuring serum AST and ALT levels, H & E staining, and Masson's trichrome staining. The expression levels of fibrosis indicators and PLC-IP3-Ca2+/DAG-PKC signaling pathway were detected by quantitative real-time PCR, western blotting, ELISA, and calcium assay. Hepatic stellate cell (HSC) apoptosis was detected using the Annexin V-FITC/PI cell apoptosis detection kit. Knockdown of CD73 significantly attenuated the accumulation of α-SMA and COL1a1 damaged the histological architecture of the mouse liver induced by alcohol and CCl4. In vitro, CD73 inhibition attenuated acetaldehyde-induced fibrosis and downregulated A1R expression in HSC-T6 cells. Inhibition of CD73/A1R downregulated the expression of the PLC-IP3-Ca2+/DAG-PKC signaling pathway. In addition, silencing of CD73/A1R promoted apoptosis in HSC-T6 cells. In conclusion, the CD73-A1R axis can regulate the activation and apoptosis of HSCs through the PLC-IP3-Ca2+/DAG-PKC signaling pathway.
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Affiliation(s)
- Zhenni Liu
- Inflammation and Immune Mediated Diseases Laboratory of Anhui Province, Anhui Institute of Innovative Drugs, School of Pharmacy, Anhui Medical University, Hefei, China
- Institute for Liver Diseases of Anhui Medical University, Hefei, China
| | - Xue Wu
- Inflammation and Immune Mediated Diseases Laboratory of Anhui Province, Anhui Institute of Innovative Drugs, School of Pharmacy, Anhui Medical University, Hefei, China
- Institute for Liver Diseases of Anhui Medical University, Hefei, China
| | - Qi Wang
- Seventh Affiliated Hospital of Sun Yat-Sen University, Shenzhen, China
| | - Zixuan Li
- Inflammation and Immune Mediated Diseases Laboratory of Anhui Province, Anhui Institute of Innovative Drugs, School of Pharmacy, Anhui Medical University, Hefei, China
- Institute for Liver Diseases of Anhui Medical University, Hefei, China
| | - Xueqi Liu
- Inflammation and Immune Mediated Diseases Laboratory of Anhui Province, Anhui Institute of Innovative Drugs, School of Pharmacy, Anhui Medical University, Hefei, China
- Institute for Liver Diseases of Anhui Medical University, Hefei, China
| | - Xiaodong Sheng
- Inflammation and Immune Mediated Diseases Laboratory of Anhui Province, Anhui Institute of Innovative Drugs, School of Pharmacy, Anhui Medical University, Hefei, China
- Institute for Liver Diseases of Anhui Medical University, Hefei, China
| | - Hong Zhu
- Inflammation and Immune Mediated Diseases Laboratory of Anhui Province, Anhui Institute of Innovative Drugs, School of Pharmacy, Anhui Medical University, Hefei, China
- Institute for Liver Diseases of Anhui Medical University, Hefei, China
| | - Mengda Zhang
- Inflammation and Immune Mediated Diseases Laboratory of Anhui Province, Anhui Institute of Innovative Drugs, School of Pharmacy, Anhui Medical University, Hefei, China
- Institute for Liver Diseases of Anhui Medical University, Hefei, China
| | - Junrui Xu
- General Thoracic Surgery, The First Affiliated Hospital of Anhui Medical University, Hefei, China
| | - Xiaowen Feng
- Inflammation and Immune Mediated Diseases Laboratory of Anhui Province, Anhui Institute of Innovative Drugs, School of Pharmacy, Anhui Medical University, Hefei, China
- Institute for Liver Diseases of Anhui Medical University, Hefei, China
| | - Baoming Wu
- Inflammation and Immune Mediated Diseases Laboratory of Anhui Province, Anhui Institute of Innovative Drugs, School of Pharmacy, Anhui Medical University, Hefei, China
- Institute for Liver Diseases of Anhui Medical University, Hefei, China
| | - Xiongwen Lv
- Inflammation and Immune Mediated Diseases Laboratory of Anhui Province, Anhui Institute of Innovative Drugs, School of Pharmacy, Anhui Medical University, Hefei, China
- Institute for Liver Diseases of Anhui Medical University, Hefei, China
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Robertson FP, Fuller BJ, Davidson BR. An Evaluation of Ischaemic Preconditioning as a Method of Reducing Ischaemia Reperfusion Injury in Liver Surgery and Transplantation. J Clin Med 2017; 6:jcm6070069. [PMID: 28708111 PMCID: PMC5532577 DOI: 10.3390/jcm6070069] [Citation(s) in RCA: 42] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/23/2017] [Revised: 06/22/2017] [Accepted: 07/04/2017] [Indexed: 12/16/2022] Open
