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1
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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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2
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Kumar K, Singh N, Yadav HN, Maslov L, Jaggi AS. Endless Journey of Adenosine Signaling in Cardioprotective Mechanism of Conditioning Techniques: Clinical Evidence. Curr Cardiol Rev 2023; 19:56-71. [PMID: 37309766 PMCID: PMC10636797 DOI: 10.2174/1573403x19666230612112259] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/01/2023] [Revised: 04/10/2023] [Accepted: 05/11/2023] [Indexed: 06/14/2023] Open
Abstract
Myocardial ischemic injury is a primary cause of death among various cardiovascular disorders. The condition occurs due to an interrupted supply of blood and vital nutrients (necessary for normal cellular activities and viability) to the myocardium, eventually leading to damage. Restoration of blood supply to ischemic tissue is noted to cause even more lethal reperfusion injury. Various strategies, including some conditioning techniques, like preconditioning and postconditioning, have been developed to check the detrimental effects of reperfusion injury. Many endogenous substances have been proposed to act as initiators, mediators, and end effectors of these conditioning techniques. Substances, like adenosine, bradykinin, acetylcholine, angiotensin, norepinephrine, opioids, etc., have been reported to mediate cardioprotective activity. Among these agents, adenosine has been widely studied and suggested to have the most pronounced cardioprotective effects. The current review article highlights the role of adenosine signaling in the cardioprotective mechanism of conditioning techniques. The article also provides an insight into various clinical studies that substantiate the applicability of adenosine as a cardioprotective agent in myocardial reperfusion injury.
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Affiliation(s)
- Kuldeep Kumar
- Department of Pharmaceutical Sciences and Drug Research, Punjabi University, Patiala, Punjab 147002, India
| | - Nirmal Singh
- Department of Pharmaceutical Sciences and Drug Research, Punjabi University, Patiala, Punjab 147002, India
| | - Harlokesh Narayan Yadav
- Department of Pharmacology, All India Institute of Medical Sciences (AIIMS), New Delhi 110029, India
| | - Leonid Maslov
- Cardiology Research Institute, Tomsk National Research Medical Center of the Russian Academy of Science, Tomsk, Russia
| | - Amteshwar Singh Jaggi
- Department of Pharmaceutical Sciences and Drug Research, Punjabi University, Patiala, Punjab 147002, India
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3
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Park SM, He YC, Gong C, Gao W, Bae YS, Si C, Park KH, Choi SE. Effects of taxifolin from enzymatic hydrolysis of Rhododendron mucrotulatum on hair growth promotion. Front Bioeng Biotechnol 2022; 10:995238. [PMID: 36159701 PMCID: PMC9492874 DOI: 10.3389/fbioe.2022.995238] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/15/2022] [Accepted: 08/04/2022] [Indexed: 11/22/2022] Open
Abstract
Flavonoid aglycones possess biological activities, such as antioxidant and antidiabetic activities compared to glycosides. Taxifolin, a flavonoid aglycones, is detected only in trace amounts in nature and is not easily observed. Therefore, in this study, to investigate the hair tonic and hair loss inhibitors effect of taxifolin, high content of taxifolin aglycone extract was prepared by enzymatic hydrolysis. Taxifolin effectively regulates the apoptosis of dermal papilla cells, which is associated with hair loss, based on its strong antioxidant activities. However, inhibition of dihydrotestosterone (DHT), which is a major cause of male pattern hair loss, was significantly reduced with taxifolin treatment compared with minoxidil, as a positive control. It was also confirmed that a representative factor for promoting hair growth, IGF-1, was significantly increased, and that TGF-β1, a representative biomarker for hair loss, was significantly reduced with taxifolin treatment. These results suggest that taxifolin from enzymatic hydrolysis of RM is a potential treatment for hair loss and a hair growth enhancer.
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Affiliation(s)
- Sun-Min Park
- Department of Forest Biomaterials Engineering, College of Forest and Environmental Sciences, Kangwon National University, Kangwon, South Korea
| | - Yi-Chang He
- Key Lab of Agricultural Resources and Ecology of Poyang Lake Basin, College of Land Resources and Environment, Jiangxi Agricultural University, Nanchang, Jiangxi, China
- Jiangxi Academy of Forestry, Nanchang, Jiangxi, China
| | - Chun Gong
- Jiangxi Academy of Forestry, Nanchang, Jiangxi, China
| | - Wei Gao
- Jiangxi Academy of Forestry, Nanchang, Jiangxi, China
| | - Young-Soo Bae
- Department of Forest Biomaterials Engineering, College of Forest and Environmental Sciences, Kangwon National University, Kangwon, South Korea
- Jiangxi Academy of Forestry, Nanchang, Jiangxi, China
| | - Chuanling Si
- Tianjin Key Laboratory of Pulp and Paper, Tianjin University of Science and Technology, Tianjin, China
| | - Kwang-Hyun Park
- Department of Emergency Medicine and BioMedical Science Graduate Program (BMSGP), Chonnam National University, Hwasun, South Korea
- Department of Emergency Medical Rescue, Nambu University, Gwangju, South Korea
| | - Sun-Eun Choi
- Department of Forest Biomaterials Engineering, College of Forest and Environmental Sciences, Kangwon National University, Kangwon, South Korea
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4
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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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5
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Méndez-Carmona N, Wyss RK, Arnold M, Segiser A, Kalbermatter N, Joachimbauer A, Carrel TP, Longnus SL. Effects of graft preservation conditions on coronary endothelium and cardiac functional recovery in a rat model of donation after circulatory death. J Heart Lung Transplant 2021; 40:1396-1407. [PMID: 34509349 DOI: 10.1016/j.healun.2021.07.028] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/04/2021] [Revised: 07/15/2021] [Accepted: 07/26/2021] [Indexed: 01/15/2023] Open
Abstract
BACKGROUND Use of cardiac grafts obtained with donation after circulatory death (DCD) could significantly improve donor heart availability. As DCD hearts undergo potentially deleterious warm ischemia and reperfusion, clinical protocols require optimization to ensure graft quality. Thus, we investigated effects of alternative preservation conditions on endothelial and/or vascular and contractile function in comparison with the current clinical standard. METHODS Using a rat DCD model, we compared currently used graft preservation conditions, St. Thomas n°2 (St. T) at 4°C, with potentially more suitable conditions for DCD hearts, adenosine-lidocaine preservation solution (A-L) at 4°C or 22°C. Following general anesthesia and diaphragm transection, hearts underwent either 0 or 18 min of in-situ warm ischemia, were explanted, flushed and stored for 15 min with either St. T at 4°C or A-L at 4°C or 22°C, and then reperfused under normothermic, aerobic conditions. Endothelial integrity and contractile function were determined. RESULTS Compared to 4°C preservation, 22°C A-L significantly increased endothelial nitric oxide synthase (eNOS) dimerization and reduced oxidative tissue damage (p < 0.05 for all). Furthermore, A-L at 22°C better preserved the endothelial glycocalyx and coronary flow compared with St. T, tended to reduce tissue calcium overload, and stimulated pro-survival signaling. No significant differences were observed in cardiac function among ischemic groups. CONCLUSIONS Twenty-two-degree Celsius A-L solution better preserves the coronary endothelium compared to 4°C St. T, which likely results from greater eNOS dimerization, reduced oxidative stress, and activation of the reperfusion injury salvage kinase (RISK) pathway. Improving heart preservation conditions immediately following warm ischemia constitutes a promising approach for the optimization of clinical protocols in DCD heart transplantation.
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Affiliation(s)
- Natalia Méndez-Carmona
- Department of Cardiovascular Surgery, Inselspital, Bern University Hospital and Department for BioMedical Research (DBMR), University of Bern, Bern, Switzerland
| | - Rahel K Wyss
- Department of Cardiovascular Surgery, Inselspital, Bern University Hospital and Department for BioMedical Research (DBMR), University of Bern, Bern, Switzerland
| | - Maria Arnold
- Department of Cardiovascular Surgery, Inselspital, Bern University Hospital and Department for BioMedical Research (DBMR), University of Bern, Bern, Switzerland
| | - Adrian Segiser
- Department of Cardiovascular Surgery, Inselspital, Bern University Hospital and Department for BioMedical Research (DBMR), University of Bern, Bern, Switzerland
| | - Nina Kalbermatter
- Department of Cardiovascular Surgery, Inselspital, Bern University Hospital and Department for BioMedical Research (DBMR), University of Bern, Bern, Switzerland
| | - Anna Joachimbauer
- Department of Cardiovascular Surgery, Inselspital, Bern University Hospital and Department for BioMedical Research (DBMR), University of Bern, Bern, Switzerland
| | - Thierry P Carrel
- Department of Cardiovascular Surgery, Inselspital, Bern University Hospital and Department for BioMedical Research (DBMR), University of Bern, Bern, Switzerland
| | - Sarah L Longnus
- Department of Cardiovascular Surgery, Inselspital, Bern University Hospital and Department for BioMedical Research (DBMR), University of Bern, Bern, Switzerland.
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6
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Mitochondria and Pharmacologic Cardiac Conditioning-At the Heart of Ischemic Injury. Int J Mol Sci 2021; 22:ijms22063224. [PMID: 33810024 PMCID: PMC8004818 DOI: 10.3390/ijms22063224] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/24/2021] [Revised: 03/12/2021] [Accepted: 03/16/2021] [Indexed: 02/07/2023] Open
Abstract
Pharmacologic cardiac conditioning increases the intrinsic resistance against ischemia and reperfusion (I/R) injury. The cardiac conditioning response is mediated via complex signaling networks. These networks have been an intriguing research field for decades, largely advancing our knowledge on cardiac signaling beyond the conditioning response. The centerpieces of this system are the mitochondria, a dynamic organelle, almost acting as a cell within the cell. Mitochondria comprise a plethora of functions at the crossroads of cell death or survival. These include the maintenance of aerobic ATP production and redox signaling, closely entwined with mitochondrial calcium handling and mitochondrial permeability transition. Moreover, mitochondria host pathways of programmed cell death impact the inflammatory response and contain their own mechanisms of fusion and fission (division). These act as quality control mechanisms in cellular ageing, release of pro-apoptotic factors and mitophagy. Furthermore, recently identified mechanisms of mitochondrial regeneration can increase the capacity for oxidative phosphorylation, decrease oxidative stress and might help to beneficially impact myocardial remodeling, as well as invigorate the heart against subsequent ischemic insults. The current review highlights different pathways and unresolved questions surrounding mitochondria in myocardial I/R injury and pharmacological cardiac conditioning.
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7
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Impact of Adenosine A2 Receptor Ligands on BCL2 Expression in Skeletal Muscle Cells. APPLIED SCIENCES-BASEL 2021. [DOI: 10.3390/app11052272] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 11/16/2022]
Abstract
Background: Adenosine plays the role of regulating cell differentiation, proliferation, and apoptosis in various kinds of cells through the B-cell lymphoma 2 (BCL2) pathway. Objectives: Since anti-apoptotic (BCL2) expression plays a role in controlling apoptosis in some cell lines, this study was designed to investigate whether adenosine analogue, NECA (non-selective adenosine receptors agonist), selective adenosine A2B receptor antagonist, PSB 603, and a selective adenosine A2A receptor agonist, CG21680, affect BCL2-gene expression in the skeletal muscle cells of rats. The purpose of this investigation was to test the hypothesis that CG21680 treatment would significantly intensify BCL2 gene expression in rat skeletal muscle. Methods: Flasks measuring 25 cm2 were employed in culturing the rat L6 skeletal muscle cells. After treating these differential cells, the relative mRNA expression level for the BCL2 gene, at varying conditions of treatment, was measured using quantitative reverse transcription-polymerase chain reaction (qRT-PCR). Results: From the qRT-PCR analysis results, it was concluded that BCL2 expression was markedly amplified after selective adenosine A2A receptor agonist, CGS21680 (p < 0.01) treatment. More prospective validation for the adenosine receptors’ contribution in modulating apoptosis by NECA was delivered by the outcomes from the combined pre-treatment of the cells with NECA and PSB 603. These outcomes show that when starved skeletal muscle cells are treated with a combination of NECA and 100 nM PSB 603, there was a substantial decrease in comparison to either treatment used on its own. Conclusions: This study’s results showed, for the first time, an increase in BCL2 gene expression within skeletal muscle after CGS21680 treatment. Hence, the prospective escalation in BCL2 protein expression might have a protective role to play against apoptosis and avert damage to the skeletal muscle.
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8
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Wang W, Wang B, Sun S, Cao S, Zhai X, Zhang C, Zhang Q, Yuan Q, Sun Y, Xue M, Ma J, Xu F, Wei S, Chen Y. Inhibition of adenosine kinase attenuates myocardial ischaemia/reperfusion injury. J Cell Mol Med 2021; 25:2931-2943. [PMID: 33523568 PMCID: PMC7957171 DOI: 10.1111/jcmm.16328] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/24/2020] [Revised: 12/31/2020] [Accepted: 01/15/2021] [Indexed: 12/12/2022] Open
Abstract
Increased adenosine helps limit infarct size in ischaemia/reperfusion‐injured hearts. In cardiomyocytes, 90% of adenosine is catalysed by adenosine kinase (ADK) and ADK inhibition leads to higher concentrations of both intracellular adenosine and extracellular adenosine. However, the role of ADK inhibition in myocardial ischaemia/reperfusion (I/R) injury remains less obvious. We explored the role of ADK inhibition in myocardial I/R injury using mouse left anterior ligation model. To inhibit ADK, the inhibitor ABT‐702 was intraperitoneally injected or AAV9 (adeno‐associated virus)—ADK—shRNA was introduced via tail vein injection. H9c2 cells were exposed to hypoxia/reoxygenation (H/R) to elucidate the underlying mechanisms. ADK was transiently increased after myocardial I/R injury. Pharmacological or genetic ADK inhibition reduced infarct size, improved cardiac function and prevented cell apoptosis and necroptosis in I/R‐injured mouse hearts. In vitro, ADK inhibition also prevented cell apoptosis and cell necroptosis in H/R‐treated H9c2 cells. Cleaved caspase‐9, cleaved caspase‐8, cleaved caspase‐3, MLKL and the phosphorylation of MLKL and CaMKII were decreased by ADK inhibition in reperfusion‐injured cardiomyocytes. X‐linked inhibitor of apoptosis protein (XIAP), which is phosphorylated and stabilized via the adenosine receptors A2B and A1/Akt pathways, should play a central role in the effects of ADK inhibition on cell apoptosis and necroptosis. These data suggest that ADK plays an important role in myocardial I/R injury by regulating cell apoptosis and necroptosis.
