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Abstract
Mechanical stress from haemodynamic perturbations or interventional manipulation of epicardial coronary atherosclerotic plaques with inflammatory destabilization can release particulate debris, thrombotic material and soluble substances into the coronary circulation. The physical material obstructs the coronary microcirculation, whereas the soluble substances induce endothelial dysfunction and facilitate vasoconstriction. Coronary microvascular obstruction and dysfunction result in patchy microinfarcts accompanied by an inflammatory reaction, both of which contribute to progressive myocardial contractile dysfunction. In clinical studies, the benefit of protection devices to retrieve atherothrombotic debris during percutaneous coronary interventions has been modest, and the treatment of microembolization has mostly relied on antiplatelet and vasodilator agents. The past 25 years have witnessed a relative proportional increase in non-ST-segment elevation myocardial infarction in the presentation of acute coronary syndromes. An associated increase in the incidence of plaque erosion rather than rupture has also been recognized as a key mechanism in the past decade. We propose that coronary microembolization is a decisive link between plaque erosion at the culprit lesion and the manifestation of non-ST-segment elevation myocardial infarction. In this Review, we characterize the features and mechanisms of coronary microembolization and discuss the clinical trials of drugs and devices for prevention and treatment.
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Affiliation(s)
- Petra Kleinbongard
- grid.5718.b0000 0001 2187 5445Institute for Pathophysiology, West German Heart and Vascular Center, University of Essen Medical School, Essen, Germany
| | - Gerd Heusch
- grid.5718.b0000 0001 2187 5445Institute for Pathophysiology, West German Heart and Vascular Center, University of Essen Medical School, Essen, Germany
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2
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Han X, Xu J, Xu S, Sun Y, He M, Li X, Li X, Pi J, Yu R, Tian W. [Role of mitochondrial permeability transition pore in mediating the inhibitory effect of gastrodin on oxidative stress in cardiac myocytes in vitro]. NAN FANG YI KE DA XUE XUE BAO = JOURNAL OF SOUTHERN MEDICAL UNIVERSITY 2019; 38:1306-1311. [PMID: 30514677 DOI: 10.12122/j.issn.1673-4254.2018.11.05] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Subscribe] [Scholar Register] [Indexed: 01/13/2023]
Abstract
OBJECTIVE To explore the role of mitochondrial permeability transition pore (mPTP) in mediating the protective effect of gastrodin against oxidative stress damage in H9c2 cardiac myocytes. METHODS H9c2 cardiac myocytes were treated with H2O2, gastrodin, gastrodin+H2O2, cyclosporin A (CsA), or CsA+gas+H2O2 group. MTT assay was used to detect the survival ratio of H9c2 cells, and flow cytometry with Annexin V-FITC/PI double staining was used to analyze the early apoptosis rate after the treatments. The concentration of ATP and level of reactive oxygen species (ROS) in the cells were detected using commercial kits. The mitochondrial membrane potential of the cells was detected with laser confocal microscopy. The expression of cytochrome C was detected with Western blotting, and the activity of caspase-3 was also assessed in the cells. RESULTS Gastrodin pretreatment could prevent oxidative stress-induced reduction of mitochondrial membrane potential, and this effect was inhibited by the application of CsA. Gastrodin significantly lowered the levels of ROS and apoptosis-related factors in H2O2-exposed cells, and such effects were reversed by CsA. CsA significantly antagonized the protective effect of gastrodin against apoptosis in H2O2-exposed cells. CONCLUSIONS Gastrodin prevents oxidative stress-induced injury in H9c2 cells by inhibiting mPTP opening to reduce the cell apoptosis.
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Affiliation(s)
- Xuechao Han
- Medical Research Center (International Scientific and Technological Cooperation Base of Geriatrics Medicine), North China University of Science and Technology, Tangshan 063000, China
| | - Jingman Xu
- Medical Research Center (International Scientific and Technological Cooperation Base of Geriatrics Medicine), North China University of Science and Technology, Tangshan 063000, China
| | - Sen Xu
- Medical Research Center (International Scientific and Technological Cooperation Base of Geriatrics Medicine), North China University of Science and Technology, Tangshan 063000, China
| | - Yahan Sun
- Medical Research Center (International Scientific and Technological Cooperation Base of Geriatrics Medicine), North China University of Science and Technology, Tangshan 063000, China
| | - Mali He
- Medical Research Center (International Scientific and Technological Cooperation Base of Geriatrics Medicine), North China University of Science and Technology, Tangshan 063000, China
| | - Xiaodong Li
- Medical Research Center (International Scientific and Technological Cooperation Base of Geriatrics Medicine), North China University of Science and Technology, Tangshan 063000, China
| | - Xinyu Li
- Medical Research Center (International Scientific and Technological Cooperation Base of Geriatrics Medicine), North China University of Science and Technology, Tangshan 063000, China
| | - Jiayi Pi
- Medical Research Center (International Scientific and Technological Cooperation Base of Geriatrics Medicine), North China University of Science and Technology, Tangshan 063000, China
| | - Rui Yu
- Medical Research Center (International Scientific and Technological Cooperation Base of Geriatrics Medicine), North China University of Science and Technology, Tangshan 063000, China
| | - Wei Tian
- Medical Research Center (International Scientific and Technological Cooperation Base of Geriatrics Medicine), North China University of Science and Technology, Tangshan 063000, China
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3
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García-Méndez RC, Almeida-Gutierrez E, Serrano-Cuevas L, Sánchez-Díaz JS, Rosas-Peralta M, Ortega-Ramirez JA, Palomo-Villada JA, Isordia-Salas I, Alonso-Bravo RM, Borrayo-Sanchez G. Reduction of No Reflow with a Loading Dose of Atorvastatin before Primary Angioplasty in Patients with Acute ST Myocardial Infarction. Arch Med Res 2018; 49:620-629. [PMID: 30446246 DOI: 10.1016/j.arcmed.2018.10.006] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/18/2018] [Revised: 09/27/2018] [Accepted: 10/25/2018] [Indexed: 12/21/2022]
Abstract
BACKGROUND No reflow defined as an altered myocardial reperfusion and failure at microvascular level is a frequent complication in acute myocardial infarction that attenuates beneficial effect of reperfusion therapy leading to poor outcomes. There is not enough evidence to support that previous use of statins improves coronary flow in patients undergoing primary percutaneous coronary intervention (PCI). AIM OF STUDY To determine if a loading dose of 80 mg of atorvastatin before primary angioplasty reduces the frequency of no reflow, hs-CRP, IL6 intracoronary levels, and major combined cardiovascular events at 30 d. METHODS In this controlled clinical trial, we randomly assigned 103 adult patients within the 12 h of acute ST-elevation myocardial infarction (STEMI) to receive 80 mg of atorvastatin additional to standard treatment (AST) before performing primary PCI versus standard treatment (ST) alone. The primary outcomes were the occurrence of no reflow and high sensitivity C-reactive protein (hs-CRP) and interleukin 6 levels and secondary outcomes were major adverse cardiovascular events at 30 d. RESULTS 103 patients were analyzed, 49 (48%) received AST, 54 (52%) ST. Frequency of no reflow among groups was 27 vs. 63% respectively, p ≤0.0001. hs-CRP level was 2.69 mg/dL for AST vs. 2.2 mg/dL in ST, meanwhile IL-6 levels were 5.2 pg/mL vs. 6.35 pg/mL respectively, p = ns. Cox regression model demonstrated that the treatment assigned is an independent predictor for no reflow occurrence (HR 0.34 95%, CI 0.18-0.61, p ≤0.001). CONCLUSION The administration of a loading dose of 80 mg atorvastatin before primary PCI is an effective strategy for prevention of no reflow improving also clinical outcomes and free survival rate for the presentation of major adverse cardiovascular events at 30 d.
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Affiliation(s)
- Rosalba C García-Méndez
- División de Investigación en Salud, Unidad Médica de Alta Especialidad, Hospital de Cardiología, Centro Médico Nacional Siglo XXI, Instituto Mexicano del Seguro Social, Ciudad de México, México
| | - Eduardo Almeida-Gutierrez
- Dirección de Educación e Investigación en Salud, Unidad Médica de Alta Especialidad, Hospital de Cardiología, Centro Médico Nacional Siglo XXI, Instituto Mexicano del Seguro Social, Ciudad de México, México.
| | - Leonor Serrano-Cuevas
- Coordinación de Unidades Médicas de Alta Especialidad, División de Evaluación y Rendición de Cuentas de los Procesos de Atención Médica de las Unidades Médicas de Alta Especialidad, Instituto Mexicano del Seguro Social, Ciudad de México, México
| | - Jesús Salvador Sánchez-Díaz
- Unidad de Cuidados Intensivos, Unidad Médica de Alta Especialidad, Hospital de Especialidades, Centro Médico Nacional Adolfo Ruiz Cortines, Instituto Mexicano del Seguro Social, Veracuz, México
| | - Martín Rosas-Peralta
- Área de Proyectos Especiales, División de Evaluación y Rendición de Cuentas de Procesos de Atención Médica en Unidad Médica de Alta Especialidad, Instituto Mexicano del Seguro Social, Ciudad de México, México
| | - Jose Alberto Ortega-Ramirez
- Departamento de Cardiología Nuclear, Unidad Médica de Alta Especialidad, Hospital de Cardiología, Centro Médico Nacional Siglo XXI, Instituto Mexicano del Seguro Social, Ciudad de México, México
| | - Jose Antonio Palomo-Villada
- Departament de Hemodinamia, Unidad Médica de Alta Especialidad, Hospital de Cardiología, Centro Médico Nacional Siglo XXI, Instituto Mexicano del Seguro Social, Ciudad de México, México
| | - Irma Isordia-Salas
- Unidad de Investigación en Trombosis Hemostasis y Aterogénsis, Hospital General Regional no. 1, Instituto Mexicano del Seguro Social, Ciudad de México, México
| | - Rosa Marisol Alonso-Bravo
- Departamento de Cardiología Nuclear Unidad Médica de Alta Especialidad, Hospital de Cardiología Centro Médico Nacional Siglo XXI, Instituto Mexicano del Seguro Social, Ciudad de México, México
| | - Gabriela Borrayo-Sanchez
- Código Infarto, Hospital de Cardiología, Unidad Médica de Alta Especialidad, Hospital de Cardiología, Centro Médico Nacional Siglo XXI, Instituto Mexicano del Seguro Social, Ciudad de México, México
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4
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Abstract
The endoplasmic reticulum (ER) is critical in protein processing and particularly in ensuring that proteins undergo their correct folding to exert their functionality. What is becoming increasingly clear is that the ER may undergo increasing stress brought about by nutrient deprivation, hypoxia, oxidized lipids, point mutations in secreted proteins, cellular differentiation or significant deviation from metabolic set points, and loss of Ca2+ homeostasis, with detrimental effects on ER-resident calcium-dependent chaperones, alone or in combination. This results in the unfolded protein response (UPR) that is a repair mechanism to limit the formation of newly damaged proteins until ER homeostasis is restored, though may result in increased cell death. ER stress has been shown to be implicated in a variety of diseases. Statins are well-known cholesterol-lowering drugs and have been extensively reported to possess beneficial cholesterol-independent effects in a variety of human diseases. This review focuses on the concept of ER stress, the underlying molecular mechanisms and their relationship to the pathophysiology and, finally, the role of statins in moderating ER stress and UPR.
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Sandhu K, Mamas M, Butler R. Endothelial progenitor cells: Exploring the pleiotropic effects of statins. World J Cardiol 2017; 9:1-13. [PMID: 28163831 PMCID: PMC5253189 DOI: 10.4330/wjc.v9.i1.1] [Citation(s) in RCA: 23] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/21/2016] [Revised: 08/29/2016] [Accepted: 11/02/2016] [Indexed: 02/07/2023] Open
Abstract
Statins have become a cornerstone of risk modification for ischaemic heart disease patients. A number of studies have shown that they are effective and safe. However studies have observed an early benefit in terms of a reduction in recurrent infarct and or death after a myocardial infarction, prior to any significant change in lipid profile. Therefore, pleiotropic mechanisms, other than lowering lipid profile alone, must account for this effect. One such proposed pleiotropic mechanism is the ability of statins to augment both number and function of endothelial progenitor cells. The ability to augment repair and maintenance of a functioning endothelium may have profound beneficial effect on vascular repair and potentially a positive impact on clinical outcomes in patients with cardiovascular disease. The following literature review will discuss issues surrounding endothelial progenitor cell (EPC) identification, role in vascular repair, factors affecting EPC numbers, the role of statins in current medical practice and their effects on EPC number.