Abstract
Liver Ischaemia Reperfusion (IR) injury is a major cause of post-operative liver dysfunction, morbidity and mortality following liver resection surgery and transplantation. There are no proven therapies for IR injury in clinical practice and new approaches are required. Ischaemic Preconditioning (IPC) can be applied in both a direct and remote fashion and has been shown to ameliorate IR injury in small animal models. Its translation into clinical practice has been difficult, primarily by a lack of knowledge regarding the dominant protective mechanisms that it employs. A review of all current studies would suggest that IPC/RIPC relies on creating a small tissue injury resulting in the release of adenosine and l-arginine which act through the Adenosine receptors and the haem-oxygenase and endothelial nitric oxide synthase systems to reduce hepatocyte necrosis and improve the hepatic microcirculation post reperfusion. The next key step is to determine how long the stimulus requires to precondition humans to allow sufficient injury to occur to release the potential mediators. This would open the door to a new therapeutic chapter in this field.
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Affiliation(s)
- Francis P Robertson
- Division of Surgery and Interventional Science, Royal Free Campus, University College London, 9th Floor, Royal Free Hospital, Pond Street, London NW3 2QG, UK.
| | - Barry J Fuller
- Division of Surgery and Interventional Science, Royal Free Campus, University College London, 9th Floor, Royal Free Hospital, Pond Street, London NW3 2QG, UK.
| | - Brian R Davidson
- Division of Surgery and Interventional Science, Royal Free Campus, University College London, 9th Floor, Royal Free Hospital, Pond Street, London NW3 2QG, UK.
- Department of Hepaticopancreatobiliary Surgery and Liver Transplantation, Royal Free Foundation Trust, 9th Floor, Royal Free Hospital, Pond Street, London NW3 2QG, UK.
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Björnsson B, Winbladh A, Bojmar L, Sundqvist T, Gullstrand P, Sandström P. Conventional, but not remote ischemic preconditioning, reduces iNOS transcription in liver ischemia/reperfusion. World J Gastroenterol 2014; 20:9506-9512. [PMID: 25071345 PMCID: PMC4110582 DOI: 10.3748/wjg.v20.i28.9506] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/12/2014] [Revised: 04/12/2014] [Accepted: 05/26/2014] [Indexed: 02/06/2023] Open
Abstract
AIM: To study the effects of preconditioning on inducible nitric oxide synthase (iNOS) and interleukin 1 (IL-1) receptor transcription in rat liver ischemia/reperfusion injury (IRI).
METHODS: Seventy-two male rats were randomized into 3 groups: the one-hour segmental ischemia (IRI, n = 24) group, the ischemic preconditioning (IPC, n = 24) group or the remote ischemic preconditioning (R-IPC, n = 24) group. The IPC and R-IPC were performed as 10 min of ischemia and 10 min of reperfusion. The iNOS and the IL-1 receptor mRNA in the liver tissue was analyzed with real time PCR. The total Nitrite and Nitrate (NOx) in continuously sampled microdialysate (MD) from the liver was analyzed. In addition, the NOx levels in the serum were analyzed.
RESULTS: After 4 h of reperfusion, the iNOS mRNA was significantly higher in the R-IPC (ΔCt: 3.44 ± 0.57) group than in the IPC (ΔCt: 5.86 ± 0.82) group (P = 0.025). The IL-1 receptor transcription activity was reduced in the IPC group (ΔCt: 1.88 ± 0.53 to 4.81 ± 0.21), but not in the R-IPC group, during reperfusion (P = 0.027). In the MD, a significant drop in the NOx levels was noted in the R-IPC group (12.3 ± 2.2 to 4.7 ± 1.2 μmol/L) at the end of ischemia compared with the levels in early ischemia (P = 0.008). A similar trend was observed in the IPC group (11.8 ± 2.1 to 6.4 ± 1.5 μmol/L), although this difference was not statistically significant. The levels of NOx rose quickly during reperfusion in both groups.