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Affiliation(s)
- Wenjun Wang
- Department of Emergency and Chest Pain Center, Qilu Hospital, Cheeloo College of Medicine, Shandong University, Jinan, China.,Clinical Research Center for Emergency and Critical Care Medicine of Shandong Province, Institute of Emergency and Critical Care Medicine of Shandong University, Qilu Hospital, Cheeloo College of Medicine, Shandong University, Jinan, China.,Key Laboratory of Emergency and Critical Care Medicine of Shandong Province, Key Laboratory of Cardiopulmonary-Cerebral Resuscitation Research of Shandong Province, Qilu Hospital, Cheeloo College of Medicine, Shandong University, Jinan, China.,The Key Laboratory of Cardiovascular Remodeling and Function Research, Chinese Ministry of Education, Chinese Ministry of Health and Chinese Academy of Medical Sciences, Qilu Hospital, Cheeloo College of Medicine, Shandong University, Jinan, China.,The State and Shandong Province Joint Key Laboratory of Translational Cardiovascular Medicine, Qilu Hospital, Cheeloo College of Medicine, Shandong University, Jinan, China
| | - Bailu Wang
- Clinical Trial Center, Qilu Hospital, Cheeloo College of Medicine, Shandong University, Jinan, China
| | - Shukun Sun
- Department of Emergency and Chest Pain Center, Qilu Hospital, Cheeloo College of Medicine, Shandong University, Jinan, China.,Clinical Research Center for Emergency and Critical Care Medicine of Shandong Province, Institute of Emergency and Critical Care Medicine of Shandong University, Qilu Hospital, Cheeloo College of Medicine, Shandong University, Jinan, China.,Key Laboratory of Emergency and Critical Care Medicine of Shandong Province, Key Laboratory of Cardiopulmonary-Cerebral Resuscitation Research of Shandong Province, Qilu Hospital, Cheeloo College of Medicine, Shandong University, Jinan, China.,The Key Laboratory of Cardiovascular Remodeling and Function Research, Chinese Ministry of Education, Chinese Ministry of Health and Chinese Academy of Medical Sciences, Qilu Hospital, Cheeloo College of Medicine, Shandong University, Jinan, China.,The State and Shandong Province Joint Key Laboratory of Translational Cardiovascular Medicine, Qilu Hospital, Cheeloo College of Medicine, Shandong University, Jinan, China
| | - Shengchuan Cao
- Department of Emergency and Chest Pain Center, Qilu Hospital, Cheeloo College of Medicine, Shandong University, Jinan, China.,Clinical Research Center for Emergency and Critical Care Medicine of Shandong Province, Institute of Emergency and Critical Care Medicine of Shandong University, Qilu Hospital, Cheeloo College of Medicine, Shandong University, Jinan, China.,Key Laboratory of Emergency and Critical Care Medicine of Shandong Province, Key Laboratory of Cardiopulmonary-Cerebral Resuscitation Research of Shandong Province, Qilu Hospital, Cheeloo College of Medicine, Shandong University, Jinan, China.,The Key Laboratory of Cardiovascular Remodeling and Function Research, Chinese Ministry of Education, Chinese Ministry of Health and Chinese Academy of Medical Sciences, Qilu Hospital, Cheeloo College of Medicine, Shandong University, Jinan, China.,The State and Shandong Province Joint Key Laboratory of Translational Cardiovascular Medicine, Qilu Hospital, Cheeloo College of Medicine, Shandong University, Jinan, China
| | - Xiaoxuan Zhai
- Department of Emergency and Chest Pain Center, Qilu Hospital, Cheeloo College of Medicine, Shandong University, Jinan, China.,Clinical Research Center for Emergency and Critical Care Medicine of Shandong Province, Institute of Emergency and Critical Care Medicine of Shandong University, Qilu Hospital, Cheeloo College of Medicine, Shandong University, Jinan, China.,Key Laboratory of Emergency and Critical Care Medicine of Shandong Province, Key Laboratory of Cardiopulmonary-Cerebral Resuscitation Research of Shandong Province, Qilu Hospital, Cheeloo College of Medicine, Shandong University, Jinan, China.,The Key Laboratory of Cardiovascular Remodeling and Function Research, Chinese Ministry of Education, Chinese Ministry of Health and Chinese Academy of Medical Sciences, Qilu Hospital, Cheeloo College of Medicine, Shandong University, Jinan, China.,The State and Shandong Province Joint Key Laboratory of Translational Cardiovascular Medicine, Qilu Hospital, Cheeloo College of Medicine, Shandong University, Jinan, China
| | - Chuanxin Zhang
- Department of Emergency and Chest Pain Center, Qilu Hospital, Cheeloo College of Medicine, Shandong University, Jinan, China.,Clinical Research Center for Emergency and Critical Care Medicine of Shandong Province, Institute of Emergency and Critical Care Medicine of Shandong University, Qilu Hospital, Cheeloo College of Medicine, Shandong University, Jinan, China.,Key Laboratory of Emergency and Critical Care Medicine of Shandong Province, Key Laboratory of Cardiopulmonary-Cerebral Resuscitation Research of Shandong Province, Qilu Hospital, Cheeloo College of Medicine, Shandong University, Jinan, China.,The Key Laboratory of Cardiovascular Remodeling and Function Research, Chinese Ministry of Education, Chinese Ministry of Health and Chinese Academy of Medical Sciences, Qilu Hospital, Cheeloo College of Medicine, Shandong University, Jinan, China.,The State and Shandong Province Joint Key Laboratory of Translational Cardiovascular Medicine, Qilu Hospital, Cheeloo College of Medicine, Shandong University, Jinan, China
| | - Qun Zhang
- Department of Emergency and Chest Pain Center, Qilu Hospital, Cheeloo College of Medicine, Shandong University, Jinan, China.,Clinical Research Center for Emergency and Critical Care Medicine of Shandong Province, Institute of Emergency and Critical Care Medicine of Shandong University, Qilu Hospital, Cheeloo College of Medicine, Shandong University, Jinan, China.,Key Laboratory of Emergency and Critical Care Medicine of Shandong Province, Key Laboratory of Cardiopulmonary-Cerebral Resuscitation Research of Shandong Province, Qilu Hospital, Cheeloo College of Medicine, Shandong University, Jinan, China.,The Key Laboratory of Cardiovascular Remodeling and Function Research, Chinese Ministry of Education, Chinese Ministry of Health and Chinese Academy of Medical Sciences, Qilu Hospital, Cheeloo College of Medicine, Shandong University, Jinan, China.,The State and Shandong Province Joint Key Laboratory of Translational Cardiovascular Medicine, Qilu Hospital, Cheeloo College of Medicine, Shandong University, Jinan, China
| | - Qiuhuan Yuan
- Department of Emergency and Chest Pain Center, Qilu Hospital, Cheeloo College of Medicine, Shandong University, Jinan, China.,Clinical Research Center for Emergency and Critical Care Medicine of Shandong Province, Institute of Emergency and Critical Care Medicine of Shandong University, Qilu Hospital, Cheeloo College of Medicine, Shandong University, Jinan, China.,Key Laboratory of Emergency and Critical Care Medicine of Shandong Province, Key Laboratory of Cardiopulmonary-Cerebral Resuscitation Research of Shandong Province, Qilu Hospital, Cheeloo College of Medicine, Shandong University, Jinan, China.,The Key Laboratory of Cardiovascular Remodeling and Function Research, Chinese Ministry of Education, Chinese Ministry of Health and Chinese Academy of Medical Sciences, Qilu Hospital, Cheeloo College of Medicine, Shandong University, Jinan, China.,The State and Shandong Province Joint Key Laboratory of Translational Cardiovascular Medicine, Qilu Hospital, Cheeloo College of Medicine, Shandong University, Jinan, China
| | - Yi Sun
- Department of Emergency and Chest Pain Center, Qilu Hospital, Cheeloo College of Medicine, Shandong University, Jinan, China.,Clinical Research Center for Emergency and Critical Care Medicine of Shandong Province, Institute of Emergency and Critical Care Medicine of Shandong University, Qilu Hospital, Cheeloo College of Medicine, Shandong University, Jinan, China.,Key Laboratory of Emergency and Critical Care Medicine of Shandong Province, Key Laboratory of Cardiopulmonary-Cerebral Resuscitation Research of Shandong Province, Qilu Hospital, Cheeloo College of Medicine, Shandong University, Jinan, China.,The Key Laboratory of Cardiovascular Remodeling and Function Research, Chinese Ministry of Education, Chinese Ministry of Health and Chinese Academy of Medical Sciences, Qilu Hospital, Cheeloo College of Medicine, Shandong University, Jinan, China.,The State and Shandong Province Joint Key Laboratory of Translational Cardiovascular Medicine, Qilu Hospital, Cheeloo College of Medicine, Shandong University, Jinan, China
| | - Mengyang Xue
- Department of Emergency and Chest Pain Center, Qilu Hospital, Cheeloo College of Medicine, Shandong University, Jinan, China.,Clinical Research Center for Emergency and Critical Care Medicine of Shandong Province, Institute of Emergency and Critical Care Medicine of Shandong University, Qilu Hospital, Cheeloo College of Medicine, Shandong University, Jinan, China.,Key Laboratory of Emergency and Critical Care Medicine of Shandong Province, Key Laboratory of Cardiopulmonary-Cerebral Resuscitation Research of Shandong Province, Qilu Hospital, Cheeloo College of Medicine, Shandong University, Jinan, China.,The Key Laboratory of Cardiovascular Remodeling and Function Research, Chinese Ministry of Education, Chinese Ministry of Health and Chinese Academy of Medical Sciences, Qilu Hospital, Cheeloo College of Medicine, Shandong University, Jinan, China.,The State and Shandong Province Joint Key Laboratory of Translational Cardiovascular Medicine, Qilu Hospital, Cheeloo College of Medicine, Shandong University, Jinan, China
| | - Jingjing Ma
- Department of Emergency and Chest Pain Center, Qilu Hospital, Cheeloo College of Medicine, Shandong University, Jinan, China.,Clinical Research Center for Emergency and Critical Care Medicine of Shandong Province, Institute of Emergency and Critical Care Medicine of Shandong University, Qilu Hospital, Cheeloo College of Medicine, Shandong University, Jinan, China.,Key Laboratory of Emergency and Critical Care Medicine of Shandong Province, Key Laboratory of Cardiopulmonary-Cerebral Resuscitation Research of Shandong Province, Qilu Hospital, Cheeloo College of Medicine, Shandong University, Jinan, China.,The Key Laboratory of Cardiovascular Remodeling and Function Research, Chinese Ministry of Education, Chinese Ministry of Health and Chinese Academy of Medical Sciences, Qilu Hospital, Cheeloo College of Medicine, Shandong University, Jinan, China.,The State and Shandong Province Joint Key Laboratory of Translational Cardiovascular Medicine, Qilu Hospital, Cheeloo College of Medicine, Shandong University, Jinan, China
| | - Feng Xu
- Department of Emergency and Chest Pain Center, Qilu Hospital, Cheeloo College of Medicine, Shandong University, Jinan, China.,Clinical Research Center for Emergency and Critical Care Medicine of Shandong Province, Institute of Emergency and Critical Care Medicine of Shandong University, Qilu Hospital, Cheeloo College of Medicine, Shandong University, Jinan, China.,Key Laboratory of Emergency and Critical Care Medicine of Shandong Province, Key Laboratory of Cardiopulmonary-Cerebral Resuscitation Research of Shandong Province, Qilu Hospital, Cheeloo College of Medicine, Shandong University, Jinan, China.,The Key Laboratory of Cardiovascular Remodeling and Function Research, Chinese Ministry of Education, Chinese Ministry of Health and Chinese Academy of Medical Sciences, Qilu Hospital, Cheeloo College of Medicine, Shandong University, Jinan, China.,The State and Shandong Province Joint Key Laboratory of Translational Cardiovascular Medicine, Qilu Hospital, Cheeloo College of Medicine, Shandong University, Jinan, China
| | - Shujian Wei
- Department of Emergency and Chest Pain Center, Qilu Hospital, Cheeloo College of Medicine, Shandong University, Jinan, China.,Clinical Research Center for Emergency and Critical Care Medicine of Shandong Province, Institute of Emergency and Critical Care Medicine of Shandong University, Qilu Hospital, Cheeloo College of Medicine, Shandong University, Jinan, China.,Key Laboratory of Emergency and Critical Care Medicine of Shandong Province, Key Laboratory of Cardiopulmonary-Cerebral Resuscitation Research of Shandong Province, Qilu Hospital, Cheeloo College of Medicine, Shandong University, Jinan, China.,The Key Laboratory of Cardiovascular Remodeling and Function Research, Chinese Ministry of Education, Chinese Ministry of Health and Chinese Academy of Medical Sciences, Qilu Hospital, Cheeloo College of Medicine, Shandong University, Jinan, China.,The State and Shandong Province Joint Key Laboratory of Translational Cardiovascular Medicine, Qilu Hospital, Cheeloo College of Medicine, Shandong University, Jinan, China
| | - Yuguo Chen
- Department of Emergency and Chest Pain Center, Qilu Hospital, Cheeloo College of Medicine, Shandong University, Jinan, China.,Clinical Research Center for Emergency and Critical Care Medicine of Shandong Province, Institute of Emergency and Critical Care Medicine of Shandong University, Qilu Hospital, Cheeloo College of Medicine, Shandong University, Jinan, China.,Key Laboratory of Emergency and Critical Care Medicine of Shandong Province, Key Laboratory of Cardiopulmonary-Cerebral Resuscitation Research of Shandong Province, Qilu Hospital, Cheeloo College of Medicine, Shandong University, Jinan, China.,The Key Laboratory of Cardiovascular Remodeling and Function Research, Chinese Ministry of Education, Chinese Ministry of Health and Chinese Academy of Medical Sciences, Qilu Hospital, Cheeloo College of Medicine, Shandong University, Jinan, China.,The State and Shandong Province Joint Key Laboratory of Translational Cardiovascular Medicine, Qilu Hospital, Cheeloo College of Medicine, Shandong University, Jinan, China
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9
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Andrejew R, Glaser T, Oliveira-Giacomelli Á, Ribeiro D, Godoy M, Granato A, Ulrich H. Targeting Purinergic Signaling and Cell Therapy in Cardiovascular and Neurodegenerative Diseases. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2020; 1201:275-353. [PMID: 31898792 DOI: 10.1007/978-3-030-31206-0_14] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
Extracellular purines exert several functions in physiological and pathophysiological mechanisms. ATP acts through P2 receptors as a neurotransmitter and neuromodulator and modulates heart contractility, while adenosine participates in neurotransmission, blood pressure, and many other mechanisms. Because of their capability to differentiate into mature cell types, they provide a unique therapeutic strategy for regenerating damaged tissue, such as in cardiovascular and neurodegenerative diseases. Purinergic signaling is pivotal for controlling stem cell differentiation and phenotype determination. Proliferation, differentiation, and apoptosis of stem cells of various origins are regulated by purinergic receptors. In this chapter, we selected neurodegenerative and cardiovascular diseases with clinical trials using cell therapy and purinergic receptor targeting. We discuss these approaches as therapeutic alternatives to neurodegenerative and cardiovascular diseases. For instance, promising results were demonstrated in the utilization of mesenchymal stem cells and bone marrow mononuclear cells in vascular regeneration. Regarding neurodegenerative diseases, in general, P2X7 and A2A receptors mostly worsen the degenerative state. Stem cell-based therapy, mainly through mesenchymal and hematopoietic stem cells, showed promising results in improving symptoms caused by neurodegeneration. We propose that purinergic receptor activity regulation combined with stem cells could enhance proliferative and differentiation rates as well as cell engraftment.