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Rohilla A, Ahmad A, Khan M, Khanam R. A comparative study on the cardioprotective potential of atorvastatin and simvastatin in hyperhomocysteinemic rat hearts. Eur J Pharmacol 2015; 764:48-54. [DOI: 10.1016/j.ejphar.2015.06.045] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/09/2014] [Revised: 06/19/2015] [Accepted: 06/23/2015] [Indexed: 01/04/2023]
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Bian B, Yu X, Wang Q, Teng T, Nie J. Atorvastatin protects myocardium against ischemia-reperfusion arrhythmia by increasing Connexin 43 expression: A rat model. Eur J Pharmacol 2015; 768:13-20. [PMID: 26386290 DOI: 10.1016/j.ejphar.2015.09.023] [Citation(s) in RCA: 18] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/11/2015] [Revised: 09/14/2015] [Accepted: 09/15/2015] [Indexed: 12/21/2022]
Abstract
Atorvastatin has protective effects against myocardial ischemia-reperfusion injuries and ischemia-reperfusion arrhythmia. This study was designed to investigate whether atorvastatin is able to protect against myocardial ischemia-reperfusion injury by enhancing the expression of Connexin 43 (Cx43) via the activation of the phosphatidylinositol-3-kinase (PI3K)/Akt pathway and mitochondrial ATP-sensitive potassium (K(ATP)) channels. Isolated perfused rat hearts were treated with classic ischemia postconditioning (IPOST), atorvastatin, and atorvastatin combined with inhibitor of PI3K and K(ATP) channels, respectively, after 30min of LAD ischemia and then subjected to reperfusion for 120min. The QRS duration and the ischemia-reperfusion ventricular arrhythmia were assessed. The lactate dehydrogenase (LDH) and creatine kinase isoenzyme (CK-MB) levels were measured and the Cx43 expression was assessed by immunoblotting and immunohistochemistry. After 120min of reperfusion, atorvastatin and IPOST significantly decreased the QRS duration and inhibited ventricular arrhythmia. They also decreased the levels of LDH and CK-MB. Meanwhile, atorvastatin and IPOST also significantly enhanced the Cx43 expression and the phosphorylation of Cx43. Such protective effects were abolished in the presence of the inhibitor of PI3K or the inhibitor of mitochondrial K(ATP) channels. This study suggests that atorvastatin protected against myocardial ischemia-reperfusion injury and enhanced the expression of Cx43 by activating the PI3K/Akt pathway and mitochondrial K(ATP) channels.
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Affiliation(s)
- Bo Bian
- Cardiology Department, Tianjin Medical University General Hospital, Tianjin, China
| | - Xuefang Yu
- Cardiology Department, Tianjin Medical University General Hospital, Tianjin, China.
| | - Qing Wang
- Cardiology Department, Tianjin Medical University General Hospital, Tianjin, China
| | - Tianming Teng
- Cardiology Department, Tianjin Medical University General Hospital, Tianjin, China
| | - Jing Nie
- Cardiology Department, Tianjin Medical University General Hospital, Tianjin, China
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8
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Gao Y, Hao J, Zhang H, Qian G, Jiang R, Hu J, Wang J, Lei Z, Zhao G. Protective effect of the combinations of glycyrrhizic, ferulic and cinnamic acid pretreatment on myocardial ischemia-reperfusion injury in rats. Exp Ther Med 2014; 9:435-445. [PMID: 25574212 PMCID: PMC4280987 DOI: 10.3892/etm.2014.2134] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/14/2014] [Accepted: 08/01/2014] [Indexed: 12/11/2022] Open
Abstract
The aim of this study was to find an effective drug cocktail pretreatment to protect myocardial tissue of the heart from ischemia-reperfusion (I/R) injury. The mechanisms underlying the effects of the drug cocktail were subsequently explored in order to expand the application of Dang-gui-si-ni-tang (DGSN), a Traditional Chinese Medicine. The active components of DGSN in the serum following oral administration were investigated using high-performance liquid chromatography. The activity of superoxide dismutase (SOD) and malondialdehyde (MDA) levels were then analyzed to show the effect of the active components in the treatment of myocardial I/R injury. An L16 (44) orthogonal experiment was utilized to determine the most effective cocktail mix and the mechanism underlying the effect of this mix on myocardial I/R injury was investigated. It was observed that FCG, a mixture of glycyrrhizic (50 mg/kg), cinnamic (200 mg/kg) and ferulic (300 mg/kg) acid, was the optimal drug cocktail present in DGSN. This was absorbed into the blood following oral administration and was shown to decrease MDA levels and increase the activity of SOD. In conclusion, the findings suggest that FCG, a combination of active ingredients in the DGSN decoction, can be absorbed into the blood and protect the myocardium from I/R injury.
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Affiliation(s)
- Yuqin Gao
- Department of Cardiology, Ninth Affiliated Hospital of the Medical College of Xi'an Jiaotong University and Railway Central Hospital of Xi'an, Xi'an, Shanxi 710054, P.R. China ; College of Medicine, Jinan University, Guangzhou, Guangdong 510632, P.R. China
| | - Jiping Hao
- Department of Cardiology, Ninth Affiliated Hospital of the Medical College of Xi'an Jiaotong University and Railway Central Hospital of Xi'an, Xi'an, Shanxi 710054, P.R. China
| | - Hongkao Zhang
- Department of Nursing Science, Huanghuai University, Zhumadian, Henan 463000, P.R. China
| | - Guoqiang Qian
- College of Pharmacy, Jinan University, Guangzhou, Guangdong 510632, P.R. China
| | - Renwang Jiang
- Department of Cardiology, Renmin Hospital, Hubei University of Medicine, Shiyan, Hubei 442000, P.R. China
| | - Jing Hu
- College of Medicine, Jinan University, Guangzhou, Guangdong 510632, P.R. China
| | - Jianing Wang
- Department of Cardiology, Renmin Hospital, Hubei University of Medicine, Shiyan, Hubei 442000, P.R. China
| | - Zhang Lei
- Department of Cardiology, Renmin Hospital, Hubei University of Medicine, Shiyan, Hubei 442000, P.R. China
| | - Guoping Zhao
- College of Medicine, Jinan University, Guangzhou, Guangdong 510632, P.R. China
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Mihos CG, Pineda AM, Santana O. Cardiovascular effects of statins, beyond lipid-lowering properties. Pharmacol Res 2014; 88:12-19. [PMID: 24631782 DOI: 10.1016/j.phrs.2014.02.009] [Citation(s) in RCA: 102] [Impact Index Per Article: 9.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/27/2013] [Revised: 02/25/2014] [Accepted: 02/27/2014] [Indexed: 12/11/2022]
Abstract
The 3-hydroxy-3-methylglutaryl-coenzyme A reductase inhibitors, better known as 'statins', are amongst the most widely used medications in the world. They have become a pivotal component in the primary and secondary prevention of coronary artery and vascular disease. However, a growing amount of evidence has suggested that statins also possess strong pleiotropic effects irrespective of their lipid-lowering properties, which include enhancement of endothelial function, anti-inflammatory and anti-atherothrombotic properties, and immunomodulation. The following provides a comprehensive and updated review of the clinical evidence regarding the pleiotropic effects of statins in cardiovascular disorders and their potential therapeutic benefits.
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Affiliation(s)
- Christos G Mihos
- Columbia University, Division of Cardiology at the Mount Sinai Heart Institute, Miami Beach, FL, United States
| | - Andres M Pineda
- Columbia University, Division of Cardiology at the Mount Sinai Heart Institute, Miami Beach, FL, United States
| | - Orlando Santana
- Columbia University, Division of Cardiology at the Mount Sinai Heart Institute, Miami Beach, FL, United States.
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Atorvastatin Post-Conditioning Attenuates Myocardial Ischemia Reperfusion Injury via Inhibiting Endoplasmic Reticulum Stress–Related Apoptosis. Shock 2014; 42:365-71. [DOI: 10.1097/shk.0000000000000224] [Citation(s) in RCA: 26] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/10/2023]
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11
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Wang TL. Statin (Mevalotin) preconditioning decreases infarct size in senile rat myocardial infarction model. J Acute Med 2014. [DOI: 10.1016/j.jacme.2014.07.001] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/26/2022]
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12
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Hu Y, Li L, Yin W, Shen L, You B, Gao H. Protective effect of proanthocyanidins on anoxia-reoxygenation injury of myocardial cells mediated by the PI3K/Akt/GSK-3β pathway and mitochondrial ATP-sensitive potassium channel. Mol Med Rep 2014; 10:2051-8. [PMID: 25109283 DOI: 10.3892/mmr.2014.2459] [Citation(s) in RCA: 20] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/30/2013] [Accepted: 04/09/2014] [Indexed: 12/26/2022] Open
Abstract
The aim of the present study was to examine the protective effect of proanthocyanidins anoxia-reoxygenation injury of myocardial cells and its association with phosphatidylinositol-3-kinase/Akt and glycogen synthase kinase (PI3K/Akt/GSK)-3β and ATP-sensitive potassium channels. Neonatal rat myocardial cells were cultured and an anoxia-reoxygenation model was established following pretreatment with various drugs. The experiment was divided into five groups according to an experimental scheme. An MTT assay was used to examine the cell survival, and reactive oxygen species (ROS) levels and apoptosis were detected by flow cytometry. Myocardial apoptosis was also examined by terminal deoxynucleotidyl transferase dUTP nick end labeling staining and western blot analysis was employed to detect the expression levels of caspase-3, p-Akt and p-glycogen synthase kinase (GSK)-3β. The results revealed that myocardial cells in the anoxia-reoxygenation group (A/R) exhibited reduced survival rates, increased ROS levels and enhanced caspase-3 expression, as compared with the control group (CN; P<0.05). However, the increase in p-Akt and p-GSK-3β expression was not significantly different. In the proanthocyanidin pretreatment group (PC) the myocardial cell survival rate was increased, ROS levels were reduced, caspase-3 expression was decreased and p-Akt and p-GSK-3β expression levels were significantly increased as compared with the A/R group (P<0.05). Blockade of the PIK3/Akt channel by LY294002 eliminated the protective effects of proanthocyanidins and induced a significant decrease in p-Akt protein and p-GSK-3β expression levels as compared with the PC group. The inhibitor of mitochondrial ATP-sensitive potassium (mitoKATP) channels, 5-HD, also significantly suppressed the protective effects of proanthocyanidins, but had no evident impact on p-Akt and p-GSK-3β expression as compared with the PC group. In conclusion, pretreatment with proanthocyanidins had a protective effect on rat myocardial cell anoxia/reoxygenation injury. This effect is associated with the activation of the PI3K/Akt/GSK-3β signaling pathway and the opening of mitoKATP channels, which may have important roles downstream of PI3K.
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Affiliation(s)
- Yanyan Hu
- Department of Geriatrics, Qilu Hospital of Shandong University, Jinan, Shandong 250012, P.R. China
| | - Li Li
- Department of Medicine, Shandong University, Jinan, Shandong 250012, P.R. China
| | - Wenbin Yin
- Department of Geriatrics, Qilu Hospital of Shandong University, Jinan, Shandong 250012, P.R. China
| | - Lin Shen
- Department of Geriatrics, Qilu Hospital of Shandong University, Jinan, Shandong 250012, P.R. China
| | - Beian You
- Department of Geriatrics, Qilu Hospital of Shandong University, Jinan, Shandong 250012, P.R. China
| | - Haiqing Gao
- Department of Geriatrics, Qilu Hospital of Shandong University, Jinan, Shandong 250012, P.R. China
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Zhang Q, Wang H, Yang YJ, Dong QT, Wang TJ, Qian HY, Li N, Wang XM, Jin C. Atorvastatin treatment improves the effects of mesenchymal stem cell transplantation on acute myocardial infarction: the role of the RhoA/ROCK/ERK pathway. Int J Cardiol 2014; 176:670-9. [PMID: 25139321 DOI: 10.1016/j.ijcard.2014.07.071] [Citation(s) in RCA: 29] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/17/2013] [Revised: 07/03/2014] [Accepted: 07/23/2014] [Indexed: 12/20/2022]
Abstract
BACKGROUND Statins protect mesenchymal stem cells (MSCs) against the harsh microenvironment and improve the efficacy of MSC transplantation after acute myocardial infarction (AMI); however, the mechanism remains uncertain. Furthermore, the transdifferentiation potential of MSCs in the post-infarct heart remains highly controversial. The RhoA/Rho-associated coiled-coil-forming kinase (ROCK) pathway participates in many aspects of the damaged heart after AMI and related to the "pleiotropic" effects of statins. This study aimed to explore whether atorvastatin (ATV) facilitates the survival and therapeutic efficacy of MSCs via the inhibition of RhoA/ROCK pathway and subsequently its downstream molecular extracellular regulated protein kinase (ERK1/2), and to investigate the transdifferentiation potential of MSCs in vivo. METHODS AND RESULTS Female rats received myocardial injections of male rat MSCs 30 min after AMI. Four weeks after AMI, ATV combined with MSC treatment resulted in improved cardiac function and reduced infarct area. ATV facilitated the MSC survival, as revealed by the increased expression of Y chromosomal genes and the increased number of Y chromosome-positive cells; however, no transdifferentiation markers were observed. ATV inhibited the production of inflammatory cytokines both in vitro and vivo, accompanied by suppression of ROCK and ERK activities. Geranylgeranyl pyrophosphate (GGPP) abrogated the effects of ATV in the H9c2 cells under hypoxia/serum deprivation (H/SD), while the ROCK inhibitor fasudil mimicked the benefits of ATV after AMI. CONCLUSIONS ATV improves the post-infarct microenvironment via RhoA/ROCK/ERK inhibition and thus facilitates the survival and efficacy of implanted MSCs. Transdifferentiation may be not responsible for the cardiac benefits that follow MSC transplantation.