CONCLUSION: IPC, but not R-IPC, reduces iNOS and IL-1 receptor transcription during early reperfusion, indicating a lower inflammatory reaction. NOx is consumed in the ischemic liver lobe.
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Burnstock G, Vaughn B, Robson SC. Purinergic signalling in the liver in health and disease. Purinergic Signal 2014; 10:51-70. [PMID: 24271096 PMCID: PMC3944046 DOI: 10.1007/s11302-013-9398-8] [Citation(s) in RCA: 70] [Impact Index Per Article: 6.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/16/2013] [Accepted: 10/24/2013] [Indexed: 12/18/2022] Open
Abstract
Purinergic signalling is involved in both the physiology and pathophysiology of the liver. Hepatocytes, Kupffer cells, vascular endothelial cells and smooth muscle cells, stellate cells and cholangiocytes all express purinoceptor subtypes activated by adenosine, adenosine 5'-triphosphate, adenosine diphosphate, uridine 5'-triphosphate or UDP. Purinoceptors mediate bile secretion, glycogen and lipid metabolism and indirectly release of insulin. Mechanical stress results in release of ATP from hepatocytes and Kupffer cells and ATP is also released as a cotransmitter with noradrenaline from sympathetic nerves supplying the liver. Ecto-nucleotidases play important roles in the signalling process. Changes in purinergic signalling occur in vascular injury, inflammation, insulin resistance, hepatic fibrosis, cirrhosis, diabetes, hepatitis, liver regeneration following injury or transplantation and cancer. Purinergic therapeutic strategies for the treatment of these pathologies are being explored.
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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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Naamani O, Chaimovitz C, Douvdevani A. Pharmacological preconditioning with adenosine A(1) receptor agonist suppresses cellular immune response by an A(2A) receptor dependent mechanism. Int Immunopharmacol 2014; 20:205-12. [PMID: 24560904 DOI: 10.1016/j.intimp.2014.02.011] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/01/2014] [Revised: 02/02/2014] [Accepted: 02/10/2014] [Indexed: 12/31/2022]
Abstract
Under stressful conditions such as ischemia, sepsis, and severe trauma, adenosine levels are elevated and protect the tissue by interaction with G coupled receptors. In a model of peritonitis, we previously found that pharmacological preconditioning (PPC) of mice with a selective adenosine A1 receptor (A1R) agonist, 2-chloro-N(6)-cyclopentyladenosine (CCPA), induced the A2AR which reduces cytokine secretion and leukocyte recruitment. In our present study we determined whether mice PPC will moderate cellular immune response by the same mechanism. Similar to the effect on inflammation, PPC reduced the response to lymphocyte mitogens and allogeneic MLR response. The inhibitory effect of PPC on the immune response was A1R and A2AR dependent as illustrated by experiments with antagonists of these receptors and mice with knock down (KO) receptors. In MLR with PPC splenocytes we found reduced levels of pro-inflammatory cytokines (IFN-γ, IL-15, TNF-α) and elevation of IL-10, as well as elevation of regulatory T-cell. Our data indicate that PPC is able to remarkably suppress cellular immune response due to the sensitization A2AR. This effect of PPC sheds light on the protective role of adenosine in ischemic preconditioning and makes this treatment candidate for the prevention of graft rejection.
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Affiliation(s)
- Oshri Naamani
- Department of Clinical Biochemistry and Pharmacology, Faculty of Health Sciences, Ben-Gurion University of the Negev, P.O.B. 653, Beer-Sheva 84105, Israel.