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Affiliation(s)
- Roberta Andrejew
- Neuroscience Laboratory, Institute of Chemistry, Department of Biochemistry, University of São Paulo, São Paulo, Brazil
| | - Talita Glaser
- Neuroscience Laboratory, Institute of Chemistry, Department of Biochemistry, University of São Paulo, São Paulo, Brazil
| | - Ágatha Oliveira-Giacomelli
- Neuroscience Laboratory, Institute of Chemistry, Department of Biochemistry, University of São Paulo, São Paulo, Brazil
| | - Deidiane Ribeiro
- Neuroscience Laboratory, Institute of Chemistry, Department of Biochemistry, University of São Paulo, São Paulo, Brazil
| | - Mariana Godoy
- Neuroscience Laboratory, Institute of Chemistry, Department of Biochemistry, University of São Paulo, São Paulo, Brazil.,Laboratory of Neurodegenerative Diseases, Institute of Biophysics Carlos Chagas Filho, Federal University of Rio de Janeiro, Rio de Janeiro, Brazil
| | - Alessandro Granato
- Neuroscience Laboratory, Institute of Chemistry, Department of Biochemistry, University of São Paulo, São Paulo, Brazil
| | - Henning Ulrich
- Neuroscience Laboratory, Institute of Chemistry, Department of Biochemistry, University of São Paulo, São Paulo, Brazil.
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10
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The Role of Adenosine A2b Receptor in Mediating the Cardioprotection of Electroacupuncture Pretreatment via Influencing Ca 2+ Key Regulators. EVIDENCE-BASED COMPLEMENTARY AND ALTERNATIVE MEDICINE 2019; 2019:6721286. [PMID: 31885657 PMCID: PMC6925712 DOI: 10.1155/2019/6721286] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 07/25/2019] [Revised: 10/29/2019] [Accepted: 11/11/2019] [Indexed: 11/24/2022]
Abstract
Objective To investigate the roles played by A2b receptor and the key Ca2+ signaling components in the mediation of the cardioprotection of electroacupuncture pretreatment in the rats subjected to myocardial ischemia and reperfusion. Methods SD rats were randomly divided into a normal control (NC) group, ischemia/reperfusion model (M) group, electroacupuncture pretreatment (EA) group, and electroacupuncture pretreatment plus A2b antagonist (EAG) group. The ischemia/reperfusion model was made by ligation and loosening of the left descending branch of the coronary artery in all groups except the NC group. The EA group was pretreated with electroacupuncture at the Neiguan (PC6) point once a day for three consecutive days before the modeling. The elevation of the ST segment, arrhythmia scores, and myocardial infarction size of each group was measured. The relative expression levels of A2b, RyR2, SERCA2a, NCX1, P-PLB(S16)/PLB, and Troponin C/Troponin I proteins in the injured myocardium were detected by multiple fluorescence western blot. Results The level of ST segment, arrhythmia scores, and infarct size in the M group was significantly higher/larger than that in the NC group after ischemia and reperfusion, while all the three indices mentioned above in the EA group were significantly lower/smaller than those in the M group after reperfusion. The expression of the proteins of adenosine receptor 2b(A2b), ryanodine receptor 2(RyR2), and sarco(endo)plasmic reticulum Ca2+-ATPase 2a (SERCA2a) in the EA group was significantly enhanced as compared with the M group, while in the EAG group, the contents of A2b were significantly lower than those in the EA group, and RyR2 was higher in the EAG group. In comparison with the NC group, the relative expression of NCX1 protein in M, EA, and EAG groups was not changed significantly. The ratio of phosphorylated phospholamban (P-PLB) over phospholamban (PLB) in the M group was significantly lower than that in the NC group, and the ratio in the EA group was significantly increased as compared with the M group, while the ratio of Troponin C/Troponin I in the EA group was significantly decreased in comparison with that in other groups. Conclusion Electroacupuncture pretreatment could reduce ischemia and reperfusion-induced myocardial injury via possibly increasing the A2b content and regulating the key Ca2+ signaling components, namely inhibiting RyR2 and enhancing P-PLB(S16)/PLB ratio and SERCA2a proteins, so as to diminish the intracellular Ca2+ overload and consequently lessen the myocardial injury.
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11
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Soleimani A, Bahreyni A, Roshan MK, Soltani A, Ryzhikov M, Shafiee M, Soukhtanloo M, Jaafari MR, Mashkani B, Hassanian SM. Therapeutic potency of pharmacological adenosine receptors agonist/antagonist on cancer cell apoptosis in tumor microenvironment, current status, and perspectives. J Cell Physiol 2018; 234:2329-2336. [PMID: 30191994 DOI: 10.1002/jcp.27249] [Citation(s) in RCA: 18] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/22/2018] [Accepted: 07/24/2018] [Indexed: 12/14/2022]
Abstract
The hypoxic niche of tumor leads to a tremendous increase in the extracellular adenosine concentration through alteration of adenosine metabolism in the tumor microenvironment (TME). This consequently affects cancer progression, local immune responses, and apoptosis of tumor cells. Regulatory effect of adenosine on apoptosis in TME depends on the cancer cell type, pharmacological characteristics of adenosine receptor subtypes, and the adenosine concentration in the tumor niche. Exploiting specific pharmacological adenosine receptor agonist and antagonist inducing apoptosis in cancer cells can be considered as a proper procedure to control cancer progression. This review summarizes the regulatory role of adenosine in cancer cell apoptosis for a better understanding, and hence better management of the disease.
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Affiliation(s)
- Anvar Soleimani
- Department of Clinical Biochemistry, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Amirhossein Bahreyni
- Department of Clinical Biochemistry and Immunogenetic Research Center, Faculty of Medicine, Mazandaran University of Medical Sciences, Sari, Mazandaran, Iran
| | - Mostafa K Roshan
- Department of Clinical Biochemistry, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Arash Soltani
- Department of Clinical Biochemistry, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Mikhail Ryzhikov
- Division of Pulmonary and Critical Care Medicine, Washington University, School of Medicine, Saint Louis, Missouri
| | - Mojtaba Shafiee
- Department of Nutrition, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Mohammad Soukhtanloo
- Department of Clinical Biochemistry, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Mahmoud R Jaafari
- Nanotechnology Research Center, Mashhad University of Medical Sciences, Mashhad, Iran.,Department of Pharmaceutical Nanotechnology, School of Pharmacy, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Baratali Mashkani
- Department of Clinical Biochemistry, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Seyed M Hassanian
- Department of Clinical Biochemistry, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran.,Metabolic Syndrome Research Center, Mashhad University of Medical Sciences, Mashhad, Iran.,Microanatomy Research Center, Mashhad University of Medical Sciences, Mashhad, Iran
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12
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White CW, Messer SJ, Large SR, Conway J, Kim DH, Kutsogiannis DJ, Nagendran J, Freed DH. Transplantation of Hearts Donated after Circulatory Death. Front Cardiovasc Med 2018; 5:8. [PMID: 29487855 PMCID: PMC5816942 DOI: 10.3389/fcvm.2018.00008] [Citation(s) in RCA: 85] [Impact Index Per Article: 12.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/05/2017] [Accepted: 01/19/2018] [Indexed: 12/17/2022] Open
Abstract
Cardiac transplantation has become limited by a critical shortage of suitable organs from brain-dead donors. Reports describing the successful clinical transplantation of hearts donated after circulatory death (DCD) have recently emerged. Hearts from DCD donors suffer significant ischemic injury prior to organ procurement; therefore, the traditional approach to the transplantation of hearts from brain-dead donors is not applicable to the DCD context. Advances in our understanding of ischemic post-conditioning have facilitated the development of DCD heart resuscitation strategies that can be used to minimize ischemia-reperfusion injury at the time of organ procurement. The availability of a clinically approved ex situ heart perfusion device now allows DCD heart preservation in a normothermic beating state and minimizes exposure to incremental cold ischemia. This technology also facilitates assessments of organ viability to be undertaken prior to transplantation, thereby minimizing the risk of primary graft dysfunction. The application of a tailored approach to DCD heart transplantation that focuses on organ resuscitation at the time of procurement, ex situ preservation, and pre-transplant assessments of organ viability has facilitated the successful clinical application of DCD heart transplantation. The transplantation of hearts from DCD donors is now a clinical reality. Investigating ways to optimize the resuscitation, preservation, evaluation, and long-term outcomes is vital to ensure a broader application of DCD heart transplantation in the future.
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Affiliation(s)
| | - Simon J Messer
- Papworth Hospital NHS Foundation Trust, Cambridge, United Kingdom
| | - Stephen R Large
- Papworth Hospital NHS Foundation Trust, Cambridge, United Kingdom
| | | | - Daniel H Kim
- Cardiology, University of Alberta, Edmonton, AB, Canada
| | | | - Jayan Nagendran
- Cardiac Surgery, University of Alberta, Edmonton, AB, Canada
| | - Darren H Freed
- Cardiac Surgery, University of Alberta, Edmonton, AB, Canada.,Department of Physiology, University of Alberta, Edmonton, AB, Canada.,Department of Biomedical Engineering, University of Alberta, Edmonton, AB, Canada
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13
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Zhang C, Liu X, Zhang C, Li J, Guo W, Yan D, Yang C, Zhao J, Wu X, Shi J. Phosphorylated eEF2 is SUMOylated and induces cardiomyocyte apoptosis during myocardial ischemia reperfusion. J Cardiol 2017; 69:689-698. [DOI: 10.1016/j.jjcc.2016.05.020] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/21/2016] [Revised: 05/21/2016] [Accepted: 05/27/2016] [Indexed: 12/13/2022]
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A2 Adenosine Receptor-mediated Cardioprotection Against Reperfusion Injury in Rat Hearts Is Associated With Autophagy Downregulation. J Cardiovasc Pharmacol 2015; 66:25-34. [DOI: 10.1097/fjc.0000000000000239] [Citation(s) in RCA: 21] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/27/2022]
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15
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Liang Y, Li Z, Mo N, Li M, Zhuang Z, Wang J, Wang Y, Guo X. Isoflurane preconditioning ameliorates renal ischemia-reperfusion injury through antiinflammatory and antiapoptotic actions in rats. Biol Pharm Bull 2014; 37:1599-605. [PMID: 25088045 DOI: 10.1248/bpb.b14-00211] [Citation(s) in RCA: 24] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/22/2022]
Abstract
Renal ischemia-reperfusion (I/R) injury is a major cause of acute kidney injury via inflammation and cell apoptosis. Volatile anesthetics have been shown to exert organ-protective effects against kidney damage in vivo and in vitro. In the present study, we investigated the effects of isoflurane, a commonly used volatile anesthetic, on renal I/R injury and the underlying mechanisms. Rats subjected to renal I/R displayed higher serum creatinine and blood urea nitrogen levels than sham rats as well as severe histopathological damage. Renal I/R also resulted in a nuclear factor-κB (NF-κB)-mediated inflammatory response and dysfunction of the p53-Bax-caspase-3 apoptotic pathway. Rats preconditioned with 1.5% isoflurane for 2 h had better renal function and less tubular apoptosis 24 h after I/R injury than control rats. Pretreatment with isoflurane suppressed renal NF-κB activation, leading to a reduction in proinflammatory molecules (high-mobility group box 1, interleukin-1β, and tumor necrosis factor-α) both in the kidneys and circulation. In addition, rats subjected to isoflurane preconditioning had a higher Bcl-2/Bax ratio and less cleaved caspase-3. Our findings suggest that preconditioning with a clinically relevant concentration of isoflurane attenuates renal I/R injury, based at least in part on its ability to modulate renal inflammation and apoptosis.