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Affiliation(s)
- Qian Zhang
- State Key Laboratory of Cardiovascular Disease, Fuwai Hospital, National Center for Cardiovascular Diseases, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100037, PR China
| | - Hong Wang
- State Key Laboratory of Cardiovascular Disease, Fuwai Hospital, National Center for Cardiovascular Diseases, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100037, PR China
| | - Yue-Jin Yang
- State Key Laboratory of Cardiovascular Disease, Fuwai Hospital, National Center for Cardiovascular Diseases, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100037, PR China.
| | - Qiu-Ting Dong
- State Key Laboratory of Cardiovascular Disease, Fuwai Hospital, National Center for Cardiovascular Diseases, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100037, PR China
| | - Tian-Jie Wang
- State Key Laboratory of Cardiovascular Disease, Fuwai Hospital, National Center for Cardiovascular Diseases, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100037, PR China
| | - Hai-Yan Qian
- State Key Laboratory of Cardiovascular Disease, Fuwai Hospital, National Center for Cardiovascular Diseases, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100037, PR China
| | - Na Li
- State Key Laboratory of Cardiovascular Disease, Fuwai Hospital, National Center for Cardiovascular Diseases, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100037, PR China
| | - Xi-Mei Wang
- State Key Laboratory of Cardiovascular Disease, Fuwai Hospital, National Center for Cardiovascular Diseases, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100037, PR China
| | - Chen Jin
- State Key Laboratory of Cardiovascular Disease, Fuwai Hospital, National Center for Cardiovascular Diseases, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100037, PR China
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Suzuki-Banhesse VF, Azevedo FF, Araujo EP, do Amaral MEC, Caricilli AM, Saad MJA, Lima MHM. Effect of atorvastatin on wound healing in rats. Biol Res Nurs 2014; 17:159-68. [PMID: 24924353 DOI: 10.1177/1099800414537348] [Citation(s) in RCA: 21] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/23/2022]
Abstract
Skin-wound healing is a complex and dynamic biological process involving inflammation, proliferation, and remodeling. Recent studies have shown that statins are new therapeutical options because of their actions, such as anti-inflammatory and antioxidant activity, on vasodilation, endothelial dysfunction and neoangiogenesis, which are independent of their lipid-lowering action. Our aim was to investigate the effect of atorvastatin on tissue repair after acute injury in healthy animals. Rats were divided into four groups: placebo-treated (P), topical atorvastatin-treated (AT), oral atorvastatin-treated (AO), topical and oral atorvastatin-treated (ATO). Under anesthesia, rats were wounded with an 8-mm punch in the dorsal region. Lesions were photographed on Days 0, 1, 3, 7, 10, 12, and 14 post-injury and samples taken on Days 1, 3, 7, and 14 for protein-expression analysis of insulin receptor substrate (IRS)-1, phosphatidylinositol 3-kinase (PI3K), protein kinase B (Akt), glycogen synthase kinase (GSK)-3, endothelial nitric oxide synthase (eNOS), vascular endothelial growth factor (VEGF), extracellular signal-regulated kinase (ERK), interleukin (IL)-10, IL-1β, IL-6, and tumor necrosis factor (TNF)-α. Upon macroscopic examination, we observed significant reductions of lesion areas in groups AT, AO, and ATO compared to the P group. Additionally, AT and AO groups showed increased expression of IRS-1, PI3K, Akt, GSK-3, and IL-10 on Days 1 and 3 when compared with the P group. All atorvastatin-treated groups showed higher expression of IRS-1, PI3K, Akt, GSK-3, IL-10, eNOS, VEGF, and ERK on Day 7. On Days 1, 3, and 7, all atorvastatin-treated groups showed lower expression of IL-6 and TNF-α when compared with the P group. We conclude that atorvastatin accelerated tissue repair of acute lesions in rats and modulated expressions of proteins and cytokines associated with cell-growth pathways.
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Affiliation(s)
| | | | - Eliana Pereira Araujo
- Faculty of Nursing, State University of Campinas (UNICAMP), Campinas, São Paulo, Brazil
| | | | | | - Mario Jose Abdalla Saad
- Department of Internal Medicine, Faculty of Medical Sciences, State University of Campinas (UNICAMP), Campinas, São Paulo, Brazil
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15
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NEMČEKOVÁ M, ČARNICKÁ S, FERKO M, MURÁRIKOVÁ M, LEDVÉNYIOVÁ V, RAVINGEROVÁ T. Treatment of Rats With Hypolipidemic Compound Pirinixic Acid Protects Their Hearts Against Ischemic Injury: Are Mitochondrial KATP Channels and Reactive Oxygen Species Involved? Physiol Res 2013; 62:577-84. [DOI: 10.33549/physiolres.932591] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/01/2023] Open
Abstract
Hypolipidemic compound pirinixic acid (WY-14643, WY) is known to exert pleiotropic (other than primary) effects, such as activation of peroxisome proliferator-activated receptors (PPAR-α), transcription factors regulating different cardiac functions. Their role in ischemia-reperfusion (I/R) injury and cardioprotection is less clear, although protective effects of PPAR agonists have been documented. This study was designed to explore the effects of WY on the I/R injury in the rat heart and potential mechanisms involved, including mitochondrial KATP channels (mitoKATP) opening and production of reactive oxygen species (ROS). Langendorff-perfused hearts of rats intragastrally treated with WY (3 mg/kg/day) for 5 days and of control animals were subjected to 30-min global ischemia and 2-h reperfusion with or without 15-min perfusion with mitoKATP blocker 5-hydroxydecanoate (5-HD) prior to I/R. Evaluation of the infarct size (IS, TTC staining) served as the main end-point of protection. Lipid peroxidation (a marker of ROS production) was determined by measurement of myocardial concentration of conjugated dienes (CD), whereas protein expression of endothelial NO synthase was analysed by Western blotting. A 2-fold increase in the cardiac protein levels of eNOS after treatment with WY was accompanied by lower post-I/R levels of CD compared with those in the hearts of untreated controls, although WY itself enhanced ROS generation prior to ischemia. IS was reduced by 47 % in the hearts of WY-treated rats (P<0.05), and this effect was reversed by 5-HD. Results suggest that PPAR-α activation may confer protection against lethal I/R injury in the rat heart that involves up-regulation of eNOS, mitoKATP opening and reduced oxidative stress during I/R.
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Affiliation(s)
| | | | | | | | | | - T. RAVINGEROVÁ
- Institute for Heart Research, Slovak Academy of Sciences, Centre of Excellence of SAS NOREG, Bratislava, Slovak Republic
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16
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Nykänen AI, Tuuminen R, Lemström KB. Donor simvastatin treatment and cardiac allograft ischemia/reperfusion injury. Trends Cardiovasc Med 2013; 23:85-90. [PMID: 23295079 DOI: 10.1016/j.tcm.2012.09.005] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/30/2012] [Revised: 06/30/2012] [Accepted: 07/02/2012] [Indexed: 01/14/2023]
Abstract
Ischemia/reperfusion injury of a transplanted heart may result in serious early and late adverse effects such as primary graft dysfunction, increased allograft immunogenicity, and initiation of fibroproliferative cascades that compromise the survival of the recipient. Microvascular dysfunction has a central role in ischemia/reperfusion injury through increased vascular permeability, leukocyte adhesion and extravasation, thrombosis, vasoconstriction, and the no-reflow phenomenon. Here we review the involvement of microvascular endothelial cells and their surrounding pericytes in ischemia/reperfusion injury, and the pleiotropic, cholesterol-independent effects of statins on microvascular dysfunction. In addition, we delineate how the rapid vasculoprotective effects of statins could be used to protect cardiac allografts against ischemia/reperfusion injury by administering statins to the organ donor before graft removal and transplantation.
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Affiliation(s)
- Antti I Nykänen
- Transplantation Laboratory, Haartman Institute, P.O. Box 21 (Haartmaninkatu 3), FI-00014, University of Helsinki, Finland.
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17
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Sharma V, Bell RM, Yellon DM. Targeting reperfusion injury in acute myocardial infarction: a review of reperfusion injury pharmacotherapy. Expert Opin Pharmacother 2012; 13:1153-75. [PMID: 22594845 DOI: 10.1517/14656566.2012.685163] [Citation(s) in RCA: 60] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/05/2022]
Abstract
INTRODUCTION Acute myocardial infarction (AMI) (secondary to lethal ischemia-reperfusion [IR]) contributes to much of the mortality and morbidity from ischemic heart disease. Currently, the treatment for AMI is early reperfusion; however, this itself contributes to the final myocardial infarct size, in the form of what has been termed 'lethal reperfusion injury'. Over the last few decades, the discovery of the phenomena of ischemic preconditioning and postconditioning, as well as remote preconditioning and remote postconditioning, along with significant advances in our understanding of the cardioprotective pathways underlying these phenomena, have provided the possibility of successful mechanical and pharmacological interventions against reperfusion injury. AREAS COVERED This review summarizes the evidence from clinical trials evaluating pharmacological agents as adjuncts to standard reperfusion therapy for ST-elevation AMI. EXPERT OPINION Reperfusion injury pharmacotherapy has moved from bench to bedside, with clinical evaluation and ongoing clinical trials providing us with valuable insights into the shortcomings of current research in establishing successful treatments for reducing reperfusion injury. There is a need to address some key issues that may be leading to lack of translation of cardioprotection seen in basic models to the clinical setting. These issues are discussed in the Expert opinion section.
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Affiliation(s)
- Vikram Sharma
- The Hatter Cardiovascular Institute, 67 Chenies Mews, London WC1E 6HX, UK
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18
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Abisambra JF, Jinwal UK, Jones JR, Blair LJ, Koren J, Dickey CA. Exploiting the diversity of the heat-shock protein family for primary and secondary tauopathy therapeutics. Curr Neuropharmacol 2012; 9:623-31. [PMID: 22654720 PMCID: PMC3263456 DOI: 10.2174/157015911798376226] [Citation(s) in RCA: 24] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/13/2010] [Revised: 11/01/2010] [Accepted: 12/06/2010] [Indexed: 12/17/2022] Open
Abstract
The heat shock protein (Hsp) family is an evolutionarily conserved system that is charged with preventing unfolded or misfolded proteins in the cell from aggregating. In Alzheimer’s disease, extracellular accumulation of the amyloid β peptide (Aβ) and intracellular aggregation of the microtubule associated protein tau may result from mechanisms involving chaperone proteins like the Hsps. Due to the ability of Hsps to regulate aberrantly accumulating proteins like Aβ and tau, therapeutic strategies are emerging that target this family of chaperones to modulate their pathobiology. This article focuses on the use of Hsp-based therapeutics for treating primary and secondary tauopathies like Alzheimer’s disease. It will particularly focus on the pharmacological targeting of the Hsp70/90 system and the value of manipulating Hsp27 for treating Alzheimer’s disease.