| | - Cidio Chaimovitz
- Department of Nephrology, Soroka Medical University Center and Ben-Gurion University of the Negev, Beer-Sheva, Israel
| | - Amos Douvdevani
- Department of Clinical Biochemistry and Pharmacology, Faculty of Health Sciences, Ben-Gurion University of the Negev, P.O.B. 653, Beer-Sheva 84105, Israel
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Módis K, Gerő D, Stangl R, Rosero O, Szijártó A, Lotz G, Mohácsik P, Szoleczky P, Coletta C, Szabó C. Adenosine and inosine exert cytoprotective effects in an in vitro model of liver ischemia-reperfusion injury. Int J Mol Med 2012; 31:437-46. [PMID: 23232950 PMCID: PMC3981016 DOI: 10.3892/ijmm.2012.1203] [Citation(s) in RCA: 20] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/30/2012] [Accepted: 10/05/2012] [Indexed: 12/13/2022] Open
Abstract
Liver ischemia represents a common clinical problem. In the present study, using an in vitro model of hepatic ischemia-reperfusion injury, we evaluated the potential cytoprotective effect of the purine metabolites, such as adenosine and inosine, and studied the mode of their pharmacological actions. The human hepatocellular carcinoma-derived cell line HepG2 was subjected to combined oxygen-glucose deprivation (COGD; 0-14-24 h), followed by re-oxygenation (0-4-24 h). Adenosine or inosine (300-1,000 µM) were applied in pretreatment. Cell viability and cytotoxicity were measured by the 3-(4,5-dimethyl-2-thiazolyl)-2,5-diphenyl-2H-tetrazolium bromide and lactate dehydrogenase methods, respectively. The results showed that both adenosine and inosine exerted cytoprotective effects, and these effects were not related to receptor-mediated actions, since they were not prevented by selective adenosine receptor antagonists. On the other hand, the adenosine deaminase inhibitor erythro-9-(2-hydroxy-3-nonyl) adenine hydrochloride (EHNA, 10 µM) markedly and almost fully reversed the protective effect of adenosine during COGD, while it did not influence the cytoprotective effect of inosine in the same assay conditions. These results suggest that the cytoprotective effects are related to intracellular actions, and, in the case of adenosine also involve intracellular conversion to inosine. The likely interpretation of these findings is that inosine serves as an alternative source of energy to produce ATP during hypoxic conditions. The protective effects are also partially dependent on adenosine kinase, as the inhibitor 4-amino-5-(3-bromophenyl)-7-(6‑morpholino-pyridin-3-yl)pyrido[2,3-d]pyrimidine, 2HCl (ABT 702, 30 µM) significantly reversed the protective effect of both adenosine and inosine during hypoxia and re-oxygenation. Collectively, the current results support the view that during hypoxia, adenosine and inosine exert cytoprotective effects via receptor-independent, intracellular modes of action, which, in part, depend on the restoration of cellular bioenergetics. The present study supports the view that testing of inosine for protection against various forms of warm and cold liver ischemia is relevant.
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Affiliation(s)
- Katalin Módis
- Department of Anesthesiology, University of Texas Medical Branch, Galveston, TX 77555, USA
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Pol HWD, Sibma E, Zeebregts CJ, Pierik EGJM, Meerwaldt R. Increased skin autofluorescence after colorectal operation reflects surgical stress and postoperative outcome. Am J Surg 2011; 202:583-9. [PMID: 21890102 DOI: 10.1016/j.amjsurg.2010.10.019] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/27/2010] [Revised: 10/01/2010] [Accepted: 10/01/2010] [Indexed: 01/08/2023]
Abstract
BACKGROUND Abdominal surgery is a major oxidative stress effector. The increase in oxidative stress has been related to postoperative complications. Oxidative stress leads to the formation and accumulation of oxidation protein end products, which exhibit autofluorescence (AF) and induce inflammatory reactions. METHODS Skin AF was assessed perioperatively in 40 consecutive colorectal surgery patients until discharge. Duration of surgery, estimated blood loss, and urinary production per hour were analyzed as measures of surgical stress. The clinical occurrence of anastomotic leakage, systemic infections, and cardiopulmonary complications within 30 days of surgery were analyzed. RESULTS A perioperative increase in skin AF of 19 ± .2% was observed. Duration of operation and blood loss were independently associated with the perioperative increase in skin AF. Skin AF correlated with C-reactive protein levels postoperatively. American Society of Anesthesiologists classification, duration of operation, and preoperative and perioperative increases in AF were independently associated with postoperative complications. CONCLUSIONS This is the first study to demonstrate an association between skin AF and surgical stress and outcomes, which may rate the condition of a patient after operation.