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Affiliation(s)
- Yaoxian Liang
- Department of Nephrology, Peking University Third Hospital
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Scarfì S. Purinergic receptors and nucleotide processing ectoenzymes: Their roles in regulating mesenchymal stem cell functions. World J Stem Cells 2014; 6:153-162. [PMID: 24772242 PMCID: PMC3999773 DOI: 10.4252/wjsc.v6.i2.153] [Citation(s) in RCA: 26] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/28/2013] [Revised: 02/10/2014] [Accepted: 03/12/2014] [Indexed: 02/06/2023] Open
Abstract
Human mesenchymal stem cells (MSCs) are a rare population of non-hematopoietic stem cells with multilineage potential, originally identified in the bone marrow. Due to the lack of a single specific marker, MSCs can be recognized and isolated by a series of features such as plastic adherence, a panel of surface markers, the clonogenic and the differentiation abilities. The recognized role of MSCs in the regulation of hemopoiesis, in cell-degeneration protection and in the homeostasis of mesodermal tissues through their differentiation properties, justifies the current interest in identifying the biochemical signals produced by MSCs and their active crosstalk in tissue environments. Only recently have extracellular nucleotides (eNTPs) and their metabolites been included among the molecular signals produced by MSCs. These molecules are active on both ionotropic and metabotropic receptors present in most cell types. MSCs possess a significant display of these receptors and of nucleotide processing ectoenzymes on their plasma membrane. Thus, from their niche, MSCs give a significant contribution to the complex signaling network of eNTPs and its derivatives. Recent studies have demonstrated the multifaceted aspects of eNTP metabolism and their signal transduction in MSCs and revealed important roles in specifying differentiation lineages and modulating MSC physiology and communication with other cells. This review discusses the roles of eNTPs, their receptors and ectoenzymes, and the relevance of the signaling network and MSC functions, and also focuses on the importance of this emerging area of interest for future MSC-based cell therapies.
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A cardioprotective preservation strategy employing ex vivo heart perfusion facilitates successful transplant of donor hearts after cardiocirculatory death. J Heart Lung Transplant 2013; 32:734-43. [PMID: 23796155 DOI: 10.1016/j.healun.2013.04.016] [Citation(s) in RCA: 64] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/01/2013] [Revised: 04/20/2013] [Accepted: 04/30/2013] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND Ex vivo heart perfusion (EVHP) has been proposed as a means to facilitate the resuscitation of donor hearts after cardiocirculatory death (DCD) and increase the donor pool. However, the current approach to clinical EVHP may exacerbate myocardial injury and impair function after transplant. Therefore, we sought to determine if a cardioprotective EVHP strategy that eliminates myocardial exposure to hypothermic hyperkalemia cardioplegia and minimizes cold ischemia could facilitate successful DCD heart transplantation. METHODS Anesthetized pigs sustained a hypoxic cardiac arrest and a 15-minute warm ischemic standoff period. Strategy 1 hearts (S1, n = 9) underwent initial reperfusion with a cold hyperkalemic cardioplegia, normothermic EVHP, and transplantation after a cold hyperkalemic cardioplegic arrest (current EVHP strategy). Strategy 2 hearts (S2, n = 8) underwent initial reperfusion with a tepid adenosine-lidocaine cardioplegia, normothermic EVHP, and transplantation with continuous myocardial perfusion (cardioprotective EVHP strategy). RESULTS At completion of EVHP, S2 hearts exhibited less weight gain (9.7 ± 6.7 [S2] vs 21.2 ± 6.7 [S1] g/hour, p = 0.008) and less troponin-I release into the coronary sinus effluent (4.2 ± 1.3 [S2] vs 6.3 ± 1.5 [S1] ng/ml; p = 0.014). Mass spectrometry analysis of oxidized pleural in post-transplant myocardium revealed less oxidative stress in S2 hearts. At 30 minutes after wean from cardiopulmonary bypass, post-transplant systolic (pre-load recruitable stroke work: 33.5 ± 1.3 [S2] vs 19.7 ± 10.9 [S1], p = 0.043) and diastolic (isovolumic relaxation constant: 42.9 ± 6.7 [S2] vs 65.2 ± 21.1 [S1], p = 0.020) function were superior in S2 hearts. CONCLUSION In this experimental model of DCD, an EVHP strategy using initial reperfusion with a tepid adenosine-lidocaine cardioplegia and continuous myocardial perfusion minimizes myocardial injury and improves short-term post-transplant function compared with the current EVHP strategy using cold hyperkalemic cardioplegia before organ procurement and transplantation.
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18
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Cardiovascular adenosine receptors: Expression, actions and interactions. Pharmacol Ther 2013; 140:92-111. [DOI: 10.1016/j.pharmthera.2013.06.002] [Citation(s) in RCA: 163] [Impact Index Per Article: 13.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/28/2013] [Accepted: 05/28/2013] [Indexed: 12/26/2022]
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19
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Jeong YJ, Kang KJ. Effect of Angelica keiskei Extract on Apoptosis of MDA-MB-231 Human Breast Cancer Cells. ACTA ACUST UNITED AC 2011. [DOI: 10.3746/jkfn.2011.40.12.1654] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
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20
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Gessi S, Merighi S, Sacchetto V, Simioni C, Borea PA. Adenosine receptors and cancer. BIOCHIMICA ET BIOPHYSICA ACTA-BIOMEMBRANES 2011; 1808:1400-12. [DOI: 10.1016/j.bbamem.2010.09.020] [Citation(s) in RCA: 176] [Impact Index Per Article: 12.6] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Received: 04/08/2010] [Revised: 09/14/2010] [Accepted: 09/20/2010] [Indexed: 01/25/2023]
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Rondeau I, Picard S, Bah TM, Roy L, Godbout R, Rousseau G. Effects of different dietary omega-6/3 polyunsaturated fatty acids ratios on infarct size and the limbic system after myocardial infarction. Can J Physiol Pharmacol 2011; 89:169-76. [DOI: 10.1139/y11-007] [Citation(s) in RCA: 24] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/10/2023]
Abstract
Changes in dietary omega-6/3 polyunsaturated fatty acids (PUFA) ratios affect anti- and proinflammatory equilibrium. As reperfused myocardial infarction (MI) is an inflammatory pathology that alters the cell integrity of the myocardium but also of other tissues, such as the hippocampus and amygdala, attenuation of the inflammation could be helpful in maintaining cell integrity after MI. Therefore, we hypothesized that a decrease in the dietary omega-6/3 PUFA ratio, without altering the diet content in total fat, proteins, or carbohydrates, will result in a reduction of infarct size and a diminution of postreperfusion apoptosis observed in the amygdala and hippocampus. Male Sprague–Dawley rats were fed 1 of 3 diets containing different omega-6/3 PUFA ratios for 2 weeks (5:1; 1:1; 1:5). Then, myocardial ischemia was induced by left anterior descending coronary artery occlusion for 40 min, followed by reperfusion. Cardioprotective mechanisms were studied in the myocardium at 15 min of reperfusion, along with myocardial infarct size after 24 h of reperfusion. Apoptosis was evaluated in the hippocampus and the amygdala. We found that infarct size was significantly reduced by 32% in groups 1:5 and 1:1 vs. group 5:1. Akt activity was higher in groups 1:5 and 1:1 compared with group 5:1. Caspase-3 enzymatic activity doubled in area CA1 and the dentate gyrus (DG) in group 5:1 compared with groups 1:1 and 1:5. In addition, caspase-8 enzymatic activity was increased in the DG at 24 h, and caspase-9 was enhanced in CA1 at 24 h in group 5:1 vs. groups 1:1 and 1:5. These results demonstrate that the increase in the dietary omega-3 PUFA, at the expense of omega-6 PUFA, reduces infarct size and helps to inhibit apoptosis in the limbic system after MI.
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Affiliation(s)
- I. Rondeau
- Centre de biomédecine, Hôpital du Sacré-Cœur de Montréal, 5400 Boul. Gouin Ouest, Montreal, QC H4J 1C5, Canada
- Département de pharmacologie, Université de Montréal, C.P. 6128, Succ. Centre-Ville, Montreal, QC H3C 3J7, Canada
- Département de psychiatrie, Université de Montréal, C.P. 6128, Succ. Centre-Ville, Montreal, QC H3C 3J7, Canada
| | - S. Picard
- Centre de biomédecine, Hôpital du Sacré-Cœur de Montréal, 5400 Boul. Gouin Ouest, Montreal, QC H4J 1C5, Canada
- Département de pharmacologie, Université de Montréal, C.P. 6128, Succ. Centre-Ville, Montreal, QC H3C 3J7, Canada
- Département de psychiatrie, Université de Montréal, C.P. 6128, Succ. Centre-Ville, Montreal, QC H3C 3J7, Canada
| | - T. M. Bah
- Centre de biomédecine, Hôpital du Sacré-Cœur de Montréal, 5400 Boul. Gouin Ouest, Montreal, QC H4J 1C5, Canada
- Département de pharmacologie, Université de Montréal, C.P. 6128, Succ. Centre-Ville, Montreal, QC H3C 3J7, Canada
- Département de psychiatrie, Université de Montréal, C.P. 6128, Succ. Centre-Ville, Montreal, QC H3C 3J7, Canada
| | - L. Roy
- Centre de biomédecine, Hôpital du Sacré-Cœur de Montréal, 5400 Boul. Gouin Ouest, Montreal, QC H4J 1C5, Canada
- Département de pharmacologie, Université de Montréal, C.P. 6128, Succ. Centre-Ville, Montreal, QC H3C 3J7, Canada
- Département de psychiatrie, Université de Montréal, C.P. 6128, Succ. Centre-Ville, Montreal, QC H3C 3J7, Canada
| | - R. Godbout
- Centre de biomédecine, Hôpital du Sacré-Cœur de Montréal, 5400 Boul. Gouin Ouest, Montreal, QC H4J 1C5, Canada
- Département de pharmacologie, Université de Montréal, C.P. 6128, Succ. Centre-Ville, Montreal, QC H3C 3J7, Canada
- Département de psychiatrie, Université de Montréal, C.P. 6128, Succ. Centre-Ville, Montreal, QC H3C 3J7, Canada
| | - G. Rousseau
- Centre de biomédecine, Hôpital du Sacré-Cœur de Montréal, 5400 Boul. Gouin Ouest, Montreal, QC H4J 1C5, Canada
- Département de pharmacologie, Université de Montréal, C.P. 6128, Succ. Centre-Ville, Montreal, QC H3C 3J7, Canada
- Département de psychiatrie, Université de Montréal, C.P. 6128, Succ. Centre-Ville, Montreal, QC H3C 3J7, Canada
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Desmet W, Bogaert J, Dubois C, Sinnaeve P, Adriaenssens T, Pappas C, Ganame J, Dymarkowski S, Janssens S, Belmans A, Van de Werf F. High-dose intracoronary adenosine for myocardial salvage in patients with acute ST-segment elevation myocardial infarction. Eur Heart J 2010; 32:867-77. [PMID: 21196444 DOI: 10.1093/eurheartj/ehq492] [Citation(s) in RCA: 114] [Impact Index Per Article: 7.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/15/2022] Open
Abstract
AIMS Previous studies have suggested that intravenous administration of adenosine improves myocardial reperfusion and reduces infarct size in ST-elevation myocardial infarction (STEMI) patients. Intracoronary administration of adenosine has shown conflicting results. METHODS AND RESULTS In a prospective, single-centre, double-blind, placebo-controlled clinical study, we assessed whether selective intracoronary administration of adenosine distal to the occlusion site immediately before initial balloon inflation results in myocardial salvage and decreased microvascular obstruction (MVO) as assessed with cardiac magnetic resonance imaging (MRI). Using a combination of T(2)-weighted and contrast-enhanced sequences, myocardial salvage index (MSI) was defined as the percentage of the area at risk that did not become necrotic. We randomized 112 patients presenting with STEMI within 12 h from symptom onset to selective intracoronary administration of adenosine 4 mg or matching placebo. In 100/110 (91%) patients receiving study drug, MRI was performed on Days 2-3. No significant difference in MSI was found between adenosine- and placebo-treated patients: 41.3% (20.8, 66.7) vs. 47.8% (39.8, 60.9) [median (Q1, Q3)] (P = 0.52). The extent of MVO was comparable in both groups, with a trend favouring the placebo group: 2.4 g (0.0, 6.8) vs. 5.9 g (0.0, 12.8) after adenosine (P = 0.07). TIMI flow grade, TIMI frame count, myocardial blush grade, and ST-segment resolution after primary percutaneous coronary intervention were similar between groups. After 4 months, infarct size was similar in both treatment groups. CONCLUSION We found no evidence that selective high-dose intracoronary administration of adenosine distal to the occlusion site of the culprit lesion in STEMI patients results in incremental myocardial salvage or a decrease in microvascular obstruction.