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Affiliation(s)
- Jose F Abisambra
- Department of Molecular Medicine, USF Health Byrd Alzheimer's Institute, Tampa, FL 33613, USA
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19
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Ravingerová T, Čarnická S, Nemčeková M, Ledvényiová V, Adameová A, Kelly T, Barlaka E, Galatou E, Khandelwal VKM, Lazou A. PPAR-alpha activation as a preconditioning-like intervention in rats in vivo confers myocardial protection against acute ischaemia–reperfusion injury: involvement of PI3K–Akt. Can J Physiol Pharmacol 2012; 90:1135-44. [DOI: 10.1139/y2012-052] [Citation(s) in RCA: 39] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/22/2022]
Abstract
Peroxisome proliferator-activated receptors (PPAR) regulate the expression of genes involved in lipid metabolism, energy production, and inflammation. Their role in ischaemia–reperfusion (I/R) is less clear, although research indicates involvement of PPARs in some forms of preconditioning. This study aimed to explore the effects of PPAR-α activation on the I/R injury and potential cardioprotective downstream mechanisms involved. Langendorff-perfused hearts of rats pretreated with the selective PPAR-α agonist WY-14643 (WY, pirinixic acid; 3 mg·(kg body mass)·day–1; 5 days) were subjected to 30 min ischaemia – 2 h reperfusion with or without the phosphatidylinositol 3-kinase (PI3K)–Akt inhibitor wortmannin for the evaluation of functional (left ventricular developed pressure, LVDP) recovery, infarct size (IS), and reperfusion-induced arrhythmias. A 2-fold increase in baseline PPAR-α mRNA levels (qPCR) in the WY-treated group and higher post-I/R PPAR-α levels compared with those in untreated controls were accompanied by similar changes in the expression of PPAR-α target genes PDK4 and mCPT-1, regulating glucose and fatty acid metabolism, and by enhanced Akt phosphorylation. Post-ischaemic LVDP restoration in WY-treated hearts reached 60% ± 9% of the pre-ischaemic values compared with 24% ± 3% in the control hearts (P < 0.05), coupled with reduced IS and incidence of ventricular fibrillation that was blunted by wortmannin. Results indicate that PPAR-α up-regulation may confer preconditioning-like protection via metabolic effects. Downstream mechanisms of PPAR-α-mediated cardioprotection may involve PI3K–Akt activation.
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Affiliation(s)
- Táňa Ravingerová
- Institute for Heart Research, Slovak Academy of Sciences and Centre of Excellence of SAS NOREG, POB 104, Dubravská cesta 9, 840 05 Bratislava, Slovak Republic
| | - Slávka Čarnická
- Institute for Heart Research, Slovak Academy of Sciences and Centre of Excellence of SAS NOREG, POB 104, Dubravská cesta 9, 840 05 Bratislava, Slovak Republic
| | - Martina Nemčeková
- Institute for Heart Research, Slovak Academy of Sciences and Centre of Excellence of SAS NOREG, POB 104, Dubravská cesta 9, 840 05 Bratislava, Slovak Republic
| | - Veronika Ledvényiová
- Institute for Heart Research, Slovak Academy of Sciences and Centre of Excellence of SAS NOREG, POB 104, Dubravská cesta 9, 840 05 Bratislava, Slovak Republic
| | - Adriana Adameová
- Department of Pharmacology and Toxicology, Faculty of Pharmacy, Comenius University, Bratislava, Slovak Republic
| | - Tara Kelly
- School of Biology, Aristotle University of Thessaloniki, Thessaloniki, Greece
| | - Eleftheria Barlaka
- School of Biology, Aristotle University of Thessaloniki, Thessaloniki, Greece
| | - Eleftheria Galatou
- School of Biology, Aristotle University of Thessaloniki, Thessaloniki, Greece
| | | | - Antigone Lazou
- School of Biology, Aristotle University of Thessaloniki, Thessaloniki, Greece
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20
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Phosphorylation of endothelial NOS contributes to simvastatin protection against myocardial no-reflow and infarction in reperfused swine hearts: partially via the PKA signaling pathway. Acta Pharmacol Sin 2012; 33:879-87. [PMID: 22659627 DOI: 10.1038/aps.2012.27] [Citation(s) in RCA: 23] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/04/2023]
Abstract
AIM The cholesterol-lowering drugs statins could enhance the activities of endothelial nitric oxide synthase (eNOS) and protect myocardium during ischemia and reperfusion. The aim of this study was to examine whether protein kinase A (PKA) was involved in statin-mediated eNOS phosphorylation and cardioprotection. METHODS 6-Month-old Chinese minipigs (20-30 kg) underwent a 1.5-h occlusion and 3-h reperfusion of the left anterior descending coronary artery (LAD). In the sham group, the LAD was encircled by a suture but not occluded. Hemodynamic and cardiac function was monitored using a polygraph. Plasma activity of creatine kinase and the tissue activities of PKA and NOS were measured spectrophotometrically. p-CREB, eNOS and p-eNOS levels were detected using Western blotting. Sizes of the area at risk, the area of no-reflow and the area of necrosis were measured morphologically. RESULTS Pretreatment of the animals with simvastatin (SIM, 2 mg/kg, po) before reperfusion significantly decreased the plasma activity of creatine kinase, an index of myocardial necrosis, and reduced the no-reflow size (from 50.4%±2.4% to 36.1%±2.1%, P<0.01) and the infarct size (from 79.0%±2.7% to 64.1%±4.5%, P<0.01). SIM significantly increased the activities of PKA and constitutive NOS, and increased Ser(133) p-CREB protein, Ser(1179) p-eNOS, and Ser(635) p-eNOS in ischemic myocardium. Intravenous infusion of the PKA inhibitor H-89 (1 μg·kg(-1)·min(-1)) partially abrogated the SIM-induced cardioprotection and eNOS phosphorylation. In contrast, intravenous infusion of the eNOS inhibitor L-NNA (10 mg·kg(-1)) completely abrogated the SIM-induced cardioprotection and eNOS phosphorylation during ischemia and reperfusion, but did not affect the activity of PKA. CONCLUSION Pretreatment with a single dose of SIM 2.5 h before reperfusion attenuates myocardial no-reflow and infarction through increasing eNOS phosphorylation at Ser(1179) and Ser(635) that was partially mediated via the PKA signaling pathway.
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21
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Guo S, Olm-Shipman A, Walters A, Urciuoli WR, Devito S, Nadtochiy SM, Wojtovich AP, Brookes PS. A cell-based phenotypic assay to identify cardioprotective agents. Circ Res 2012; 110:948-57. [PMID: 22394516 DOI: 10.1161/circresaha.111.263715] [Citation(s) in RCA: 27] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
RATIONALE Tissue ischemia/reperfusion (IR) injury underlies several leading causes of death such as heart-attack and stroke. The lack of clinical therapies for IR injury may be partly due to the difficulty of adapting IR injury models to high-throughput screening (HTS). OBJECTIVE To develop a model of IR injury that is both physiologically relevant and amenable to HTS. METHODS AND RESULTS A microplate-based respirometry apparatus was used. Controlling gas flow in the plate head space, coupled with the instrument's mechanical systems, yielded a 24-well model of IR injury in which H9c2 cardiomyocytes were transiently trapped in a small volume, rendering them ischemic. After initial validation with known protective molecules, the model was used to screen a 2000-molecule library, with post-IR cell death as an end point. Po2 and pH monitoring in each well also afforded metabolic data. Ten protective, detrimental, and inert molecules from the screen were subsequently tested in a Langendorff-perfused heart model of IR injury, revealing strong correlations between the screening end point and both recovery of cardiac function (negative, r2=0.66) and infarct size (positive, r2=0.62). Relationships between the effects of added molecules on cellular bioenergetics and protection against IR injury were also studied. CONCLUSIONS This novel cell-based assay can predict either protective or detrimental effects on IR injury in the intact heart. Its application may help identify therapeutic or harmful molecules.
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Affiliation(s)
- Stephanie Guo
- School of Medicine, University of Rochester Medical Center, 601 Elmwood Ave, Rochester, NY 14642, USA
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22
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Meijering RAM, Zhang D, Hoogstra-Berends F, Henning RH, Brundel BJJM. Loss of proteostatic control as a substrate for atrial fibrillation: a novel target for upstream therapy by heat shock proteins. Front Physiol 2012; 3:36. [PMID: 22375124 PMCID: PMC3284689 DOI: 10.3389/fphys.2012.00036] [Citation(s) in RCA: 21] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/24/2011] [Accepted: 02/09/2012] [Indexed: 12/19/2022] Open
Abstract
Atrial fibrillation (AF) is the most common, sustained clinical tachyarrhythmia associated with significant morbidity and mortality. AF is a persistent condition with progressive structural remodeling of the atrial cardiomyocytes due to the AF itself, resulting in cellular changes commonly observed in aging and in other heart diseases. While rhythm control by electrocardioversion or drug treatment is the treatment of choice in symptomatic AF patients, its efficacy is still limited. Current research is directed at preventing first-onset AF by limiting the development of substrates underlying AF progression and resembles mechanism-based therapy. Upstream therapy refers to the use of non-ion channel anti-arrhythmic drugs that modify the atrial substrate- or target-specific mechanisms of AF, with the ultimate aim to prevent the occurrence (primary prevention) or recurrence of the arrhythmia following (spontaneous) conversion (secondary prevention). Heat shock proteins (HSPs) are molecular chaperones and comprise a large family of proteins involved in the protection against various forms of cellular stress. Their classical function is the conservation of proteostasis via prevention of toxic protein aggregation by binding to (partially) unfolded proteins. Our recent data reveal that HSPs prevent electrical, contractile, and structural remodeling of cardiomyocytes, thus attenuating the AF substrate in cellular, Drosophila melanogaster, and animal experimental models. Furthermore, studies in humans suggest a protective role for HSPs against the progression from paroxysmal AF to persistent AF and in recurrence of AF. In this review, we discuss upregulation of the heat shock response system as a novel target for upstream therapy to prevent derailment of proteostasis and consequently progression and recurrence of AF.
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Affiliation(s)
- Roelien A M Meijering
- Department of Clinical Pharmacology, Groningen University Institute for Drug Exploration, University Medical Center Groningen, University of Groningen Groningen, Netherlands
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23
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Tuuminen R, Syrjälä S, Krebs R, Keränen MA, Koli K, Abo-Ramadan U, Neuvonen PJ, Tikkanen JM, Nykänen AI, Lemström KB. Donor Simvastatin Treatment Abolishes Rat Cardiac Allograft Ischemia/Reperfusion Injury and Chronic Rejection Through Microvascular Protection. Circulation 2011; 124:1138-50. [DOI: 10.1161/circulationaha.110.005249] [Citation(s) in RCA: 57] [Impact Index Per Article: 4.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/31/2023]
Affiliation(s)
- Raimo Tuuminen
- From the Transplantation Laboratory, Haartman Institute, University of Helsinki and HUSLAB, Helsinki University Central Hospital (R.T., S.S., R.K., M.A.I.K., J.M.T., A.I.N., K.B.L.); Department of Clinical Pharmacology, University of Helsinki and HUSLAB, Helsinki University Central Hospital (P.J.N.); Department of Cardiothoracic Surgery, Helsinki University Central Hospital (A.I.N., K.B.L.); Departments of Virology and Pathology, Haartman Institute, University of Helsinki (K.K.); and Experimental
| | - Simo Syrjälä
- From the Transplantation Laboratory, Haartman Institute, University of Helsinki and HUSLAB, Helsinki University Central Hospital (R.T., S.S., R.K., M.A.I.K., J.M.T., A.I.N., K.B.L.); Department of Clinical Pharmacology, University of Helsinki and HUSLAB, Helsinki University Central Hospital (P.J.N.); Department of Cardiothoracic Surgery, Helsinki University Central Hospital (A.I.N., K.B.L.); Departments of Virology and Pathology, Haartman Institute, University of Helsinki (K.K.); and Experimental
| | - Rainer Krebs
- From the Transplantation Laboratory, Haartman Institute, University of Helsinki and HUSLAB, Helsinki University Central Hospital (R.T., S.S., R.K., M.A.I.K., J.M.T., A.I.N., K.B.L.); Department of Clinical Pharmacology, University of Helsinki and HUSLAB, Helsinki University Central Hospital (P.J.N.); Department of Cardiothoracic Surgery, Helsinki University Central Hospital (A.I.N., K.B.L.); Departments of Virology and Pathology, Haartman Institute, University of Helsinki (K.K.); and Experimental
| | - Mikko A.I. Keränen
- From the Transplantation Laboratory, Haartman Institute, University of Helsinki and HUSLAB, Helsinki University Central Hospital (R.T., S.S., R.K., M.A.I.K., J.M.T., A.I.N., K.B.L.); Department of Clinical Pharmacology, University of Helsinki and HUSLAB, Helsinki University Central Hospital (P.J.N.); Department of Cardiothoracic Surgery, Helsinki University Central Hospital (A.I.N., K.B.L.); Departments of Virology and Pathology, Haartman Institute, University of Helsinki (K.K.); and Experimental