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Björnsson B, Winbladh A, Bojmar L, Trulsson LM, Olsson H, Sundqvist T, Gullstrand P, Sandström P. Remote or conventional ischemic preconditioning--local liver metabolism in rats studied with microdialysis. J Surg Res 2011; 176:55-62. [PMID: 21962739 DOI: 10.1016/j.jss.2011.07.038] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/20/2011] [Revised: 07/16/2011] [Accepted: 07/22/2011] [Indexed: 01/17/2023]
Abstract
BACKGROUND Ischemic preconditioning (IPC) of the liver decreases liver injury secondary to ischemia and reperfusion. An attractive alternative to IPC is remote ischemic preconditioning (R-IPC), but these two methods have not previously been compared. MATERIAL AND METHODS Eighty-seven rats were randomized into four groups: sham operated (n = 15), 1 h segmental ischemia (IRI, n = 24), preceded by IPC (n = 24), or R-IPC (n = 24) (to the left hindleg). IPC and R-IPC were performed with 10 min ischemia and 10 min of reperfusion. Analyses of liver microdialysate (MD), serum transaminase levels, and liver histology were made. RESULTS Rats treated with IPC and R-IPC had significantly lower AST, 71.5 (19.6) IU/L respective 96.6 (12.4) at 4 h reperfusion than those subjected to IRI alone, 155 (20.9), P = 0.0004 and P = 0.04 respectively. IPC also had lower ALT levels, 41.6 (11.3) IU/L than had IRI 107.4 (15.5), P = 0.003. The MD glycerol was significantly higher during ischemia in the R-IPC [759 (84) μM] and the IRI [732 (67)] groups than in the IPC 514 (70) group, P = 0.022 and P = 0.046 respectively. The MD glucose after ischemia was lower in the IPC group 7.1 (1.2) than in the IRI group 12.7 (1.6), P = 0.005. Preconditioning to the liver caused an direct increase in lactate, glucose and glycerol in the ischemic segment compared with the control segment an effect not seen in the R-IPC and IRI groups. CONCLUSIONS IPC affects glucose metabolism in the rat liver, observed with MD. IPC reduces liver cell injury during ischemic and reperfusion in rats. R-IPC performed over the same length of time as IPC does not have the same effect as the latter on ALT levels and MD glycerol; this may suggest that R-IPC does not offer the same protection as IPC in this setting of rat liver IRI.
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Affiliation(s)
- Bergthor Björnsson
- Department of Surgery, Faculty of Health Sciences, Linköping University, Surgical Clinic, County Council of Östergötland, Linköping, Sweden.
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Abstract
IMPORTANCE OF THE FIELD Ischemia-reperfusion (IR) injury is a common problem after transplantation as well as myocardial infarction and stroke. IR initiates an inflammatory response leading to rapid tissue damage. Adenosine, produced in response to IR, is generally considered a protective signaling molecule and elicits its physiological responses through four distinct adenosine receptors. The short half-life, lack of specificity and rapid metabolism limits the use of adenosine as a therapeutic agent. Thus, intense research efforts have focused on the synthesis and implementation of specific adenosine receptor agonists and antagonists as potential therapeutic agents for a variety of inflammatory conditions including IR injury. AREAS COVERED IN THIS REVIEW Current knowledge on IR injury with a focus on lung, heart and kidney and studies that have advanced our understanding of the role of adenosine receptors and the therapeutic potential of adenosine receptor agonists and antagonists for the prevention of IR injury. WHAT THE READER WILL GAIN Insight into the role of adenosine receptor signaling in IR injury. TAKE HOME MESSAGE No therapies are currently available that specifically target IR injury; however, targeting of specific adenosine receptors may offer therapeutic strategies in this regard.
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Affiliation(s)
- Victor E Laubach
- University of Virginia Health System, Charlottesville, 22908, USA.