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Affiliation(s)
- Walter Desmet
- Department of Cardiovascular Medicine, University Hospitals Leuven, Gasthuisberg, Herestraat 49, Leuven, Belgium.
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Headrick JP, Peart JN, Reichelt ME, Haseler LJ. Adenosine and its receptors in the heart: regulation, retaliation and adaptation. BIOCHIMICA ET BIOPHYSICA ACTA-BIOMEMBRANES 2010; 1808:1413-28. [PMID: 21094127 DOI: 10.1016/j.bbamem.2010.11.016] [Citation(s) in RCA: 80] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Received: 07/02/2010] [Revised: 11/05/2010] [Accepted: 11/07/2010] [Indexed: 10/18/2022]
Abstract
The purine nucleoside adenosine is an important regulator within the cardiovascular system, and throughout the body. Released in response to perturbations in energy state, among other stimuli, local adenosine interacts with 4 adenosine receptor sub-types on constituent cardiac and vascular cells: A(1), A(2A), A(2B), and A(3)ARs. These G-protein coupled receptors mediate varied responses, from modulation of coronary flow, heart rate and contraction, to cardioprotection, inflammatory regulation, and control of cell growth and tissue remodeling. Research also unveils an increasingly complex interplay between members of the adenosine receptor family, and with other receptor groups. Given generally favorable effects of adenosine receptor activity (e.g. improving the balance between myocardial energy utilization and supply, limiting injury and adverse remodeling, suppressing inflammation), the adenosine receptor system is an attractive target for therapeutic manipulation. Cardiovascular adenosine receptor-based therapies are already in place, and trials of new treatments underway. Although the complex interplay between adenosine receptors and other receptors, and their wide distribution and functions, pose challenges to implementation of site/target specific cardiovascular therapy, the potential of adenosinergic pharmacotherapy can be more fully realized with greater understanding of the roles of adenosine receptors under physiological and pathological conditions. This review addresses some of the major known and proposed actions of adenosine and adenosine receptors in the heart and vessels, focusing on the ability of the adenosine receptor system to regulate cell function, retaliate against injurious stressors, and mediate longer-term adaptive responses.
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Affiliation(s)
- John P Headrick
- Griffith Health Institute, Griffith University, Southport QLD, Australia.
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Lim JY, Han TR. Effect of electromyostimulation on apoptosis-related factors in denervation and reinnervation of rat skeletal muscles. Muscle Nerve 2010; 42:422-30. [PMID: 20589896 DOI: 10.1002/mus.21719] [Citation(s) in RCA: 14] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/06/2022]
Abstract
Electromyostimulation (EMS) has been utilized to reduce muscle atrophy, but its effect on denervated muscles is controversial. This study was performed to determine the effect of EMS on intramuscular changes and apoptosis during denervation and reinnervation following nerve damage. Rat sciatic nerves were denervated completely (CD) or partially (PD), and EMS was applied for 2 weeks. The same numbers of cases were followed without EMS. Nerve conduction studies, muscle weights, terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) assay to measure apoptotic changes, and Western blot were done 4, 8, and 12 weeks after injury. TUNEL-positive nuclei of CD muscles (18.6 +/- 5.5%) were more prevalent than those of PD muscles (7.5 +/- 3.3%). The EMS group showed greater muscle weight, fewer positive nuclei (4.7 +/- 1.9%), and lower BAX and Bcl-2 expression levels compared with the non-EMS group at 4 weeks after PD but not after CD. Denervated muscle atrophy delayed by EMS may be linked with enhanced anti-apoptosis under the control of apoptosis-related factors.
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Affiliation(s)
- Jae-Young Lim
- Department of Rehabilitation Medicine, Seoul National University College of Medicine, Seoul National University Bundang Hospital, Seoul, Republic of Korea
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Shalaby A, Rinne T, Järvinen O, Latva-Hirvelä J, Nuutila K, Saraste A, Laurikka J, Porkkala H, Saukko P, Tarkka M. The Impact of Adenosine Fast Induction of Myocardial Arrest during CABG on Myocardial Expression of Apoptosis-Regulating Genes Bax and Bcl-2. Cardiol Res Pract 2010; 2009:658965. [PMID: 20069048 PMCID: PMC2801008 DOI: 10.4061/2009/658965] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/17/2009] [Revised: 08/11/2009] [Accepted: 10/19/2009] [Indexed: 12/04/2022] Open
Abstract
Background. We studied the effect of fast induction of cardiac arrest with denosine on myocardial bax and bcl-2 expression. Methods and Results. 40 elective CABG patients were allocated into two groups. The adenosine group (n = 20) received 250 μg/kg adenosine into the aortic root followed by blood potassium cardioplegia. The control group received potassium cardioplegia in blood. Bcl-2 and bax were measured. Bax was reduced in the postoperative biopsies (1.38 versus 0.47, P = .002) in the control group. Bcl-2 showed a reducing tendency (0.14 versus 0.085, P = .07). After the adenosine treatment, the expression of both bax (0.52 versus 0.59, P = .4) and bcl-2 (0.104 versus 0.107, P = .4) remained unaltered after the operation. Conclusion. Open heart surgery is associated with rapid reduction in the expression of apoptosis regulating genes bax and bcl-2. Fast Adenosine induction abolished changes in their expression.
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Affiliation(s)
- Ahmed Shalaby
- Division of Cardiothoracic Surgery, Heart Center, Pirkanmaa Hospital District, P.O. Box 2000, 33521 Tampere, Finland
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van der Pals J, Koul S, Götberg MI, Olivecrona GK, Ugander M, Kanski M, Otto A, Götberg M, Arheden H, Erlinge D. Apyrase treatment of myocardial infarction according to a clinically applicable protocol fails to reduce myocardial injury in a porcine model. BMC Cardiovasc Disord 2010; 10:1. [PMID: 20047685 PMCID: PMC2820435 DOI: 10.1186/1471-2261-10-1] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/08/2009] [Accepted: 01/04/2010] [Indexed: 11/10/2022] Open
Abstract
Background Ectonucleotidase dependent adenosine generation has been implicated in preconditioning related cardioprotection against ischemia-reperfusion injury, and treatment with a soluble ectonucleotidase has been shown to reduce myocardial infarct size (IS) when applied prior to induction of ischemia. However, ectonucleotidase treatment according to a clinically applicable protocol, with administration only after induction of ischemia, has not previously been evaluated. We therefore investigated if treatment with the ectonucleotidase apyrase, according to a clinically applicable protocol, would reduce IS and microvascular obstruction (MO) in a large animal model. Methods A percutaneous coronary intervention balloon was inflated in the left anterior descending artery for 40 min, in 16 anesthetized pigs (40-50 kg). The pigs were randomized to 40 min of 1 ml/min intracoronary infusion of apyrase (10 U/ml, n = 8) or saline (0.9 mg/ml, n = 8), twenty minutes after balloon inflation. Area at risk (AAR) was evaluated by ex vivo SPECT. IS and MO were evaluated by ex vivo MRI. Results No differences were observed between the apyrase group and saline group with respect to IS/AAR (75.7 ± 4.2% vs 69.4 ± 5.0%, p = NS) or MO (10.7 ± 4.8% vs 11.4 ± 4.8%, p = NS), but apyrase prolonged the post-ischemic reactive hyperemia. Conclusion Apyrase treatment according to a clinically applicable protocol, with administration of apyrase after induction of ischemia, does not reduce myocardial infarct size or microvascular obstruction.
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Sumida A, Horiba M, Ishiguro H, Takenaka H, Ueda N, Ooboshi H, Opthof T, Kadomatsu K, Kodama I. Midkine gene transfer after myocardial infarction in rats prevents remodelling and ameliorates cardiac dysfunction. Cardiovasc Res 2009; 86:113-21. [PMID: 19969622 DOI: 10.1093/cvr/cvp386] [Citation(s) in RCA: 38] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/20/2023] Open
Abstract
AIM We have previously reported that therapy with midkine (MK) has a protective effect in mouse models of myocardial infarction (MI) and ischemia/reperfusion. The underlying mechanism was proved to be anti-apoptosis and prevention of left ventricular (LV) remodelling following angiogenesis. Here we investigated the effects of overexpression of MK by adenoviral gene transfer on cardiac function and remodelling in an experimental rat MI model. METHODS AND RESULTS MI was created in male Wistar rats. Adenoviral vectors encoding mouse MK (AdMK) or beta-galactosidase (AdLacZ; as controls) were injected in myocardium at the onset of MI. One week after injection, in vivo adenoviral gene expression was assessed by western blot and histological analysis. After echocardiographic analysis at 4 weeks and haemodynamic analysis at 6 weeks after MI, AdMK animals had better cardiac function compared with AdLacZ animals. Heart weight (HW) and relative HW of AdMK animals were not different from sham-operated animals after 6 weeks, pointing to a very potent effect in the prevention of ischemic cardiomyopathy. In histological studies at 6 weeks after MI, AdMK animals had less fibrosis in the non-infarcted myocardium and higher vascular density in the border-zone area compared with AdLacZ animals. AdMK animals had strongly upregulated levels of phosphorylated extracellular signal-regulated kinase, Akt, PI 3-kinase, and Bcl-2, whereas the level of Bax was downregulated compared with AdLacZ animals. CONCLUSION Overexpression of MK prevents LV remodelling and ameliorates LV dysfunction by anti-apoptotic and pro-angiogenic effects. MK gene transfer may provide a new therapeutic modality in ischemic cardiomyopathy and ischemic heart failure.
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Affiliation(s)
- Arihiro Sumida
- Department of Cardiovascular Research, Research Institute of Environmental Medicine, Nagoya University, Huro-cho, Chikusa-ku, Nagoya 464-8601, Japan
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Xi J, McIntosh R, Shen X, Lee S, Chanoit G, Criswell H, Zvara DA, Xu Z. Adenosine A2A and A2B receptors work in concert to induce a strong protection against reperfusion injury in rat hearts. J Mol Cell Cardiol 2009; 47:684-90. [PMID: 19695259 PMCID: PMC2782744 DOI: 10.1016/j.yjmcc.2009.08.009] [Citation(s) in RCA: 76] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/16/2009] [Revised: 07/28/2009] [Accepted: 08/09/2009] [Indexed: 01/28/2023]
Abstract
We aimed to test if stimulation of both adenosine A2A and A2B receptors is required to produce an effective cardioprotection against reperfusion injury. Isolated rat hearts were subjected to 30-min regional ischemia followed by 2 h of reperfusion. The adenosine A1/A2 receptor agonist 5'-(N-ethylcarboxamido) adenosine (NECA) given at reperfusion reduced infarct size, an effect that was reversed by both the adenosine A2A antagonist SCH58261 and the A2B antagonist MRS1706. The A2B agonist BAY 60-6583 but not the selective A2A agonist CGS21680 reduced infarct size. Interestingly, a combination of BAY 60-6583 and CGS21680 further reduced infarct size. These results suggest that both A2A and A2B receptors are involved in NECA's anti-infarct effect at reperfusion. NECA attenuated mitochondrial swelling upon reperfusion and this was blocked by both SCH58261 and MRS1706, indicating that activation of A2 receptors with NECA can modulate reperfusion-induced mitochondrial permeability transition pore (mPTP) opening. In support, NECA also prevented oxidant-induced loss of mitochondrial membrane potential (DeltaPsi(m)) and matrix Ca2+ overload in cardiomyocytes via both the A2 receptors. In addition, NECA increased mitochondrial glycogen synthase kinase-3beta (GSK-3beta) phosphorylation upon reperfusion and this was again blocked by SCH58261 and MRS1706. In conclusion, A2A and A2B receptors work in concert to prevent reperfusion injury in rat hearts treated with NECA. NECA may protect the heart by modulating the mPTP opening through inactivating mitochondrial GSK-3beta. A simultaneous stimulation of A2A and A2B receptors at reperfusion is required to produce a strong cardioprotection against reperfusion injury.