| | - Katri Koli
- From the Transplantation Laboratory, Haartman Institute, University of Helsinki and HUSLAB, Helsinki University Central Hospital (R.T., S.S., R.K., M.A.I.K., J.M.T., A.I.N., K.B.L.); Department of Clinical Pharmacology, University of Helsinki and HUSLAB, Helsinki University Central Hospital (P.J.N.); Department of Cardiothoracic Surgery, Helsinki University Central Hospital (A.I.N., K.B.L.); Departments of Virology and Pathology, Haartman Institute, University of Helsinki (K.K.); and Experimental
| | - Usama Abo-Ramadan
- From the Transplantation Laboratory, Haartman Institute, University of Helsinki and HUSLAB, Helsinki University Central Hospital (R.T., S.S., R.K., M.A.I.K., J.M.T., A.I.N., K.B.L.); Department of Clinical Pharmacology, University of Helsinki and HUSLAB, Helsinki University Central Hospital (P.J.N.); Department of Cardiothoracic Surgery, Helsinki University Central Hospital (A.I.N., K.B.L.); Departments of Virology and Pathology, Haartman Institute, University of Helsinki (K.K.); and Experimental
| | - Pertti J. Neuvonen
- From the Transplantation Laboratory, Haartman Institute, University of Helsinki and HUSLAB, Helsinki University Central Hospital (R.T., S.S., R.K., M.A.I.K., J.M.T., A.I.N., K.B.L.); Department of Clinical Pharmacology, University of Helsinki and HUSLAB, Helsinki University Central Hospital (P.J.N.); Department of Cardiothoracic Surgery, Helsinki University Central Hospital (A.I.N., K.B.L.); Departments of Virology and Pathology, Haartman Institute, University of Helsinki (K.K.); and Experimental
| | - Jussi M. Tikkanen
- From the Transplantation Laboratory, Haartman Institute, University of Helsinki and HUSLAB, Helsinki University Central Hospital (R.T., S.S., R.K., M.A.I.K., J.M.T., A.I.N., K.B.L.); Department of Clinical Pharmacology, University of Helsinki and HUSLAB, Helsinki University Central Hospital (P.J.N.); Department of Cardiothoracic Surgery, Helsinki University Central Hospital (A.I.N., K.B.L.); Departments of Virology and Pathology, Haartman Institute, University of Helsinki (K.K.); and Experimental
| | - Antti I. Nykänen
- From the Transplantation Laboratory, Haartman Institute, University of Helsinki and HUSLAB, Helsinki University Central Hospital (R.T., S.S., R.K., M.A.I.K., J.M.T., A.I.N., K.B.L.); Department of Clinical Pharmacology, University of Helsinki and HUSLAB, Helsinki University Central Hospital (P.J.N.); Department of Cardiothoracic Surgery, Helsinki University Central Hospital (A.I.N., K.B.L.); Departments of Virology and Pathology, Haartman Institute, University of Helsinki (K.K.); and Experimental
| | - Karl B. Lemström
- From the Transplantation Laboratory, Haartman Institute, University of Helsinki and HUSLAB, Helsinki University Central Hospital (R.T., S.S., R.K., M.A.I.K., J.M.T., A.I.N., K.B.L.); Department of Clinical Pharmacology, University of Helsinki and HUSLAB, Helsinki University Central Hospital (P.J.N.); Department of Cardiothoracic Surgery, Helsinki University Central Hospital (A.I.N., K.B.L.); Departments of Virology and Pathology, Haartman Institute, University of Helsinki (K.K.); and Experimental
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Feeney JM, Jayaraman V, Spilka J, Shapiro DS, Ellner S, Marshall WT, Jacobs LM. Prehospital HMG Co-A reductase inhibitor use and reduced mortality in hemorrhagic shock due to trauma. Eur J Trauma Emerg Surg 2011; 38:171-6. [DOI: 10.1007/s00068-011-0144-z] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/31/2011] [Accepted: 07/11/2011] [Indexed: 12/12/2022]
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Sussman MA, Völkers M, Fischer K, Bailey B, Cottage CT, Din S, Gude N, Avitabile D, Alvarez R, Sundararaman B, Quijada P, Mason M, Konstandin MH, Malhowski A, Cheng Z, Khan M, McGregor M. Myocardial AKT: the omnipresent nexus. Physiol Rev 2011; 91:1023-70. [PMID: 21742795 PMCID: PMC3674828 DOI: 10.1152/physrev.00024.2010] [Citation(s) in RCA: 181] [Impact Index Per Article: 12.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/25/2022] Open
Abstract
One of the greatest examples of integrated signal transduction is revealed by examination of effects mediated by AKT kinase in myocardial biology. Positioned at the intersection of multiple afferent and efferent signals, AKT exemplifies a molecular sensing node that coordinates dynamic responses of the cell in literally every aspect of biological responses. The balanced and nuanced nature of homeostatic signaling is particularly essential within the myocardial context, where regulation of survival, energy production, contractility, and response to pathological stress all flow through the nexus of AKT activation or repression. Equally important, the loss of regulated AKT activity is primarily the cause or consequence of pathological conditions leading to remodeling of the heart and eventual decompensation. This review presents an overview compendium of the complex world of myocardial AKT biology gleaned from more than a decade of research. Summarization of the widespread influence that AKT exerts upon myocardial responses leaves no doubt that the participation of AKT in molecular signaling will need to be reckoned with as a seemingly omnipresent regulator of myocardial molecular biological responses.
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Affiliation(s)
- Mark A Sussman
- Department of Biology, San Diego State University, SDSU Heart Institute, San Diego, California 92182, USA.
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Haylor JL, Harris KPG, Nicholson ML, Waller HL, Huang Q, Yang B. Atorvastatin improving renal ischemia reperfusion injury via direct inhibition of active caspase-3 in rats. Exp Biol Med (Maywood) 2011; 236:755-63. [DOI: 10.1258/ebm.2011.010350] [Citation(s) in RCA: 30] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/18/2022] Open
Abstract
Caspase-3 is a key molecule involved in the inflammation and apoptosis of ischemia reperfusion (IR) injury. Statins are known to inhibit IR injury, but the mechanism of action remains uncertain. In the present study, the effect and underlying mechanism of ischemia alone, and reperfusion with or without atorvastatin (AT) as a timed intervention were examined, since clinically the kidney is only exposed to drug delivery during reperfusion. Male Sprague‐Dawley rats were subjected to 45‐min clamping of the left renal hilus followed by four hours reperfusion with a right nephrectomy. AT 10 mg/kg was intravenously administered after clamping the renal hilus, but prior to kidney reperfusion. Ischemia alone did cause tubulointerstitial damage (TID), protein carbonylation and caspase-3 activation with an increase in 12 kDa subunit, while reperfusion further enhanced TID, monocyte (ED-1+ cell) infiltration, apoptosis and necrosis together with caspase-3 activity and 17 kDa subunit, but reversed protein carbonylation. AT significantly reduced TID (26%), ED-1+ cell infiltration (74%), tubular apoptosis (47%) and necrosis (73%), and interstitial apoptosis (64%), as well as caspase-3 activity (26%), but did not change serum creatinine and cholesterol. Importantly, without affecting either caspase-3 active protein cleavage or S-nitrosylation, AT directly inhibited caspase-3 active enzyme in a dose-dependent manner in vitro. In conclusions, IR and AT exerted opposing effects on caspase-3 activity by differing mechanisms, with IR stimulating caspase-3 proteolytic cleavage and AT inhibiting active caspase-3 enzyme. This new inhibitory mechanism of AT may improve reperfusion tolerance in ischemic kidneys and benefit transplant recipients.
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Affiliation(s)
- John L Haylor
- Academic Nephrology Unit, University of Sheffield, Sheffield
| | - Kevin P G Harris
- Department of Infection, Immunity and Inflammation, University of Leicester, Leicester General Hospital, University Hospitals of Leicester, Leicester, UK
| | - Michael L Nicholson
- Department of Infection, Immunity and Inflammation, University of Leicester, Leicester General Hospital, University Hospitals of Leicester, Leicester, UK
| | - Helen L Waller
- Department of Infection, Immunity and Inflammation, University of Leicester, Leicester General Hospital, University Hospitals of Leicester, Leicester, UK
| | - Qiang Huang
- Department of Infection, Immunity and Inflammation, University of Leicester, Leicester General Hospital, University Hospitals of Leicester, Leicester, UK
| | - Bin Yang
- Department of Infection, Immunity and Inflammation, University of Leicester, Leicester General Hospital, University Hospitals of Leicester, Leicester, UK
- Department of Nephrology, University of Nantong, Nantong, Jiangsu, PR China
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Ravingerová T, Adameová A, Kelly T, Antonopoulou E, Pancza D, Ondrejcáková M, Khandelwal VKM, Carnická S, Lazou A. Changes in PPAR gene expression and myocardial tolerance to ischaemia: relevance to pleiotropic effects of statins. Can J Physiol Pharmacol 2010; 87:1028-36. [PMID: 20029539 DOI: 10.1139/y09-071] [Citation(s) in RCA: 22] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/22/2022]
Abstract
Peroxisome proliferator-activated receptors (PPAR), which are key transcriptional regulators of lipid metabolism and energy production, have been suggested to play an important role in myocardial ischaemia-reperfusion (I/R) injury. Their role in cardioprotection, however, is not yet fully elucidated. Statins have shown beneficial effects on I/R damage beyond lipid lowering, and some of their cardioprotective cholesterol-independent effects may be related to the regulation of PPAR. To clarify this issue, we explored a potential link between a response to I/R and changes in cardiac PPARalpha protein and gene expression in simvastatin-treated normocholesterolaemic rats. After 5 days of treatment with simvastatin (10 mg/kg per day, p.o.), Langendorff-perfused hearts were subjected to 30 min regional ischaemia (occlusion of the left anterior descending coronary artery) or global ischaemia and 2 h reperfusion for the evaluation of the infarct size (triphenyltetrazolium chloride and planimetry; as percentage of risk area), ischaemic arrhythmias, and postischaemic contractile recovery. Baseline PPARalpha mRNA and protein levels were increased by 3-fold and 2-fold, respectively, in simvastatin-treated hearts compared with the untreated controls. Simvastatin-treated hearts exhibited smaller size of infarction (11.5% +/- 0.4% vs. 33.7% +/- 4% in controls; p < 0.01), improved postischaemic contractile recovery, and lower severity of arrhythmias during ischaemia and early reperfusion. Enhanced resistance to I/R injury was associated with preservation of mRNA and protein levels of PPARalpha in contrast to their marked downregulation in controls. In conclusion, statin-induced changes in the expression of PPARalpha may contribute to attenuation of myocardial I/R injury and thus suggest the involvement of cardioprotective mechanisms independent of inhibition of HMG-CoA reductase.
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Affiliation(s)
- Tána Ravingerová
- Institute for Heart Research, Centre of Excellence for Cardiovascular Research of the SAS, Bratislava, Slovak Republic.
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28
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Qi XF, Kim DH, Yoon YS, Li JH, Jin D, Teng YC, Kim SK, Lee KJ. Fluvastatin inhibits expression of the chemokine MDC/CCL22 induced by interferon-gamma in HaCaT cells, a human keratinocyte cell line. Br J Pharmacol 2009; 157:1441-50. [PMID: 19594754 DOI: 10.1111/j.1476-5381.2009.00311.x] [Citation(s) in RCA: 30] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/29/2022] Open
Abstract
BACKGROUND AND PURPOSE The macrophage-derived chemokine (MDC/CCL22) is a prototypic Th2-type chemokine intimately involved in Th2-skewed allergic diseases, such as atopic dermatitis and asthma. The statins (3-hydroxy-3-methyl glutaryl coenzyme A reductase inhibitors) have been demonstrated to relieve allergic inflammation. However, the immunological effects and mechanisms of statins against atopic dermatitis remain unknown, at least in vitro. This study aimed to define how different statins affect MDC expression in HaCaT cells, a human keratinocyte cell line. EXPERIMENTAL APPROACH To measure the effects of statins on MDC expression in HaCaT cells, we used a cell viability assay, reverse transcription-polymerase chain reaction, enzyme-linked immunosorbent assay and Western blotting analyses. KEY RESULTS Fluvastatin, but not atorvastatin or simvastatin, inhibited MDC expression induced by interferon (IFN)-gamma and NF-kappaB activation. A NF-kappaB inhibitor, but not a STAT1 inhibitor, suppressed MDC expression in HaCaT cells. Further, inhibition of p38 mitogen-activated protein kinases (MAPKs) significantly suppressed IFN-gamma-induced MDC expression and NF-kappaB activation. Interestingly, fluvastatin suppressed IFN-gamma-induced NF-kappaB activation in parallel with p38 MAPK phosphorylation. CONCLUSIONS AND IMPLICATIONS These results indicate that fluvastatin inhibited expression of the CC chemokine MDC induced by IFN-gamma in HaCaT cells, by inhibiting NF-kappaB activation via the p38 MAPK pathway. This blockade of a Th2 chemokine by fluvastatin may suppress the infiltration of Th2 cells into skin lesions and lessen the skin inflammation seen in atopic dermatitis, suggesting a potential therapeutic use of fluvastatin for this condition.