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Brown SB, Libonati JR, Selak MA, Shannon RP, Simmons RA. Neonatal exendin-4 leads to protection from reperfusion injury and reduced rates of oxidative phosphorylation in the adult rat heart. Cardiovasc Drugs Ther 2010; 24:197-205. [PMID: 20582459 DOI: 10.1007/s10557-010-6242-z] [Citation(s) in RCA: 18] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/18/2022]
Abstract
PURPOSE Glucagon like peptide-1 (7-36) amide (GLP-1) is an incretin hormone with multiple salutary cardiovascular effects. A short course of the GLP-1 analogue Exendin-4 (Ex-4) in the neonatal period prevents the development of mitochondrial dysfunction and oxidative stress in a rat prone to obesity and diabetes. We sought to evaluate whether neonatal Ex-4 can exert the same effect in the normal rat heart, as well as whether Ex-4 could affect susceptibility to cardiac reperfusion injury. METHODS After birth, Sprague Dawley rat pups were given either Ex-4 (1 nmole/kg body weight) or vehicle (1% BSA in 0.9% saline) subcutaneously for 6 days. Animals were studied at juvenile (4-6 weeks) and adult (8-9 months) ages. Using the Langendorff isolated perfused heart, cardiovascular function was assessed at baseline and following ischemia-reperfusion. Mitochondria were isolated from fresh heart tissue, and oxidative phosphorylation and calcium sequestration were analyzed. TBARS, MnSOD activity, and non-enzymatic anti-oxidant capacity were measured to assess the degree of oxidative stress present in the two groups. RESULTS Both at the juvenile and adult age, Ex-4 treated rats demonstrated improved recovery from an ischemic insult. Rates of oxidative phosphorylation were globally reduced in adult, but not juvenile Ex-4 treated animals. Furthermore, mitochondria isolated from adult Ex-4 treated rats sequestered less calcium before undergoing the mitochondrial permeability transition. Oxidative stress did not differ between groups at any time point. CONCLUSION A short course of Exendin-4 in the neonatal period leads to protection from ischemic injury and a preconditioned mitochondrial phenotype in the adult rat.
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Affiliation(s)
- Suzanne B Brown
- Hospital of the University of Pennsylvania, Philadelphia, PA, USA
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Teixeira ARF, Molan NT, Kubrusly MS, Bellodi-Privato M, Coelho AM, Leite KR, Machado MAC, Bacchella T, Machado MCC. Postconditioning ameliorates lipid peroxidation in liver ischemia-reperfusion injury in rats. Acta Cir Bras 2010; 24:52-6. [PMID: 19169543 DOI: 10.1590/s0102-86502009000100011] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/27/2008] [Accepted: 11/25/2008] [Indexed: 11/22/2022] Open
Abstract
PURPOSE Liver ischemia-reperfusion injury is a phenomenon presents in events like liver resections and transplantation. The restoration of blood flow may leads to local and systemic injury. Several techniques have been developed in order to avoid or ameliorate ischemia-reperfusion injury in clinical situations. The application of a stutter reperfusion after the ischemic event (postconditioning) could alters the hydrodynamics and stimulates endogenous mechanisms that attenuate the reperfusion injury. The present study was designed to evaluate the potential protective effect of postconditioning in a model of ischemia-reperfusion in rats. METHODS Hepatic anterior pedicle of median and left anterolateral segments were exposed and clamped for 1 hour. Two hours later, clamp was released in two different ways: Control Group (n=7): clamp was release straightforward; Postconditioning Group (n=7): clamp was released intermittently. Lipid peroxidation (malondialdehyde) and expression of the glutathione-s-transferase-alpha-3 gene were studied. RESULTS Lipid peroxidation was significantly decreased in ischemic and non-ischemic liver by postconditioning. GST- alpha3 gene was overexpressed in post-conditioned group, but not significantly. CONCLUSION Postconditioning induced hepatoprotection by reducing lipid peroxidation in the ischemic and non-ischemic liver.