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MESH Headings
- Adenosine-5'-(N-ethylcarboxamide)/pharmacology
- Animals
- Blotting, Western
- Heart/drug effects
- Male
- Microscopy, Confocal
- Myocardium/metabolism
- Myocardium/pathology
- Myocytes, Cardiac/drug effects
- Myocytes, Cardiac/metabolism
- Myocytes, Cardiac/pathology
- Rats
- Rats, Wistar
- Receptor, Adenosine A2A/genetics
- Receptor, Adenosine A2A/metabolism
- Receptor, Adenosine A2A/physiology
- Receptor, Adenosine A2B/genetics
- Receptor, Adenosine A2B/metabolism
- Receptor, Adenosine A2B/physiology
- Reperfusion Injury/chemically induced
- Reperfusion Injury/prevention & control
- Reverse Transcriptase Polymerase Chain Reaction
- Vasodilator Agents/pharmacology
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Affiliation(s)
- Jinkun Xi
- Department of Anesthesiology, The University of North Carolina at Chapel Hill, Chapel Hill, NC 27599
- Heart Institute, North China Coal Medical University, Tangshan, China 063000
| | - Rachel McIntosh
- Department of Anesthesiology, The University of North Carolina at Chapel Hill, Chapel Hill, NC 27599
| | - Xiangjun Shen
- Department of Anesthesiology, The University of North Carolina at Chapel Hill, Chapel Hill, NC 27599
| | - SungRyul Lee
- Department of Anesthesiology, The University of North Carolina at Chapel Hill, Chapel Hill, NC 27599
| | - Guillaume Chanoit
- Department of Anesthesiology, The University of North Carolina at Chapel Hill, Chapel Hill, NC 27599
| | - Hugh Criswell
- Department of Anesthesiology, The University of North Carolina at Chapel Hill, Chapel Hill, NC 27599
| | - David A. Zvara
- Department of Anesthesiology, The University of North Carolina at Chapel Hill, Chapel Hill, NC 27599
| | - Zhelong Xu
- Department of Anesthesiology, The University of North Carolina at Chapel Hill, Chapel Hill, NC 27599
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Choi EA, Kim KH, Yoo BC, Yoo HS. Induction of Apoptotic Cell Death by Egg white combined-Chalcanthite on NCI-H460 Human Lung Cancer Cells. J Pharmacopuncture 2009. [DOI: 10.3831/kpi.2009.12.3.049] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/08/2023] Open
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Hussain A, Karjian P, Maddock H. The role of nitric oxide in A3 adenosine receptor-mediated cardioprotection. ACTA ACUST UNITED AC 2009; 29:97-104. [DOI: 10.1111/j.1474-8673.2009.00438.x] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/30/2022]
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Sadat U. Signaling pathways of cardioprotective ischemic preconditioning. Int J Surg 2009; 7:490-8. [PMID: 19540944 DOI: 10.1016/j.ijsu.2009.06.004] [Citation(s) in RCA: 20] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/01/2009] [Revised: 06/10/2009] [Accepted: 06/11/2009] [Indexed: 12/26/2022]
Abstract
BACKGROUND Ischemia/reperfusion (I/R) injury is a major contributory factor to cardiac dysfunction and infarct size that determines patient prognosis after acute myocardial infarction. During the last 20 years, since the appearance of the first publication on ischemic preconditioning (IP), our knowledge of this phenomenon has increased exponentially. RESULTS AND CONCLUSION Basic scientific experiments and preliminary clinical trials in humans suggest that IP confers resistance to subsequent sustained ischemic insults not only in the regional tissue but also in distant organs (remote ischemic preconditioning), which may provide a simple, cost-effective means of reducing the risk of perioperative myocardial ischemia. The mechanism may be humoral, neural, or a combination of both, and involves adenosine, bradykinin, protein kinases and K(ATP) channels, although the precise end-effector remains unclear. This review describes different signaling pathways involved in acute ischemic preconditioning in detail.
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Affiliation(s)
- Umar Sadat
- Addenbrooke's Hospital, Cambridge University Hospitals NHS Foundation Trust, Cambridge, UK.
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Katebi M, Soleimani M, Cronstein BN. Adenosine A2A receptors play an active role in mouse bone marrow-derived mesenchymal stem cell development. J Leukoc Biol 2009; 85:438-44. [PMID: 19056861 PMCID: PMC3059135 DOI: 10.1189/jlb.0908520] [Citation(s) in RCA: 76] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/03/2008] [Revised: 10/09/2008] [Accepted: 10/14/2008] [Indexed: 12/16/2022] Open
Abstract
Bone marrow-derived mesenchymal stem cells (BM-MSCs) play a role in wound healing and tissue repair and may also be useful for organ regeneration. As we have demonstrated previously that A(2A) adenosine receptors (A(2A)R) promote tissue repair and wound healing by stimulating local repair mechanisms and enhancing accumulation of endothelial progenitor cells, we investigated whether A(2A)R activation modulates BM-MSC proliferation and differentiation. BM-MSCs were isolated and cultured from A(2A)-deficient and ecto-5'nucleotidase (CD73)-deficient female mice; the MSCs were identified and quantified by a CFU-fibroblast (CFU-F) assay. Procollagen alpha2 type I expression was determined by Western blotting and immunocytochemistry. MSC-specific markers were examined in primary cells and third-passage cells by cytofluorography. PCR and real time-PCR were used to quantitate adenosine receptor and CD73 expression. There were significantly fewer CFU-Fs in cultures of BM-MSCs from A(2A)R knockout (KO) mice or BM-MSCs treated with the A(2A)R antagonist ZM241385, 1 microM. Similarly, there were significantly fewer procollagen alpha2 type I-positive MSCs in cultures from A(2A)R KO and antagonist-treated cultures as well. In late passage cells, there were significantly fewer MSCs from A(2A) KO mice expressing CD90, CD105, and procollagen type I (P<0.05 for all; n=3). These findings indicate that adenosine and adenosine A(2A)R play a critical role in promoting the proliferation and differentiation of mouse BM-MSCs.
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Affiliation(s)
- Majid Katebi
- New York University School of Medicine, 550 First Avenue, New York, NY 10016, USA
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Yang Z, Linden J, Berr SS, Kron IL, Beller GA, French BA. Timing of adenosine 2A receptor stimulation relative to reperfusion has differential effects on infarct size and cardiac function as assessed in mice by MRI. Am J Physiol Heart Circ Physiol 2008; 295:H2328-35. [PMID: 18849340 DOI: 10.1152/ajpheart.00091.2008] [Citation(s) in RCA: 18] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/22/2022]
Abstract
The activation of adenosine 2A receptors before reperfusion following coronary artery occlusion reduces infarct size and improves ejection fraction (EF). In this study, we examined the effects of delaying treatment with the adenosine 2A receptor agonist ATL146e (ATL) until 1 h postreperfusion. The infarct size and EF were serially assessed by gadolinium-diethylenetriaminepentaacetic acid-enhanced MRI in C57BL/6 mice at 1 and 24 h postreperfusion. The infarct size was also assessed by 2,3,5-triphenyltetrazolium chloride staining at 24 h. Mice were treated with ATL (10 microg/kg ip) either 2 min before reperfusion (early ATL) or 1 h postreperfusion (late ATL) following the 45-min coronary occlusion. The two methods used to assess infarct size at 24 h postreperfusion (MRI and 2,3,5-triphenyltetrazolium chloride) showed an excellent correlation (R=0.96). The risk region, determined at 24 h postreperfusion, was comparable between the control and ATL-treated groups. The infarct size by MRI at 1 versus 24 h postreperfusion was 25+/-1 vs. 26+/-1% of left ventricular mass (means+/-SE) in control mice, 16+/-2 versus 17+/-2% in early-ATL mice, and 24+/-2 versus 25+/-2% in late-ATL mice (intragroup, P=not significant; and intergroup, early ATL vs. control or late ATL, P<0.05). EF was reduced in control mice but was largely preserved between 1 and 24 h in both early-ATL and late-ATL mice (P<0.05). In conclusion, after coronary occlusion in mice, the extent of myocellular death due to ischemia-reperfusion injury is 95% complete within 1 h of reperfusion. The infarct size was significantly reduced by ATL when given just before reperfusion, but not 1 h postreperfusion. Either treatment window helped preserve the EF between 1 and 24 h postreperfusion.
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Affiliation(s)
- Zequan Yang
- Department of Surgery, University of Virginia, MR5 Bldg. Rm. 1219, Box 800759, 415 Lane Rd., Charlottesville, VA 22903, USA
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Song SW, Liu YF. Effect of adenosine A2 receptor agonist on oxygen free radicals and apoptosis during ischemia reperfusion injury in rat pancreas. Shijie Huaren Xiaohua Zazhi 2008; 16:3099-3102. [DOI: 10.11569/wcjd.v16.i27.3099] [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
AIM: To investigate the role of adenosine A2 receptor agonist in protection from production of oxygeon free radicals and induction of apoptosis during ischemia and reperfusion injury in rat pancreas.
METHODS: The rats were divided randomly into sham, control and experimental groups. After 30 min clamping of subsplenic artery, normal saline (2 mL/kg body weight) or A2 receptor agonist CGS21680 (300 µg/kg body weight) was injected via dorsal penis vein, and at 15 min, 30 min and 60 min reperfusion, the changes of lipoperoxides (LPO), apoptosis and morphology in pancreas tissues were examined.
RESULTS: After 15, 30 and 60 min reperfusion, LPO increased significantly in control group compared with the sham operation group (8.25 ± 1.15 vs 1.63 ± 0.46, 10.67 ± 2.04 vs 1.85 ± 0.62, 15.31 ± 3.02 vs 2.02 ± 0.86, all P < 0.05) and experimental group (8.25 ± 1.15 vs 6.51 ± 1.38, 10.67 ± 2.04 vs 6.84 ± 1.74, 15.31 ± 3.02 vs 10.22 ± 2.91 µmol/L, all P < 0.05). Apoptosis increased significantly in control group compared with the sham operation group (0.55 ± 0.08 vs 0.18 ± 0.04, 1.21 ± 0.15 vs 0.20 ± 0.06, 2.63 ± 0.52 vs 0.23 ± 0.06, P < 0.05 or 0.01) and experimental group (0.55 ± 0.08 vs 0.32 ± 0.16 P < 0.05; 1.21 ± 0.15 vs 0.44 ± 0.20, 2.63 ± 0.52 vs 0.50 ± 0.43, all P < 0.05 or 0.01). In the control group, compared with 15 min reperfusion, LPO and apoptosis increased significantly at 30 min or 60 min reperfusion (P < 0.05 or 0.01). In sham operation group and experimental group, no remarked damage of pancreas was detected, but in control group, the pancreas damage became more serious with the prolonging of reperfusion.
CONCLUSION: Adenosine A2 receptor agonist attenuates postischemic production of oxygen free radicals and induction of apoptosis in pancreas tissues, thereby minimizes the ischemia reperfusion injury.
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Abstract
OBJECTIVES We consider the conundrum suggested by myocardial hibernation and late restoration of function despite the absence of a substantial lateral peri-infarction border zone with respect to oxygenation, and suggest a pivotal role for apoptosis and its attenuation in salvaging jeopardized myocardium. METHODS Selective pertinent literature is reviewed, and some recent observations indicating difficulties in identifying and quantifying apoptosis microscopically are summarized. RESULTS Apoptosis seems to occur primarily after reperfusion following ischemia rather than persistent ischemia leading to necrosis. Refinements of markers of its presence are needed in vitro for use ultimately in vivo and should be pivotal in defining the extent to which tissue-protective interventions can salvage myocardium in the context of a fixed magnitude and duration of ischemia. CONCLUSION Apoptosis is strongly implicated in the overall demise of jeopardized myocardium. Its attenuation seems likely to be potentially beneficial. Validation of this hypothesis will require progress in identification, delineation, and assessment of the extent of apoptosis in the threatened heart.
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Rose JB, Coe IR. Physiology of Nucleoside Transporters: Back to the Future. . . . Physiology (Bethesda) 2008; 23:41-8. [DOI: 10.1152/physiol.00036.2007] [Citation(s) in RCA: 36] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/22/2022] Open
Abstract
Nucleoside transporters (NTs) are integral membrane proteins responsible for mediating and facilitating the flux of nucleosides and nucleobases across cellular membranes. NTs are also responsible for the uptake of nucleoside analog drugs used in the treatment of cancer and viral infections, and they are the target of certain compounds used in the treatment of some types of cardiovascular disease. The important role of NTs as drug transporters and therapeutic targets has necessarily led to intense interest into their structure and function and the relationship between these proteins and drug efficacy. In contrast, we still know relatively little about the fundamental physiology of NTs. In this review, we discuss various aspects of the physiology of NTs in mammalian systems, particularly noting tissues and cells where there has been little recent research. Our central thesis is reference back to some of the older literature, combined with current findings, will provide direction for future research into NT physiology that will lead to a fuller understanding of the role of these intriguing proteins in the everyday lives of cells, tissues, organs, and whole animals.
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Affiliation(s)
- Jennifer B. Rose
- Department of Biology, York University, Toronto, Ontario, Canada,
| | - Imogen R. Coe
- Department of Biology, York University, Toronto, Ontario, Canada,
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Abstract
Adenosine, a purine nucleoside, is ubiquitous in the body, and is a critical component of ATP. Its concentration jumps 100-fold during periods of oxygen depletion and ischemia. There are four adenosine receptors: A(1) and A(3) coupled to G(i/o) and the high-affinity A(2A) and low-affinity A(2B) coupled to G(s). Adenosine is one of three autacoids released by ischemic tissue which are important triggers of ischemic preconditioning (IPC). It is the A(1) and to some extent A(3) receptors which participate in the intracellular signaling that triggers cardioprotection. Unlike bradykinin and opioids, the other two autacoids, adenosine is not dependent on opening of mitochondrial K(ATP) channels or release of reactive oxygen species (ROS), but rather activates phospholipase C and/or protein kinase C (PKC) directly. Another signaling cascade at reperfusion involves activated PKC which initiates binding to and activation of an A(2) adenosine receptor that we believe is the A(2B). Although the latter is the low-affinity receptor, its interaction with PKC increases its affinity and makes it responsive to the accumulated tissue adenosine. A(2B) agonists, but not adenosine or A(1) agonists, infused at reperfusion can initiate this second signaling cascade and mimic preconditioning's protection. The same A(2B) receptors are critical for postconditioning's protection. Thus adenosine is both an important trigger and a mediator of cardioprotection.