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Affiliation(s)
- Xu-Feng Qi
- Department of Environmental Medical Biology, Wonju College of Medicine, Yonsei University, Wonju, Gangwon, Korea
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29
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Feeney JM, Burns K, Staff I, Bai J, Rodrigues N, Fortier J, Jacobs LM. Prehospital HMG Co-A Reductase Inhibitor Use and Reduced Mortality in Ruptured Abdominal Aortic Aneurysm. J Am Coll Surg 2009; 209:41-6. [DOI: 10.1016/j.jamcollsurg.2009.03.005] [Citation(s) in RCA: 14] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/05/2009] [Revised: 03/03/2009] [Accepted: 03/04/2009] [Indexed: 11/29/2022]
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Abstract
Our objective was to determine whether human diabetic myocardium is amenable to the cardioprotective actions of ischaemic preconditioning. Human right atrial appendages were harvested from diabetic and non-diabetic patients undergoing elective coronary artery bypass graft surgery. The atrial trabeculae were isolated and subjected to 90 min. of hypoxia followed by 120 min. of reoxygenation, following which the percentage recovery of baseline contractile function was determined. The atrial trabeculae were randomized to: (i) controls (groups 1 and 3); (ii) standard hypoxic preconditioning (HPC) protocol consisting of 4 min. of hypoxia/16 min. of reoxygenation before the 90 min. index hypoxic period (groups 2 and 4); (iii) Prolonged HPC protocol consisting of: 7 min. of hypoxia /16 min. of reoxygenation before the index hypoxic period (group 5). In addition, basal levels of Akt phosphorylation were determined in right atrial appendages harvested from non-diabetic patients and diabetic patients to determine whether PI3K-Akt signalling is down-regulated in the diabetic heart. Standard HPC improved baseline contractile function in human atrial trabeculae harvested from non-diabetic patients (52.4 +/- 3.8% with HPC versus 30.0 +/- 3.2% in control: P = 0.001; N = 6/group), but not in atrial trabeculae isolated from diabetic patients (22.6 +/- 3.3% with HPC versus 28.5 +/- 1.9% in control: P > 0.05; N = 6/group). However, the prolonged HPC protocol did improve baseline contractile function in atrial trabeculae harvested from diabetic patients (42.0 +/- 2.4% with HPC versus 28.5 +/- 1.9% in control: P= 0.001; N > or = 6/group). Western blot analysis demonstrated lower levels of phosphorylated Akt in diabetic myocardium compared to non-diabetic myocardium (0.13 +/- 0.03 arbitrary units versus 0.39 +/- 0.11 arbitrary units: P= 0.047; N > or = 4/group). From the data obtained it appears that the threshold for preconditioning the diabetic myocardium is elevated which may be related to the down-regulation of the PI3K-Akt pathway.
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Affiliation(s)
- Vivek Sivaraman
- The Hatter Cardiovascular Institute, University College London, UK
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31
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Zeng XJ, Zhang LK, Wang HX, Lu LQ, Ma LQ, Tang CS. Apelin protects heart against ischemia/reperfusion injury in rat. Peptides 2009; 30:1144-52. [PMID: 19463748 DOI: 10.1016/j.peptides.2009.02.010] [Citation(s) in RCA: 136] [Impact Index Per Article: 8.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/23/2009] [Revised: 02/11/2009] [Accepted: 02/11/2009] [Indexed: 12/20/2022]
Abstract
Apelin, the endogenous ligand of the G protein-coupled APJ receptor, is a peptide mediator with emerging regulatory actions in the heart. We aimed to determine whether the endogenous apelin/APJ system is an intrinsic protective pathway in ischemic/reperfusion injury. A Langendorff model of perfused isolated rat hearts and primary cultured myocardial cells from neonatal rats were used. Cardiac function was monitored and apelin/APJ expression was determined by real-time PCR and Western blot analysis. In rats under I/R, cardiac function was significantly decreased as compared with controls, and APJ was over-expressed at both the mRNA and protein levels (by 7-fold and 35%, respectively, both p<0.01). However, pre-administration of apelin (30pmol/L) greatly ameliorated the reduced heart function. To gain mechanistic insight into the cardio-protective effects of apelin/APJ, cultured cardiomyocytes were treated with apelin (30 pmol/L), and those under hypoxia/re-oxygenation showed H/R-induced apoptosis and up-regulated apelin/APJ mRNA expression by 6-fold and 7-fold, respectively (both p<0.01). And lactate dehydrogenase leakage was greatly increased as well. Meanwhile, apoptosis, the generation of reactive oxygen species and malonaldehyde content as well as lactate dehydrogenase leakage were inhibited by apelin. Furthermore, apelin enhanced superoxide dismutase activity and phosphorylation of extracellular signal-regulated kinase 1/2 and Akt after hypoxia/re-oxygenation. In conclusion, apelin/APJ has protective effects in ischemic heart disease and might constitute an important therapy target.
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Affiliation(s)
- Xiang Jun Zeng
- Department of Pathophysiology, Capital Medical University, Beijing, China
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32
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Lim SY, Davidson SM, Yellon DM, Smith CCT. The cannabinoid CB1 receptor antagonist, rimonabant, protects against acute myocardial infarction. Basic Res Cardiol 2009; 104:781-92. [PMID: 19462153 DOI: 10.1007/s00395-009-0034-2] [Citation(s) in RCA: 29] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/24/2009] [Revised: 04/21/2009] [Accepted: 05/06/2009] [Indexed: 12/27/2022]
Abstract
CB1 antagonism is associated with reduced doxorubicin-induced cardiotoxicity and decreased cerebrocortical infarction. Rimonabant, a selective CB1 receptor antagonist, was, before it was withdrawn, proposed as a treatment for obesity and reported to reduce cardiovascular risk by improving glucose and lipid profiles and raising adiponectin levels. The cardioprotective actions of rimonabant in 6-week-old C57BL/6J mice fed either high-fat (HFD) or standard diets (STD) for 8 weeks were investigated. At 14 weeks, mice received rimonabant (10 mg/kg/day, i.p.) or vehicle for 1 week and were then subjected to an in vivo acute myocardial infarction. The influence of rimonabant on infarct size (IS) in CB1 knockout (CB1-/-) and wild-type (CB1+/+) mice was also examined. C57BL/6J mice that had been maintained on STD or HFD exhibited 4.3 and 21.4% reductions in body weight following 7 days rimonabant treatment. Rimonabant reduced IS in both STD (29.6 +/- 3.5% vs. 49.8 +/- 6.9% in control, P < 0.05) and HFD (26.9 +/- 1.5% vs. 48.7 +/- 7% in control, P < 0.05) mice. In CB1-/- mice rimonabant failed to reduce body weight or IS (51.0 +/- 5.3% vs. 49.7 +/- 4.7% in control, P > 0.05), although significant reductions were seen in CB1+/+ mice (IS, 48.9 +/- 4.6% control vs. 30.5 +/- 3.1% rimonabant, P < 0.05). To exclude the possibility that weight loss alone induced cardioprotection, HFD mice were switched to STD for 7 days (HFD-STD), resulting in an 11.3 +/- 1.0% decrease in body weight compared to control (+2.1 +/- 1.1% in HFD). This, however, was not associated with IS reduction (39.1 +/- 3.9% HFD-STD vs. 40.0 +/- 5.3% HFD, P > 0.05). Serum and cardiac adiponectin levels were unaltered by rimonabant treatment. HL-1 cell death was not prevented by 1 or 7 days treatment with rimonabant. We conclude that rimonabant-induced infarct limitation may involve the CB1 receptor, although not necessarily cardiac CB1 receptors, and is unrelated to weight loss or altered adiponectin synthesis.
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Affiliation(s)
- Shiang Y Lim
- The Hatter Cardiovascular Institute, University College London Hospital and Medical School, 67 Chenies Mews, London WC1E 6HX, UK
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33
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Ludman A, Venugopal V, Yellon DM, Hausenloy DJ. Statins and cardioprotection — More than just lipid lowering? Pharmacol Ther 2009; 122:30-43. [DOI: 10.1016/j.pharmthera.2009.01.002] [Citation(s) in RCA: 139] [Impact Index Per Article: 8.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/06/2009] [Indexed: 11/29/2022]
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Pharmacological targets revealed by myocardial postconditioning. Curr Opin Pharmacol 2009; 9:177-88. [DOI: 10.1016/j.coph.2008.11.009] [Citation(s) in RCA: 31] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/28/2008] [Revised: 11/11/2008] [Accepted: 11/11/2008] [Indexed: 12/22/2022]
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35
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Ye Y, Lin Y, Manickavasagam S, Perez-Polo JR, Tieu BC, Birnbaum Y. Pioglitazone protects the myocardium against ischemia-reperfusion injury in eNOS and iNOS knockout mice. Am J Physiol Heart Circ Physiol 2008; 295:H2436-46. [PMID: 18931027 DOI: 10.1152/ajpheart.00690.2008] [Citation(s) in RCA: 42] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/22/2022]
Abstract
Endothelial nitric oxide synthase (eNOS) activation with subsequent inducible NOS (iNOS), cytosolic phospholipase A2 (cPLA2), and cyclooxygenase-2 (COX2) activation is essential to statin inhibition of myocardial infarct size (IS). In the rat, the peroxisome proliferator-activated receptor-gamma agonist pioglitazone (Pio) limits IS, upregulates and activates cPLA2 and COX2, and increases myocardial 6-keto-PGF1alpha levels without activating eNOS and iNOS. We asked whether Pio also limits IS in eNOS-/- and iNOS-/- mice. Male C57BL/6 wild-type (WT), eNOS-/-, and iNOS-/- mice received 10 mg.kg(-1).day(-1) Pio (Pio+) or water alone (Pio-) for 3 days. Mice underwent 30 min coronary artery occlusion and 4 h reperfusion, or hearts were harvested and subjected to ELISA and immunoblotting. As a result, Pio reduced IS in the WT (15.4+/-1.4% vs. 39.0+/-1.1%; P<0.001), as well as in the eNOS-/- (32.0+/-1.6% vs. 44.2+/-1.9%; P<0.001) and iNOS-/- (18.0+/-1.2% vs. 45.5+/-2.3%; P<0.001) mice. The protective effect of Pio in eNOS-/- mice was smaller than in the WT (P<0.001) and iNOS-/- (P<0.001) mice. Pio increased myocardial Ser633 and Ser1177 phosphorylated eNOS levels in the WT and iNOS-/- mice. iNOS was undetectable in all six groups. Pio increased cPLA2, COX2, and PGI2 synthase levels in the WT, as well as in the eNOS-/- and iNOS-/-, mice. Pio increased the myocardial 6-keto-PGF1alpha levels and cPLA2 and COX2 activity in the WT, eNOS-/-, and iNOS-/- mice. In conclusion, the myocardial protective effect of Pio is iNOS independent and may be only partially dependent on eNOS. Because eNOS activity decreases with age, diabetes, and advanced atherosclerosis, this effect may be relevant in a clinical setting and should be further characterized.
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Affiliation(s)
- Yumei Ye
- Department of Biochemistry and Molecular Biology, Graduate School of Biomedical Science, University of Texas Medical Branch, Galveston, TX, USA
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36
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Ye Y, Martinez JD, Perez-Polo RJ, Lin Y, Uretsky BF, Birnbaum Y. The role of eNOS, iNOS, and NF-kappaB in upregulation and activation of cyclooxygenase-2 and infarct size reduction by atorvastatin. Am J Physiol Heart Circ Physiol 2008; 295:H343-51. [PMID: 18469150 DOI: 10.1152/ajpheart.01350.2007] [Citation(s) in RCA: 68] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/22/2022]
Abstract
Pretreatment with atorvastatin (ATV) reduces infarct size (IS) and increases myocardial expression of phosphorylated endothelial nitric oxide synthase (p-eNOS), inducible NOS (iNOS), and cyclooxygenase-2 (COX2) in the rat. Inhibiting COX2 abolished the ATV-induced IS limitation without affecting p-eNOS and iNOS expression. We investigated 1) whether 3-day ATV pretreatment limits IS in eNOS(-/-) and iNOS(-/-) mice and 2) whether COX2 expression and/or activation by ATV is eNOS, iNOS, and/or NF-kappaB dependent. Male C57BL/6 wild-type (WT), University of North Carolina eNOS(-/-) and iNOS(-/-) mice received ATV (10 mg.kg(-1).day(-1); ATV(+)) or water alone (ATV(-)) for 3 days. Mice underwent 30 min of coronary artery occlusion and 4 h of reperfusion, or hearts were harvested and subjected to ELISA, immunoblotting, biotin switch, and electrophoretic mobility shift assay. As a result, ATV reduced IS only in the WT mice. ATV increased eNOS, p-eNOS, iNOS, and COX2 levels and activated NF-kappaB in WT mice. It also increased myocardial COX2 activity. In eNOS(-/-) mice, ATV increased COX2 expression but not COX2 activity or iNOS expression. NF-kappaB was not activated by ATV in the eNOS(-/-) mice. In the iNOS(-/-) mice, eNOS and p-eNOS levels were increased but not iNOS and COX2 levels; however, NF-kappaB was activated. In conclusion, both eNOS and iNOS are essential for the IS-limiting effect of ATV. The expression of COX2 by ATV is iNOS, but not eNOS or NF-kappaB, dependent. Activation of COX2 is dependent on iNOS.