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Vollmar B, Menger MD. The hepatic microcirculation: mechanistic contributions and therapeutic targets in liver injury and repair. Physiol Rev 2009; 89:1269-339. [PMID: 19789382 DOI: 10.1152/physrev.00027.2008] [Citation(s) in RCA: 372] [Impact Index Per Article: 23.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/08/2023] Open
Abstract
The complex functions of the liver in biosynthesis, metabolism, clearance, and host defense are tightly dependent on an adequate microcirculation. To guarantee hepatic homeostasis, this requires not only a sufficient nutritive perfusion and oxygen supply, but also a balanced vasomotor control and an appropriate cell-cell communication. Deteriorations of the hepatic homeostasis, as observed in ischemia/reperfusion, cold preservation and transplantation, septic organ failure, and hepatic resection-induced hyperperfusion, are associated with a high morbidity and mortality. During the last two decades, experimental studies have demonstrated that microcirculatory disorders are determinants for organ failure in these disease states. Disorders include 1) a dysregulation of the vasomotor control with a deterioration of the endothelin-nitric oxide balance, an arterial and sinusoidal constriction, and a shutdown of the microcirculation as well as 2) an overwhelming inflammatory response with microvascular leukocyte accumulation, platelet adherence, and Kupffer cell activation. Within the sequelae of events, proinflammatory mediators, such as reactive oxygen species and tumor necrosis factor-alpha, are the key players, causing the microvascular dysfunction and perfusion failure. This review covers the morphological and functional characterization of the hepatic microcirculation, the mechanistic contributions in surgical disease states, and the therapeutic targets to attenuate tissue injury and organ dysfunction. It also indicates future directions to translate the knowledge achieved from experimental studies into clinical practice. By this, the use of the recently introduced techniques to monitor the hepatic microcirculation in humans, such as near-infrared spectroscopy or orthogonal polarized spectral imaging, may allow an early initiation of treatment, which should benefit the final outcome of these critically ill patients.
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Affiliation(s)
- Brigitte Vollmar
- Institute for Experimental Surgery, University of Rostock, Rostock, Germany.
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Wu LX, Zeng Z. Preconditioning against hepatic ischemia-reperfusion injury: recent advances. Shijie Huaren Xiaohua Zazhi 2009; 17:3426-3430. [DOI: 10.11569/wcjd.v17.i33.3426] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
Hepatic ischemia-reperfusion injury (I/R) is a major clinical problem that impedes the development of liver surgery. Recently, intensive research has improved our understanding of the mechanisms involved in I/R liver injury. Here, we will briefly review the most promising preconditioning approaches against I/R injury and discuss the mechanisms involved in their therapeutic effects.
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von Versen-Höynck F, Rajakumar A, Bainbridge SA, Gallaher MJ, Roberts JM, Powers RW. Human placental adenosine receptor expression is elevated in preeclampsia and hypoxia increases expression of the A2A receptor. Placenta 2009; 30:434-42. [PMID: 19303140 PMCID: PMC2674514 DOI: 10.1016/j.placenta.2009.02.004] [Citation(s) in RCA: 44] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/09/2009] [Revised: 02/22/2009] [Accepted: 02/23/2009] [Indexed: 10/21/2022]
Abstract
Placental hypoxia as a result of impaired trophoblast invasion is suggested to be involved in the pathophysiology of preeclampsia. Hypoxia is a potent stimulus for the release of adenosine, and the actions of adenosine are mediated through four adenosine receptors, A(1), A(2A), A(2B) and A(3). We investigated the presence, distribution and expression of adenosine receptor subtypes in the human placenta, the expression of the adenosine receptors in placentas from pregnancies complicated by preeclampsia, small for gestational age (SGA) infants and uncomplicated pregnancies, and the effect of hypoxia on placental adenosine receptor expression. Immunofluorescent microscopy localized A(1), A(2A), A(2B) and A(3) adenosine receptors to the syncytiotrophoblast, endothelial cells and myofibroblasts within the human placenta. Adenosine receptor protein and message expression levels were significantly higher in placentas from preeclamptic pregnancies with or without SGA infants, but not different in pregnancies with SGA infants alone. In vitro exposure of placental villous explants to hypoxia (2% oxygen) increased the expression of A(2A) adenosine receptor 50%. These data indicate that all four known adenosine receptors are expressed in the human placenta and adenosine receptor expression is significantly higher in pregnancies complicated by preeclampsia. These data are consistent with the hypothesis that differences in placental adenosine receptors may contribute to alterations in placental function in preeclampsia.
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Affiliation(s)
- F von Versen-Höynck
- Magee-Womens Research Institute, University of Pittsburgh, Pittsburgh, PA 15213, USA
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