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Reutershan J, Cagnina RE, Chang D, Linden J, Ley K. Therapeutic anti-inflammatory effects of myeloid cell adenosine receptor A2a stimulation in lipopolysaccharide-induced lung injury. THE JOURNAL OF IMMUNOLOGY 2007; 179:1254-63. [PMID: 17617618 DOI: 10.4049/jimmunol.179.2.1254] [Citation(s) in RCA: 105] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/19/2023]
Abstract
To determine the role of the adenosine receptor A2a in a murine model of LPS-induced lung injury, migration of polymorphonuclear leukocytes (PMNs) into the different compartments of the lung was determined by flow cytometry, microvascular permeability was assessed by the extravasation of Evans blue, and the release of chemotactic cytokines into the alveolar airspace was determined by ELISA. Measurements were performed in wild-type and A2a gene-deficient mice (A2a(-/-)). To differentiate the role of A2a on hemopoietic and nonhemopoietic cells, we created chimeric mice by transfer of bone marrow (BM) between wild-type and A2a(-/-) mice and used mice that lacked A2a expression selectively on myeloid cells (A2a(flox/flox) x LysM-cre). A specific A2a receptor agonist (ATL202) was used to evaluate its potential to reduce lung injury in vivo. In wild-type mice, therapeutic treatment with ATL202 reduced LPS-induced PMN recruitment, and release of cytokines. Pretreatment, but not posttreatment, also reduced Evans blue extravasation. In the BM chimeric mice lacking A2a on BM-derived cells, PMN migration into the alveolar space was increased by approximately 50%. These findings were confirmed in A2a(flox/flox) x LysM-cre mice. ATL202 was only effective when A2a was present on BM-derived cells. A2a agonists may be effective at curbing inflammatory lung tissue damage.
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Affiliation(s)
- Jörg Reutershan
- Robert M. Berne Cardiovascular Research Center, University of Virginia, Charlottesville, VA 22908, USA
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Rivo J, Zeira E, Galun E, Einav S, Linden J, Matot I. Attenuation of reperfusion lung injury and apoptosis by A2A adenosine receptor activation is associated with modulation of Bcl-2 and Bax expression and activation of extracellular signal-regulated kinases. Shock 2007; 27:266-73. [PMID: 17304107 DOI: 10.1097/01.shk.0000235137.13152.44] [Citation(s) in RCA: 46] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/26/2022]
Abstract
Adenosine receptors (AR) and extracellular signal-regulated kinases (ERK) have been implicated in tissue protection and apoptosis regulation during ischemia/reperfusion (I/R) injury. This study tests the hypothesis that reduction of reperfusion lung injury after A2A AR activation is associated with attenuation of apoptosis, modulation of ERK activation, and alterations in antiapoptotic and proapoptotic protein expression (Bcl-2 and Bax, respectively). Experiments were performed in intact-chest, spontaneously breathing cats in which the arterial branch of the left lower lung lobe was occluded for 2 h and reperfused for 3 h (I/R group). Animals were treated with the selective A2A AR agonist ATL313 given 5 min before reperfusion alone or in combination with the selective A2A AR antagonist ZM241385. Western blot analysis showed significant reduction in expression of Bcl-2 and increase in expression of Bax after reperfusion, compared with control lungs. Phosphorylated ERK1/2 levels were also increased after reperfusion. Compared with the I/R group, ATL313 markedly (P < 0.01) attenuated indices of injury and apoptosis including the percentage of injured alveoli, wet-dry weight ratio, myeloperoxidase activity, in situ terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate nick end-labeling-positive cells, and caspase 3 activity and expression. Furthermore, compared with reperfused lungs, in ATL313-pretreated lungs, Western blot analysis demonstrated substantial ERK1/2 activation, increased expression of Bcl-2, and attenuated expression of Bax. The protective effects of ATL313 were blocked by pretreatment with ZM241385. In summary, the present study shows that in vivo activation of A2A AR confers protection against reperfusion lung injury. This protection is associated with decreased apoptosis and involves ERK1/2 activation and alterations in antiapoptotic Bcl-2 and proapoptotic Bax proteins.
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Affiliation(s)
- Julia Rivo
- Department of Anesthesiology and Critical Care Medicine, Hadassah University Medical Center, The Hebrew University of Jerusalem, Jerusalem, Israel
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40
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Gao E, Boucher M, Chuprun JK, Zhou RH, Eckhart AD, Koch WJ. Darbepoetin alfa, a long-acting erythropoietin analog, offers novel and delayed cardioprotection for the ischemic heart. Am J Physiol Heart Circ Physiol 2007; 293:H60-8. [PMID: 17384131 DOI: 10.1152/ajpheart.00227.2007] [Citation(s) in RCA: 61] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/22/2022]
Abstract
Recent studies from our lab and others have shown that the hematopoietic cytokine erythropoietin (EPO) can protect the heart from ischemic damage in a red blood cell-independent manner. Here we examined any protective effects of the long-acting EPO analog darbepoetin alfa (DA) in a rat model of ischemia-reperfusion (I/R) injury. Rats were subjected to 30-min ischemia followed by 72-h reperfusion. In a dose-response study, DA (2, 7, 11, and 30 μg/kg) or vehicle was administered as a single bolus at the start of ischemia. To determine the time window of potential cardioprotection, a single high dose of DA (30 μg/kg) was given at either the initiation or the end of ischemia or at 1 or 24 h after reperfusion. After 3 days, cardiac function and infarct size were assessed. Acute myocyte apoptosis was quantified by TUNEL staining on myocardial sections and by caspase-3 activity assays. DA significantly reduced infarct size from 32.8 ± 3.5% (vehicle) to 11.0 ± 3.3% in a dose-dependent manner, while there was no difference in ischemic area between groups. Treatment with DA as late as 24 h after the beginning of reperfusion still demonstrated a significant reduction in infarct size (17.0 ± 1.6%). Consistent with infarction data, DA improved in vivo cardiac reserve compared with vehicle. Finally, DA significantly decreased myocyte apoptosis and caspase-3 activity after I/R. These data indicate that DA protects the heart against I/R injury and improves cardiac function, apparently through a reduction of myocyte apoptosis. Of clinical importance pointing toward a relevant therapeutic utility, we report that even if given 24 h after I/R injury, DA can significantly protect the myocardium.
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Affiliation(s)
- Erhe Gao
- Center for Translational Medicine, George Zallie and Family Laboratory for Cardiovascular Gene Therapy, Thomas Jefferson University, 1025 Walnut Street, Philadelphia, PA 19107, USA
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Arakawa M, Yasutake M, Miyamoto M, Takano T, Asoh S, Ohta S. Transduction of anti-cell death protein FNK protects isolated rat hearts from myocardial infarction induced by ischemia/reperfusion. Life Sci 2007; 80:2076-84. [PMID: 17467744 DOI: 10.1016/j.lfs.2007.03.012] [Citation(s) in RCA: 21] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/23/2006] [Revised: 03/13/2007] [Accepted: 03/18/2007] [Indexed: 12/29/2022]
Abstract
Artificial anti-cell death protein FNK, a Bcl-x(L) derivative with three amino acid-substitutions (Y22F, Q26N, and R165K) has enhanced anti-apoptotic and anti-necrotic activity and facilitates cell survival in many species and cell types. The objectives of this study were (i) to investigate whether the protein conjugated with a protein transduction domain (PTD-FNK) reduces myocardial infarct size and improves post-ischemic cardiac function in ischemic/reperfused rat hearts, and (ii) to understand the mechanism(s) by which PTD-FNK exerts a protective effect. Isolated rat hearts were subjected to 35-min global ischemia, followed by 120-min reperfusion using the Langendorff methods. PTD-FNK (a total of 30 microl) was injected intramuscularly into the anterior wall of the left ventricle either at 1 min after induction of global ischemia (group A) or at 30 min after induction of global ischemia (at 5 min before reperfusion) (group B). In group A, infarct size was significantly reduced from 47.8+/-6.8% in the control to 30.4+/-5.2, 28.7+/-3.8, and 30.4+/-6.8% with PTD-FNK at 5, 50, and 500 nmol/l, respectively (p<0.05). Temporal recovery of left ventricular developed pressure at 60 min and 120 min after reperfusion was significantly better in PTD-FNK (50 and 500 nmol/l)-treated groups than in the control (p<0.05). In contrast, PTD-FNK treatment had no effect on group B. Western blot analysis showed that PTD-FNK markedly inhibited procaspase-3 cleavage (activation of caspase-3) and reduced the number of nuclei stained by a terminal deoxynucleotidyl transferase-mediated deoxyuridine 5-triphoshate nick-end labeling (TUNEL) assay. These findings suggest that PTD-FNK reduces the volume of myocardial infarction with corresponding functional recovery, at least in part, through the suppression of myocardial apoptosis following ischemia/reperfusion.
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Affiliation(s)
- Masayuki Arakawa
- Department of Biochemistry and Cell Biology, Institute of Development and Aging Sciences, Graduate School of Medicine, Nippon Medical School, 1-396 Kosugi-cho, Nakahara-ku, Kawasaki-shi, Kanagawa, 211-8533, Japan
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42
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Peart JN, Headrick JP. Adenosinergic cardioprotection: Multiple receptors, multiple pathways. Pharmacol Ther 2007; 114:208-21. [PMID: 17408751 DOI: 10.1016/j.pharmthera.2007.02.004] [Citation(s) in RCA: 130] [Impact Index Per Article: 7.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/08/2007] [Accepted: 02/08/2007] [Indexed: 11/18/2022]
Abstract
Adenosine, formed primarily via hydrolysis of 5'-AMP, has been historically dubbed a "retaliatory" metabolite due to enhanced local release and beneficial actions during cellular/metabolic stress. From a cardiovascular perspective, evidence indicates the adenosinergic system is essential in mediation of intrinsic protection (e.g., pre- and postconditioning) and determining myocardial resistance to insult. Modulation of adenosine and its receptors thus remains a promising, though as yet not well-realized, approach to amelioration of injury in ischemic-reperfused myocardium. Adenosine exerts effects through A(1), A(2A), A(2B), and A(3) adenosine receptor subtypes (A(1)AR, A(2A)AR, A(2B)AR, and A(3)AR), which are all expressed in myocardial and vascular cells, and couple to G proteins to trigger a range of responses (generally, but not always, beneficial). Adenosine can also enhance tolerance to injurious stimuli via receptor-independent metabolic effects. Given adenosines contribution to preconditioning, it is no surprise that postreceptor signaling typically mimics that associated with preconditioning. This involves activation/translocation of PKC, PI3 kinase, and MAPKs, with ultimate effects at the level of mitochondrial targets-the mitochondrial K(ATP) channel and/or the mitochondrial permeability transition pore (mPTP). Nonetheless, differences in cytoprotective signaling and actions of the different adenosine receptor subtypes have been recently revealed. Our understanding of adenosinergic cytoprotection continues to evolve, with roles for the A(2) subtypes emerging, together with evidence of essential receptor "cross-talk" in mediation of protection. This review focuses on current research into adenosine-mediated cardioprotection, highlighting recent findings which, together with a wealth of prior knowledge, may ultimately facilitate adenosinergic approaches to clinical cardiac protection.
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Affiliation(s)
- Jason N Peart
- Heart Foundation Research Center, Griffith University, PMB 50 Gold Coast Mail Center, QLD, 4217, Australia.
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43
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Gross GJ, Auchampach JA. Reperfusion injury: does it exist? J Mol Cell Cardiol 2007; 42:12-8. [PMID: 17069848 PMCID: PMC1876792 DOI: 10.1016/j.yjmcc.2006.09.009] [Citation(s) in RCA: 82] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/28/2006] [Revised: 09/01/2006] [Accepted: 09/21/2006] [Indexed: 11/23/2022]
Abstract
It is well established that reperfusion of the heart is the optimal method of salvaging previously ischemic myocardium. However, the idea of reperfusion injury, i.e. injury caused by the process of reperfusion per se, still remains a controversial issue. In this review, we present mounting evidence supporting the concept that reperfusion injury exists, based on work conducted with adenosine and opioid receptor ligands, and the discovery of two new concepts regarding reperfusion injury: 'postconditioning' (POC) and the reperfusion injury salvage kinase (RISK) signaling pathway.
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Affiliation(s)
- Garrett J Gross
- Medical College of Wisconsin, Department of Pharmacology and Toxicology, 8701 Watertown Plank Road, Milwaukee, WI 53226, USA.
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Horiba M, Kadomatsu K, Yasui K, Lee JK, Takenaka H, Sumida A, Kamiya K, Chen S, Sakuma S, Muramatsu T, Kodama I. Midkine plays a protective role against cardiac ischemia/reperfusion injury through a reduction of apoptotic reaction. Circulation 2006; 114:1713-20. [PMID: 17015789 DOI: 10.1161/circulationaha.106.632273] [Citation(s) in RCA: 78] [Impact Index Per Article: 4.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/16/2022]
Abstract
BACKGROUND Midkine (MK) is a heparin-binding growth factor involved in diverse biological phenomena, eg, neural survival, carcinogenesis, and tissue repair. MK could have a protective action against ischemia/reperfusion (I/R) injury in the heart, because MK was shown to have cytoprotective activity in cultured neurons and tumor cells. We investigated this hypothesis in mice with and without genetic MK deletion. METHODS AND RESULTS Myocardial injury after I/R was produced by transient occlusion of coronary arteries. In wild-type (Mdk+/+) mice, MK expression was increased after I/R in the periinfarct area. Infarct size/area at risk 24 hours after I/R in MK-deficient (Mdk-/-) mice was larger than in Mdk+/+ mice (55.4+/-9.1% versus 32.1+/-5.3%, P<0.05). Terminal dUTP nick end-labeling-positive myocyte population in the periinfarct area in Mdk-/- mice was higher than in Mdk+/+ mice (6.8+/-0.9% versus 3.2+/-0.6%, P<0.05). Left ventricular fractional shortening 24 hours after I/R in Mdk-/- mice was significantly less than that in Mdk+/+ mice (34.3+/-4.4% versus 50.8+/-2.1%, P<0.05). Supplemental application of MK protein to left ventricle of Mdk-/- mice at the time of I/R resulted in reduction of the infarct size. Application of exogenous MK to cultured cardiomyocytes resulted in increased Bcl-2 expression and decreased apoptosis after hypoxia/reoxygenation. CONCLUSIONS These results suggest that MK plays a protective role against I/R injury, most likely through a prevention of apoptotic reaction. MK is a potentially important new molecular target for treatment of ischemic heart disease.