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Affiliation(s)
- Yumei Ye
- Department of Internal Medicine, Univ. of Texas Medical Branch, Galveston, TX 77555-0553, USA
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37
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Ye Y, Abu Said GH, Lin Y, Manickavasagam S, Hughes MG, McAdoo DJ, Perez-Polo RJ, Birnbaum Y. Caffeinated Coffee Blunts the Myocardial Protective Effects of Statins against Ischemia–Reperfusion Injury in the Rat. Cardiovasc Drugs Ther 2008; 22:275-82. [DOI: 10.1007/s10557-008-6105-z] [Citation(s) in RCA: 24] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/11/2008] [Accepted: 02/21/2008] [Indexed: 11/24/2022]
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Pretreatment With High-Dose Statin, But Not Low-Dose Statin, Ezetimibe, or the Combination of Low-Dose Statin and Ezetimibe, Limits Infarct Size in the Rat. J Cardiovasc Pharmacol Ther 2008; 13:72-9. [DOI: 10.1177/1074248407312839] [Citation(s) in RCA: 22] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/15/2022]
Abstract
Statins reduce infarct size by upregulating nitric oxide synthases and PGI2 production. In this article, the infarct size-limiting effect of low-dose simvastatin + ezetimibe, ezetimibe, and high-dose statins were compared. Rats received 3-day water, atorvastatin (10 mg/kg/d), simvastatin (10 mg/kg/d), simvastatin (2 mg/kg/d), simvastatin (2 mg/kg/d) + ezetimibe (1 mg/kg/d), or ezetimibe. Rats underwent 30-minute coronary artery occlusion and 4-hour reperfusion. Atorvastatin and simvastatin 10 reduced infarct size, whereas simvastatin 2, ezetimibe, and simvastatin 2 + ezetimibe had no effect. Atorvastatin and simvastatin 10 increased nitric oxide synthases activity, whereas simvastatin-2, ezetimibe, and simvastatin-2 + ezetimibe had only a small effect. Atorvastatin and simvastatin 10 significantly increased myocardial 6-ketoprostaglandin F1α levels, whereas simvastatin 2, ezetimibe, and simvastatin 2 + ezetimibe had no effect. High-dose statin is required to decrease infarct size, upregulate myocardial nitric oxide synthases activities, and increase 6-keto prostaglandin F1α levels. Combination of ezetimibe and low-dose statin is ineffective in modulating myocardial biochemical changes associated with cardioprotection.
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39
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Manickavasagam S, Ye Y, Lin Y, Perez-Polo RJ, Huang MH, Lui CY, Hughes MG, McAdoo DJ, Uretsky BF, Birnbaum Y. The cardioprotective effect of a statin and cilostazol combination: relationship to Akt and endothelial nitric oxide synthase activation. Cardiovasc Drugs Ther 2008; 21:321-30. [PMID: 17620005 DOI: 10.1007/s10557-007-6036-0] [Citation(s) in RCA: 69] [Impact Index Per Article: 4.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 10/23/2022]
Abstract
BACKGROUND Atorvastatin (ATV) protects against ischemia-reperfusion by upregulating Akt and subsequently, endothelial nitric oxide synthase (eNOS) phosphorylation at Ser-1177. However, when given orally, high doses of ATV (10 mg/kg/d) are needed to achieve maximal protective effect in the rat. Protein kinase A (PKA) also phosphorylates eNOS at Ser-1177. As PKA activity depends on cAMP, cilostazol (CIL), a phosphodiesterase type III inhibitor, may stimulate NO production by activating PKA. HYPOTHESIS CIL and ATV may have synergistic effects on eNOS phosphorylation and myocardial infarct size (IS) reduction. METHODS Sprague-Dawley rats received 3-day oral pretreatment with: (1) water; (2) low dose ATV (2 mg/kg/d); (3) CIL (20 mg/kg/d): (4) ATV+CIL. Rats underwent 30 min coronary artery occlusion and 4 h reperfusion, or hearts explanted for immunoblotting without being subjected to ischemia. Area at risk (AR) was assessed by blue dye and IS by triphenyl-tetrazolium-chloride. RESULTS Body weight and the size of AR were comparable among groups. There were no significant differences among groups in mean blood pressure and heart rate. CIL, but not ATV, reduced IS. IS in the ATV+CIL group was significantly smaller than the other three groups (P < 0.001 for each comparison). ATV, CIL and their combination did not affect total eNOS expression. ATV at 2 mg/kg/d did not affect Ser-1177 P-eNOS levels, whereas CIL increased it (258 +/- 15%). The level of myocardial P-eNOS levels was highest in the ATV+CIL group (406 +/- 7%). CONCLUSIONS ATV and CIL have synergistic effect on eNOS phosphorylation and IS reduction. By increased activation of eNOS, CIL may augment the pleiotropic effects of statins.
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Priebe HJ. Statins and other drugs that make a difference. SOUTHERN AFRICAN JOURNAL OF ANAESTHESIA AND ANALGESIA 2008. [DOI: 10.1080/22201173.2008.10872532] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/24/2022]
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Li G, Ali IS, Currie RW. Insulin-induced myocardial protection in isolated ischemic rat hearts requires p38 MAPK phosphorylation of Hsp27. Am J Physiol Heart Circ Physiol 2008; 294:H74-87. [PMID: 17906111 DOI: 10.1152/ajpheart.00675.2007] [Citation(s) in RCA: 18] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/22/2022]
Abstract
Six hours after insulin treatment, hearts express heat shock protein 70 (Hsp70) and have improved contractile function after ischemia-reperfusion injury. In this study we examined hearts 1 h after insulin treatment for contractile function and for expression of Hsp70 and Hsp27. Adult, male Sprague-Dawley rats were assigned to groups: 1) sham, 2) control, 3) insulin injected (200 μU/g body wt), 4) heat shock treated (core body temperature, 42°C for 15 min), and 5) heat shock and insulin treated. At 1 h after these treatments, hearts were isolated, equilibrated to Langendorff perfusion for 30 min, and then subjected for 30 min no-flow global ischemia (37°C) followed by 2 h of reperfusion. Insulin-treated hearts had significantly increased contractile function compared with control hearts. At 1 h after insulin treatment, a minimal change in Hsp70 and Hsp27 content were detected. By 3 h after insulin treatment, a significant increase in Hsp70, but not Hsp27, was detected by Western blot analysis. By immunofluorescence, minimal Hsp70 was detected in insulin-treated hearts, whereas Hsp27 was detected in all hearts, indicative of its constitutive expression. Phosphospecific isoforms of Hsp27 were detected in insulin-, heat shock-, and heat shock and insulin-treated hearts. After ischemia and reperfusion, the insulin-treated hearts had significantly elevated levels of phosphorylated Hsp27. Inhibition of p38 MAPK with SB-203580 blocked the insulin-induced phosphorylation of Hsp27 and the improved functional recovery. In conclusion, insulin induces an apparent rapid phosphorylation of Hsp27 that is associated with improved functional recovery after ischemia-reperfusion injury.
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Affiliation(s)
- Gefeng Li
- Department of Anatomy and Neurobiology, Dalhousie University, Halifax, Nova Scotia, Canada
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Erythropoietin protects the human myocardium against hypoxia/reoxygenation injury via phosphatidylinositol-3 kinase and ERK1/2 activation. Br J Pharmacol 2007; 153:50-6. [PMID: 17952111 DOI: 10.1038/sj.bjp.0707461] [Citation(s) in RCA: 37] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/08/2022] Open
Abstract
BACKGROUND AND PURPOSES Erythropoietin (EPO) has been shown to protect against myocardial infarction in animal studies by activating phosphatidylinositol-3 kinase (PI3K)/Akt and ERK1/2. However these pro-survival pathways are impaired in the diabetic heart. We investigated the ability of EPO to protect human atrial trabeculae from non-diabetic and diabetic patients undergoing coronary artery bypass surgery, against hypoxia-reoxygenation injury. EXPERIMENTAL APPROACH Human atrial trabeculae were exposed to 90min hypoxia and 120min reoxygenation. EPO was administered throughout reoxygenation. The developed force of contraction, calculated as a percentage of baseline force of contraction, was continuously monitored. The involvement of PI3K and ERK1/2 and the levels of activated caspase 3(AC3) were assessed. KEY RESULTS EPO improved the force of contraction in tissue from non-diabetic patients (46.7+/-1.7% vs. 30.2+/-2.2% in control, p<0.001). These beneficial effects were prevented by the PI3K inhibitor, LY294002 and the ERK1/2 inhibitor, U0126. EPO also significantly improved the force of contraction in the diabetic tissue, although to a lesser degree. The levels of activated caspase 3 were significantly reduced in EPO treated trabeculae from both non-diabetic and diabetic patients, relative to their respective untreated controls. CONCLUSIONS AND IMPLICATIONS EPO administered at reoxygenation protected human myocardial muscle by activating PI3K and ERK1/2 and reducing the level of activated caspase 3. This cardioprotection was also observed in the diabetic group. This data supports the potential of EPO being used as a novel cardioprotective strategy either alone or as an adjunct in the clinical setting alongside existing reperfusion therapies.
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Temporal Changes in Myocardial Salvage Kinases During Reperfusion Following Ischemia: Studies Involving the Cardioprotective Adipocytokine Apelin. Cardiovasc Drugs Ther 2007; 21:409-14. [DOI: 10.1007/s10557-007-6054-y] [Citation(s) in RCA: 35] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/22/2022]
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Mocanu MM, Shakkottai P, Yellon DM. The power of drug co-administration: smaller doses better outcomes. Cardiovasc Drugs Ther 2007; 21:319-20. [PMID: 17786547 DOI: 10.1007/s10557-007-6045-z] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/26/2022]
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Yin R, Zhu J, Wang Z, Huang H, Qian J, Li Z, Jing H. Simvastatin attenuates cardiac isograft ischemia-reperfusion injury by down-regulating CC chemokine receptor-2 expression. J Thorac Cardiovasc Surg 2007; 134:780-8. [PMID: 17723833 DOI: 10.1016/j.jtcvs.2007.05.001] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/01/2006] [Revised: 04/19/2007] [Accepted: 05/02/2007] [Indexed: 11/25/2022]
Abstract
OBJECTIVE Accumulating evidence reveals that statins possess direct anti-inflammatory properties through inhibition of proinflammatory cytokine and chemokine secretion in addition to their antioxidant effects, which may contribute to amelioration of ischemia-reperfusion injury. This study tested the hypothesis that perioperative treatment of simvastatin suppresses the cardiac isograft ischemia-reperfusion injury by down-regulation of CC chemokine receptor-2 expression in an inbred rat model of cardiac transplantation. METHODS Donor hearts from Lewis rats were heterotopically transplanted to Lewis rat recipients. Recipients were orally treated with simvastatin (1 mg/kg) or vehicle every morning 3 days before the surgery until the harvest day. Rats were killed at 6 hours and at 1, 3, and 7 days after transplantation. Injury was assessed by infarct size measurement, histologic and immunohistochemical examination, and intragraft myeloperoxidase activity assay. Monocyte chemoattractant protein-1 levels in serum and graft were analyzed by enzyme-linked immunosorbent assay, and intragraft CC chemokine receptor-2 expression was measured by quantitative real-time polymerase chain reaction. RESULTS The infarct size and macrophage infiltration were all significantly reduced in the simvastatin-treated group compared with those of the control group at 1 day after transplantation. Neutrophil accumulation was significantly suppressed until 3 days after transplantation, whereas myeloperoxidase activity had been significantly diminished at 1 day after transplantation. Both monocyte chemoattractant protein-1 concentrations in serum and graft were remarkably decreased at 6 hours after transplantation. Intragraft CC chemokine receptor-2 expression was also down-regulated at 1 day and 3 days after transplantation. CONCLUSIONS Perioperative treatment of simvastatin could suppress the isograft ischemia-reperfusion injury through retarding intragraft monocyte chemoattractant protein-1 accumulation and CC chemokine receptor-2 expression.