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Affiliation(s)
- Mitsuru Horiba
- Department of Cardiovascular Research, Research Institute of Environmental Medicine, Nagoya University, Furo-cho, Chikusa-ku, Nagoya 464-8601, Japan.
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45
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Ling H, Wu L, Li L. Corydalis yanhusuo rhizoma extract reduces infarct size and improves heart function during myocardial ischemia/reperfusion by inhibiting apoptosis in rats. Phytother Res 2006; 20:448-53. [PMID: 16619356 DOI: 10.1002/ptr.1875] [Citation(s) in RCA: 44] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/10/2022]
Abstract
The aim of the present investigation was to evaluate the effect of an extract from Corydalis yanhusuo W.T., a Chinese herbal medicine, on ischemia/reperfusion (I/R) injury and to determine the mechanism(s) involved. In rats, the left anterior descending (LAD) coronary artery was occluded for 30 min and then reperfused for 6 h. 0.5% carboxymethyl cellulose sodium was used as a vehicle (I/R control group) and Corydalis yanhusuo rhizoma extract (I/R + CY 200, 100 mg/kg groups) were given. Infarct size and hemodynamic parameters were measured. Apoptosis was detected quantitatively by the terminal transferase dUTP nick end-labeling (TUNEL) method and confirmed by DNA laddering on agarose gel. The expression of anti-apoptotic Bcl-2 and pro-apoptotic Bax proteins was visualized by western blot analysis. In contrast to the I/R control group, administration with CY 200 mg/kg resulted in a significant reduction in the infarct size and an improvement in heart function as evidenced by higher LVSP and +/-dp/dtmax. TUNEL-positive cells in the ischemic myocardium were also significantly reduced in the I/R + CY 200, 100 mg/kg groups, consistent with little DNA laddering in these two groups. Furthermore, greater Bcl-2 and attenuated Bax expression was found in the CY treated rats. These results suggest that the protective effect of Corydalis yanhusuo on myocardial I/R injury is closely associated with the inhibition of myocardial apoptosis through modulation of the Bcl-2 family.
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Affiliation(s)
- Haiyun Ling
- Department of Pharmacology on Traditional Chinese Medicine, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou 310031, PR China
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46
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Raphael J, Abedat S, Rivo J, Meir K, Beeri R, Pugatsch T, Zuo Z, Gozal Y. Volatile anesthetic preconditioning attenuates myocardial apoptosis in rabbits after regional ischemia and reperfusion via Akt signaling and modulation of Bcl-2 family proteins. J Pharmacol Exp Ther 2006; 318:186-94. [PMID: 16551837 DOI: 10.1124/jpet.105.100537] [Citation(s) in RCA: 59] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/31/2023] Open
Abstract
We tested whether isoflurane preconditioning inhibits cardiomyocyte apoptosis and evaluated the role of the phosphatidylinositol-3-kinase (PI3K)/Akt pathway in anesthetic preconditioning and determined whether PI3K/Akt signaling modulates the expression of pro- and antiapoptotic proteins in anesthetic preconditioning. Six-month-old New Zealand rabbits subjected to 40 min of myocardial ischemia followed by 180 min of reperfusion were assigned to the following groups: ischemia-reperfusion (I/R), isoflurane preconditioning and isoflurane plus PI3K inhibitors, wortmannin and 2-(4-morpholinyl)-8-phenyl-4H-l-benzopyran-4-one (LY294002) (0.6 and 0.3 mg/kg i.v., respectively). Sham-operated, wortmannin+I/R, wortmannin+sham, LY294002+I/R, and LY294002+sham groups were also included. Infarct size was assessed by triphenyltetrazolium chloride staining. Apoptosis was evaluated by terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling and activated caspase-3 assays. Akt phosphorylation, Bax, Bcl-2, Bad, and phosphorylated Bad (phospho-Bad) expression was assessed by immunoblotting. Isoflurane preconditioning reduced infarct size compared with the I/R group: 22+/-4 versus 41+/-5% (p<0.05). The percentage of apoptotic cells decreased in the isoflurane group (3.8+/-1.2%) compared with the I/R group (12.4+/-1.6%; p<0.05). These results were also confirmed by the activated caspase-3 assay. Wortmannin and LY294002 inhibited the effects of isoflurane. Myocardial infarction increased to 44+/-3 and 45+/-2% and the percentage of apoptotic cells was 11.9+/-2.1 and 11.7+/-3.3%, respectively. Akt phosphorylation and Bcl-2 and phospho-Bad expression increased after isoflurane preconditioning, whereas Bax expression decreased. These effects were inhibited by wortmannin and LY294002. The data indicate that isoflurane preconditioning reduces infarct size and myocardial apoptosis after I/R. Activation of PI3K and modulation of the expression of pro- and antiapoptotic proteins may play a role in isoflurane-induced myocardial protection.
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Affiliation(s)
- Jacob Raphael
- Department of Anesthesiology, the Heart Institute, Hebrew University, Jerusalem, Israel.
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47
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Forman MB, Stone GW, Jackson EK. Role of Adenosine as Adjunctive Therapy in Acute Myocardial Infarction. ACTA ACUST UNITED AC 2006; 24:116-47. [PMID: 16961725 DOI: 10.1111/j.1527-3466.2006.00116.x] [Citation(s) in RCA: 78] [Impact Index Per Article: 4.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/29/2022]
Abstract
Although early reperfusion and maintained patency is the mainstay therapy for ST elevation myocardial infarction, experimental studies demonstrate that reperfusion per se induces deleterious effects on viable ischemic cells. Thus "myocardial reperfusion injury" may compromise the full potential of reperfusion therapy and may account for unfavorable outcomes in high-risk patients. Although the mechanisms of reperfusion injury are complex and multifactorial, neutrophil-mediated microvascular injury resulting in a progressive decrease in blood flow ("no-reflow" phenomenon) likely plays an important role. Adenosine is an endogenous nucleoside found in large quantities in myocardial and endothelial cells. It activates four well-characterized receptors producing various physiological effects that attenuate many of the proposed mechanisms of reperfusion injury. The cardio-protective effects of adenosine are supported by its role as a mediator of pre- and post-conditioning. In experimental models, administration of adenosine in the peri-reperfusion period results in a marked reduction in infarct size and improvement in ventricular function. The cardioprotective effects in the canine model have a narrow time window with the drug losing its effect following three hours of ischemia. Several small clinical studies have demonstrated that administration of adenosine with reperfusion therapy reduces infarct size and improves ventricular function. In the larger AMISTAD and AMISTAD II trials a 3-h infusion of adenosine as an adjunct to reperfusion resulted in a striking reduction in infarct size (55-65%). Post hoc analysis of AMISTAD II showed that this was associated with significantly improved early and late mortality in patients treated within 3.17 h of symptoms. An intravenous infusion of adenosine for 3 h should be considered as adjunctive therapy in high risk-patients undergoing reperfusion therapy.
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Affiliation(s)
- Mervyn B Forman
- Emory University and North Atlanta Cardiovascular Associates, P.C., Atlanta, GA, USA
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48
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Boucher M, Wann BP, Kaloustian S, Cardinal R, Godbout R, Rousseau G. Reduction of apoptosis in the amygdala by an A2A adenosine receptor agonist following myocardial infarction. Apoptosis 2006; 11:1067-74. [PMID: 16832713 DOI: 10.1007/s10495-006-6313-6] [Citation(s) in RCA: 20] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/24/2022]
Abstract
It has been observed that a cytokine synthesis inhibitor, pentoxifylline, prevents the apoptotic processes taking place in the amygdala following myocardial infarction. However, it is unknown if the cardioprotective effect of A(2A) adenosine receptor agonist, CGS21680, which reduces cytokine synthesis, would lead to such amygdala apoptosis regression. Thus, this study was designed to investigate whether cardioprotective A(2A) adenosine receptor activation reduces apoptosis in the amygdala following myocardial infarction. Anesthetized rats were subjected to left anterior descending coronary artery occlusion for 40 min, followed by 72 h of reperfusion. The A(2A) agonist CGS21680 (0.2 mug/kg/min i.v.) was administered continuously for 120 min, starting (1) five minutes prior to instituting reperfusion (Early) or (2) five minutes after the beginning of reperfusion (Late). After reperfusion, myocardial infarct size was determined and the amygdala was dissected from the brain. Infarct size was reduced significantly in the Early compared to the Control group (34.6 +/- 1.8% and 52.3 +/- 2.8% respectively; p < 0.05), with no difference compared to the Late group (40.1 +/- 6.1%). Apoptosis regression was documented in the amygdala of the Early group by an enhanced phosphatidylinositol 3-kinase-Akt pathway activation and Bcl-2 expression concurrently to a caspase-3 activation limitation and reduction in TUNEL-positive cells staining. On the other hand, amygdala TUNEL-positive cell numbers were not reduced in the Late group. Moreover, TNFalpha was significantly reduced in the amygdala of the Early group compared to the Control and Late groups. These results indicate that A(2A) adenosine receptor stimulation is associated with apoptosis regression in the amygdala following myocardial infarction.
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Affiliation(s)
- M Boucher
- Centre de Biomédecine, Hôpital du Sacré-Coeur de Montréal, 5400 boulevard Gouin Ouest, Montréal, Québec, Canada
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Okonkwo DO, Reece TB, Laurent JJ, Hawkins AS, Ellman PI, Linden J, Kron IL, Tribble CG, Stone JR, Kern JA. A comparison of adenosine A2A agonism and methylprednisolone in attenuating neuronal damage and improving functional outcome after experimental traumatic spinal cord injury in rabbits. J Neurosurg Spine 2006; 4:64-70. [PMID: 16506468 DOI: 10.3171/spi.2006.4.1.64] [Citation(s) in RCA: 17] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/06/2022]
Abstract
Object
Steroid agents remain the lone pharmacological treatment in widespread use for acute spinal cord injury (SCI), although their utility remains in dispute in the neurotrauma literature. Adenosine A2A receptor activation with ATL-146e, a selective A2A agonist, has shown potential benefit in treating SCI; however, it has not been compared with the gold standard, methylprednisolone. The authors of this study evaluated ATL-146e and methylprednisolone for their ability to preserve neuronal viability and motor function in experimental SCI.
Methods
New Zealand White rabbits sustained SCI or sham injury via the Allen weight-drop technique. Ten minutes postinjury, animals received ATL-146e (ATL group, 0.06 μg/kg/min intravenously for 3 hours), methylprednisolone (steroid group, 30 mg/kg intravenously), or saline (trauma control group). Hindlimb motor function was recorded every 12 hours using the Tarlov motor grading scale (0, paralysis–5, normal hop). At 48 hours, fixed spinal cord tissue was evaluated for neuronal viability.
Hindlimb motor function in animals treated with ATL-146e was equivalent to that of sham-injured animals and was significantly better than that of trauma control animals at all time points and that of steroid-treated animals at 12 hours (p = 0.05). Motor function in steroid-treated animals was worse than in those given ATL-146e and better than that of trauma control animals at later time points, but was not statistically significant (both p > 0.05). Neuronal viability (measured in neurons/hpf) was significantly higher in both treatment groups compared with the trauma control group (12.1 ± 1.4 neurons/hpf for the ATL and 13.3 ± 1.4 neurons/hpf for the steroid group compared with 7.5 ± 1.5 neurons/hpf for the trauma control group; both p < 0.04). Neuronal viability did not differ among ATL-146e–treated, steroid-treated, and sham-injured groups.
Conclusions
The use of ATL-146e is at least as effective as methylprednisolone in preserving function and is equivalent to methylprednisolone in preserving the structure of spinal cord tissue after blunt SCI. Adenosine A2A receptor activation may be an effective treatment for acute SCI while avoiding the adverse effects of steroid agents.
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Affiliation(s)
- David O Okonkwo
- Department of Neurological Surgery, University of Virginia Health System, Charlottesville 22908-0212, USA.
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Xu Z, Mueller RA, Park SS, Boysen PG, Cohen MV, Downey JM. Cardioprotection with adenosine A2 receptor activation at reperfusion. J Cardiovasc Pharmacol 2005; 46:794-802. [PMID: 16306804 DOI: 10.1097/01.fjc.0000188161.57018.29] [Citation(s) in RCA: 28] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/26/2022]
Abstract
Pre-ischemic treatment is seldom possible in the clinical setting of acute myocardial infarction. Thus, to successfully save myocardium from infarction, it is required that protective interventions must be effective when applied after ischemia has begun or at the onset of reperfusion. Unfortunately, in spite of a large body of experimental data showing that various interventions are cardioprotective at reperfusion, no specific therapy has yet been established to be clinically applicable. However, recent data from several laboratories have shown that adenosine and its analogues given at reperfusion can markedly protect the heart from ischemia/reperfusion injury. While the experimental data suggest that factors such as adenosine A2 receptor activation, anti-neutrophil effect, attenuation of free radical generation, increased nitric oxide (NO) availability, activation of the PI3-kinase/Akt pathway and ERK, prevention of mitochondrial damage, and anti-apoptotic effects may be involved in the protective effect of adenosine or its analogues, the exact receptor subtype(s), the detailed signaling mechanisms, and interaction between those individual factors are still unknown. A definite answer to these unsolved problems will offer insights into the mechanisms of cardioprotection at reperfusion, and will be critical for developing a successful therapeutic strategy to salvage ischemic myocardium in patients with acute myocardial infarction.
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Affiliation(s)
- Zhelong Xu
- Department of Anesthesiology, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.
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