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Affiliation(s)
- Rong Yin
- Department of Cardiothoracic Surgery, Jinling Hospital, Clinical Medicine School of Nanjing University, Nanjing, China
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Merla R, Ye Y, Lin Y, Manickavasagam S, Huang MH, Perez-Polo RJ, Uretsky BF, Birnbaum Y. The central role of adenosine in statin-induced ERK1/2, Akt, and eNOS phosphorylation. Am J Physiol Heart Circ Physiol 2007; 293:H1918-28. [PMID: 17616749 DOI: 10.1152/ajpheart.00416.2007] [Citation(s) in RCA: 66] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/22/2022]
Abstract
Statins activate phosphatidylinositol-3-kinase, which activates ecto-5′-nucleotidase and phosphorylates 3-phosphoinositide-dependent kinase-1 (PDK-1). Phosphorylated (P-)PDK-1 phosphorylates Akt, which phosphorylates endothelial nitric oxide synthase (eNOS). We asked if the blockade of adenosine receptors (A1, A2A, A2B, or A3 receptors) could attenuate the induction of Akt and eNOS by atorvastatin (ATV) and whether ERK1/2 is involved in the ATV regulation of Akt and eNOS. In protocol 1, mice received intraperitoneal ATV, theophylline (TH), ATV + TH, or vehicle. In protocol 2, mice received intraperitoneal injections of ATV, U0126 (an ERK1/2 inhibitor), ATV + U0126, or vehicle; 8 h later, hearts were assessed by immunoblot analysis. In protocol 3, mice received intraperitoneal ATV alone or with 8-sulfophenyltheophylline (SPT); 1, 3, and 6 h after injection, hearts were assessed by immunoblot analysis. In protocol 4, mice received intraperitoneal ATV alone or with SPT, 1,3-dipropyl-8-cyclopentylxanthine (DPCPX), 1,3,7-trimethyl-8-(3-chlorostyryl)xanthine (CSC), alloxazine, or MRS-1523; 3 h after injection, hearts were assessed by immunoblot analysis. ATV increased P-ERK, P-PDK-1, Ser473 P-Akt, Thr308 P-Akt, and P-eNOS levels. TH blocked ATV-induced increases in P-ERK, Ser473 P-Akt, Thr308 P-Akt, and P-eNOS levels without affecting the induction of P-PDK-1 by ATV. U0126 blocked the ATV induction of Ser473 P-Akt and Thr308 P-Akt while attenuating the induction of P-eNOS. A detectable increase in P-ERK, Ser473 P-Akt and P-eNOS was seen 3 and 6 h after injection but not at 1 h. DPCPX, CSC, and alloxazine partially blocked the ATV induction of P-ERK, Ser473 P-Akt, and P-eNOS. In conclusion, blockade of adenosine A1, A2A, and A2B receptors but not A3 receptors inhibited the induction of Akt and eNOS by statins. Adenosine was required for ERK1/2 activation by statins, which resulted in Akt and eNOS phosphorylation.
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Affiliation(s)
- Ramanna Merla
- Department of Internal Medicine, University of Texas Medical Branch, Galveston, TX 77555-0553, USA
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Burley DS, Ferdinandy P, Baxter GF. Cyclic GMP and protein kinase-G in myocardial ischaemia-reperfusion: opportunities and obstacles for survival signaling. Br J Pharmacol 2007; 152:855-69. [PMID: 17700722 PMCID: PMC2078226 DOI: 10.1038/sj.bjp.0707409] [Citation(s) in RCA: 130] [Impact Index Per Article: 7.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023] Open
Abstract
It is clear that multiple signalling pathways regulate the critical balance between cell death and survival in myocardial ischaemia-reperfusion. Recent attention has focused on the activation of survival or salvage kinases, particularly during reperfusion, as a common mechanism of many cardioprotective interventions. The phosphatidyl inositol 3'-hydroxy kinase/Akt complex (PI3K/Akt) and p42/p44 mitogen-activated protein kinase cascades have been widely promoted in this respect but the cyclic guanosine 3',5'-monophosphate/cGMP-dependent protein kinase (cGMP/PKG) signal transduction cassette has been less systematically investigated as a survival cascade. We propose that activation of the cGMP/PKG signalling pathway, following activation of soluble or particulate guanylate cyclases, may play a pivotal role in survival signalling in ischaemia-reperfusion, especially in the classical preconditioning, delayed preconditioning and postconditioning paradigms. The resurgence of interest in reperfusion injury, largely as a result of postconditioning-related research, has confirmed that the cGMP/PKG pathway is a pivotal salvage mechanism in reperfusion. Numerous studies suggest that the infarct-limiting effects of preconditioning and postconditioning, exogenously donated nitric oxide (NO), natriuretic peptides, phosphodiesterase inhibitors, and other diverse drugs and mediators such as HMG co-A reductase inhibitors (statins), Rho-kinase inhibitors and adrenomedullin, whether given before and during ischaemia, or specifically at the onset of reperfusion, may be mediated by activation or enhancement of the cGMP pathway, either directly or indirectly via endogenous NO generation downstream of PI3K/Akt. Putative mechanisms of protection include PKG regulation of Ca(2+) homeostasis through the modification of sarcoplasmic reticulum Ca(2+) uptake mechanisms, and PKG-induced opening of ATP-sensitive K(+) channels during ischaemia and/or reperfusion. At present, significant technical obstacles in defining the precise roles played by cGMP/PKG signalling include the heavy reliance on pharmacological PKG inhibitors of uncertain selectivity, difficulties in determining PKG activity in intact tissue, and the growing recognition that intracellular compartmentalisation of the cGMP pool may contribute markedly to the nucleotide's biological actions and biochemical determination. Overall, the body of experimental evidence suggests that cGMP/PKG survival signalling ameliorates irreversible injury associated with ischaemia-reperfusion and may be a tractable therapeutic target.
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Affiliation(s)
- D S Burley
- Division of Pharmacology, Welsh School of Pharmacy, Cardiff University Cardiff, UK
| | - P Ferdinandy
- Cardiovascular Research Group, University of Szeged Szeged, Hungary
| | - G F Baxter
- Division of Pharmacology, Welsh School of Pharmacy, Cardiff University Cardiff, UK
- Author for correspondence:
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Simpkin JC, Yellon DM, Davidson SM, Lim SY, Wynne AM, Smith CCT. Apelin-13 and apelin-36 exhibit direct cardioprotective activity against ischemiareperfusion injury. Basic Res Cardiol 2007; 102:518-28. [PMID: 17694254 DOI: 10.1007/s00395-007-0671-2] [Citation(s) in RCA: 162] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/29/2007] [Revised: 07/05/2007] [Accepted: 07/05/2007] [Indexed: 12/16/2022]
Abstract
Protection against myocardial ischemia-reperfusion (I/R) injury involves activation of phosphatidylinositol-3-OH kinase (PI3K)- Akt/protein kinase B and p44/42 mitogen-activated protein kinase (MAPK), components of the reperfusion injury salvage kinase (RISK) pathway. The adipocytokine, apelin, activates PI3K-Akt and p44/42 in various tissues and we, therefore, hypothesised that it might demonstrate cardioprotective activity. Employing both in vivo (open-chest) and in vitro (Langendorff and cardiomyocytes) rodent (mouse and rat) models ofmyocardial I/R injury we investigated if apelin administered at reperfusion at concentrations akin to pharmacological doses possesses cardioprotective activity. Apelin-13 and the physiologically less potent peptide, apelin-36, decreased infarct size in vitro by 39.6% (p<0.01) and 26.1% (p<0.05) respectively. In vivo apelin-13 and apelin-36 reduced infarct size by 43.1% (p<0.01) and 32.7% (p<0.05). LY294002 and UO126, inhibitors of PI3K-Akt and p44/42 phosphorylation respectively, abolished the protective effects of apelin-13 in vitro.Western blot analysis provided further evidence for the involvement of PI3K-Akt and p44/42 in the cardioprotective actions of apelin. In addition,mitochondrial permeability transition pore (MPTP) opening was delayed by both apelin- 13 (127%, p<0.01) and apelin-36 (93%, p<0.01) which, in the case of apelin-13, was inhibited by LY294002 and mitogen-activated protein kinase kinase (MEK) inhibitor 1. This is the first study to yield evidence that the adipocytokine, apelin, produces direct cardioprotective actions involving the RISK pathway and the MPTP.
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Affiliation(s)
- James C Simpkin
- The Hatter Cardiovascular Institute, University College London Hospital and Medical School, London, UK.
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Merla R, Daher IN, Ye Y, Uretsky BF, Birnbaum Y. Pretreatment with statins may reduce cardiovascular morbidity and mortality after elective surgery and percutaneous coronary intervention: clinical evidence and possible underlying mechanisms. Am Heart J 2007; 154:391-402. [PMID: 17643594 DOI: 10.1016/j.ahj.2007.04.029] [Citation(s) in RCA: 30] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/10/2006] [Accepted: 04/11/2007] [Indexed: 11/27/2022]
Abstract
After Murry et al (Circulation 1986;74:1124) described ischemic preconditioning in 1986, numerous pharmacologic agents with effects simulating ischemic preconditioning have been identified. With the exception of beta-blockers, most such agents have no proven clinical benefit in the setting of myocardial ischemia. The 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors (statins) have been consistently demonstrated to reduce myocardial injury, morbidity, and mortality in the clinical setting, both perioperatively and after percutaneous coronary intervention. Although the precise mechanism underlying their additional protective effect is not yet fully understood, it appears to be immediate in action and independent of cholesterol lowering. Experimental data from several animal models of ischemia and reperfusion have demonstrated an infarct size reduction with prior statin administration. At the cellular level, statins activate the phosphoinositol-3 kinase and Akt signaling cascade. Statins also increase expression and activity of endothelial nitric oxide synthase, inducible nitric oxide synthase, ecto-5'-nucleotidase, cyclooxygenase-2, and other prostaglandin synthesis pathway enzymes. However, when given by oral route to animals, relatively high dose of statins is needed to exert maximal protective effect. Understanding the underlying mechanism may enable to maximize the protective effect by using drug combination with synergistic activity and to avoid medications that may interfere with the protective effect of statins (ie, selective and nonselective cyclooxygenase-2 inhibition). Future clinical applications include preoperative and periprocedural risk reduction.
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Affiliation(s)
- Ramanna Merla
- Department of Internal Medicine, The University of Texas Medical Branch, Galveston, TX 77555, USA
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Smith CCT, Davidson SM, Lim SY, Simpkin JC, Hothersall JS, Yellon DM. Necrostatin: a potentially novel cardioprotective agent? Cardiovasc Drugs Ther 2007; 21:227-33. [PMID: 17665295 DOI: 10.1007/s10557-007-6035-1] [Citation(s) in RCA: 257] [Impact Index Per Article: 14.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/18/2007] [Accepted: 06/12/2007] [Indexed: 12/18/2022]
Abstract
BACKGROUND Necrostatin-1 (Nec-1), a small tryptophan-based molecule, was recently reported to protect the cerebral cortex against ischemia-reperfusion (I/R) injury. We investigated the actions of Nec-1 and its so-called inactive analog, Nec-1i, in the setting of myocardial I/R injury. MATERIALS AND METHODS The actions of Nec-1 and Nec-1i were examined in cultured C2C12 and H9c2 myocytes, cardiomyocytes isolated from male Sprague-Dawley rats, Langendorff isolated perfused C57Bl/6J mouse hearts and an in vivo open-chest C57Bl/6J mouse heart model. RESULTS Nec-1 at 30 microM and 100 microM (but not 100 microM Nec-1i) reduced peroxide-induced cell death in C2C12 cells from 51.2 +/- 1.1% (control) to 26.3 +/- 2.9% (p < 0.01 vs control) and 17.8 +/- 0.9% (p < 0.001), respectively. With H9c2 cells cell death was also reduced from 73.0 +/- 0.4% (control) to 56.7 +/- 0% (30 microM Nec-1, p < 0.05) and 45.4 +/- 3.3% (100 microM Nec-1, p < 0.01). In the isolated perfused heart Nec-1 (30 microM) reduced infarct size (calculated as a percentage of the risk area) from 48.0 +/- 2.0% (control) to 32.1 +/- 5.4% (p < 0.05). Nec-1i (30 microM) also reduced infarct size (32.9 +/- 5.1%, p < 0.05). In anesthetized C57Bl/6J mice Nec-1 (1.65 mg/kg), given intraperitoneally to coincide with reperfusion following left anterior descending artery ligation (30 min), also reduced infarct size from 45.3 +/- 5.1% (control) to 26.6 +/- 4.0% (p < 0.05), whilst Nec-1i (1.74 mg/kg) was ineffective (37.8 +/- 6.0%). Stimulus-induced opening of the mitochondrial permeability transition pore (MPTP) in rat cardiomyocytes, as reflected by the time until mitochondrial depolarisation, was unaffected by Nec-1 or Nec-1i at 30 muM but increased at 100 muM i.e. 91% (p < 0.05 vs control) and 152% (p < 0.001) for Nec-1 and Nec-1i, respectively. CONCLUSION This is the first study to demonstrate that necrostatins inhibit myocardial cell death and reduce infarct size, possibly via a mechanism independent of the MPTP.
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Affiliation(s)
- Christopher C T Smith
- The Hatter Cardiovascular Institute, University College London Hospital and Medical School, 67 Chenies Mews, London, WC1E 6HX, UK
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