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1
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Muñoz-Islas E, Santiago-SanMartin ED, Mendoza-Sánchez E, Torres-Rodríguez HF, Ramírez-Quintanilla LY, Peters CM, Jiménez-Andrade JM. Long-term effects of gestational diabetes mellitus on the pancreas of female mouse offspring. World J Diabetes 2024; 15:758-768. [PMID: 38680692 PMCID: PMC11045410 DOI: 10.4239/wjd.v15.i4.758] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/12/2023] [Revised: 01/29/2024] [Accepted: 03/11/2024] [Indexed: 04/11/2024] Open
Abstract
BACKGROUND Prolonged fetal exposure to hyperglycemia may increase the risk of developing abnormal glucose metabolism and type-2 diabetes during childhood, adolescence, and adulthood; however, the mechanisms by which gestational diabetes mellitus (GDM) predisposes offspring to metabolic disorders remain unknown. AIM To quantify the nerve axons, macrophages, and vasculature in the pancreas from adult offspring born from mouse dams with GDM. METHODS GDM was induced by i.p. administration of streptozotocin (STZ) in ICR mouse dams. At 12 wk old, fasting blood glucose levels were determined in offspring. At 15 wk old, female offspring born from dams with and without GDM were sacrificed and pancreata were processed for immunohistochemistry. We quantified the density of sensory [calcitonin gene-related peptide (CGRP)] and tyrosine hydroxylase (TH) axons, blood vessels (endomucin), and macro-phages (CD68) in the splenic pancreas using confocal microscopy. RESULTS Offspring mice born from STZ-treated dams had similar body weight and blood glucose values compared to offspring born from vehicle-treated dams. However, the density of CGRP+ and TH+ axons, endomucin+ blood vessels, and CD68+ macrophages in the exocrine pancreas was significantly greater in offspring from mothers with GDM vs control offspring. Likewise, the microvasculature in the islets was significantly greater, but not the number of macrophages within the islets of offspring born from dams with GDM compared to control mice. CONCLUSION GDM induces neuronal, vascular, and inflammatory changes in the pancreas of adult progeny, which may partially explain the higher propensity for offspring of mothers with GDM to develop metabolic diseases.
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Affiliation(s)
- Enriqueta Muñoz-Islas
- Unidad Académica Multidisciplinaria Reynosa-Aztlán, Universidad Autónoma de Tamaulipas, Reynosa 88740, Tamaulipas, Mexico
| | - Edgar David Santiago-SanMartin
- Unidad Académica Multidisciplinaria Reynosa-Aztlán, Universidad Autónoma de Tamaulipas, Reynosa 88740, Tamaulipas, Mexico
| | - Eduardo Mendoza-Sánchez
- Unidad Académica Multidisciplinaria Reynosa-Aztlán, Universidad Autónoma de Tamaulipas, Reynosa 88740, Tamaulipas, Mexico
| | - Héctor Fabián Torres-Rodríguez
- Unidad Académica Multidisciplinaria Reynosa-Aztlán, Universidad Autónoma de Tamaulipas, Reynosa 88740, Tamaulipas, Mexico
| | | | - Christopher Michael Peters
- Department of Anesthesiology, Wake Forest University School of Medicine, Winston Salem, NC 27101, United States
| | - Juan Miguel Jiménez-Andrade
- Unidad Académica Multidisciplinaria Reynosa-Aztlán, Universidad Autónoma de Tamaulipas, Reynosa 88740, Tamaulipas, Mexico
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2
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Psefteli PM, Morris JK, Ehler E, Smith L, Bowe J, Mann GE, Taylor PD, Chapple SJ. Sulforaphane induced NRF2 activation in obese pregnancy attenuates developmental redox imbalance and improves early-life cardiovascular function in offspring. Redox Biol 2023; 67:102883. [PMID: 37774548 PMCID: PMC10534264 DOI: 10.1016/j.redox.2023.102883] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/21/2023] [Revised: 09/08/2023] [Accepted: 09/09/2023] [Indexed: 10/01/2023] Open
Abstract
In adverse pregnancy a perturbed redox environment is associated with abnormal early-life cardiovascular development and function. Previous studies have noted alterations in the expression and/or activity of Nuclear Factor E2 Related Factor 2 (NRF2) and its antioxidant targets during human gestational diabetic (GDM) pregnancy, however to our knowledge the functional role of NRF2 in fetal 'priming' of cardiovascular dysfunction in obese and GDM pregnancy has not been investigated. Using a murine model of obesity-induced glucose dysregulated pregnancy, we demonstrate that NRF2 activation by maternal sulforaphane (SFN) supplementation normalizes NRF2-linked NQO1, GCL and CuZnSOD expression in maternal and fetal liver placental and fetal heart tissue by gestational day 17.5. Activation of NRF2 in utero in wild type but not NRF2 deficient mice improved markers of placental efficiency and partially restored fetal growth. SFN supplementation was associated with reduced markers of fetal cardiac oxidative stress, including Nox2 and 3-nitrotyrosine, as well as attenuation of cardiac mass and cardiomyocyte area in male offspring by postnatal day 52 and improved vascular function in male and female offspring by postnatal day 98. Our findings are the first to highlight the functional consequences of NRF2 modulation in utero on early-life cardiovascular function in offspring, demonstrating that activation of NRF2 affords cardiovascular protection in offspring of pregnancies affected by redox dysregulation.
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Affiliation(s)
- Paraskevi-Maria Psefteli
- King's British Heart Foundation Centre of Research Excellence, School of Cardiovascular and Metabolic Medicine & Sciences, Faculty of Life Sciences & Medicine, King's College London, 150 Stamford Street, London SE1 9NH, United Kingdom
| | - Jessica K Morris
- King's British Heart Foundation Centre of Research Excellence, School of Cardiovascular and Metabolic Medicine & Sciences, Faculty of Life Sciences & Medicine, King's College London, 150 Stamford Street, London SE1 9NH, United Kingdom
| | - Elisabeth Ehler
- King's British Heart Foundation Centre of Research Excellence, School of Cardiovascular and Metabolic Medicine & Sciences, Faculty of Life Sciences & Medicine, King's College London, 150 Stamford Street, London SE1 9NH, United Kingdom
| | - Lorna Smith
- King's British Heart Foundation Centre of Research Excellence, School of Cardiovascular and Metabolic Medicine & Sciences, Faculty of Life Sciences & Medicine, King's College London, 150 Stamford Street, London SE1 9NH, United Kingdom
| | - James Bowe
- King's British Heart Foundation Centre of Research Excellence, School of Cardiovascular and Metabolic Medicine & Sciences, Faculty of Life Sciences & Medicine, King's College London, 150 Stamford Street, London SE1 9NH, United Kingdom
| | - Giovanni E Mann
- King's British Heart Foundation Centre of Research Excellence, School of Cardiovascular and Metabolic Medicine & Sciences, Faculty of Life Sciences & Medicine, King's College London, 150 Stamford Street, London SE1 9NH, United Kingdom
| | - Paul D Taylor
- School of Life Course Sciences and Population Health, Faculty of Life Sciences & Medicine, King's College London, United Kingdom
| | - Sarah J Chapple
- King's British Heart Foundation Centre of Research Excellence, School of Cardiovascular and Metabolic Medicine & Sciences, Faculty of Life Sciences & Medicine, King's College London, 150 Stamford Street, London SE1 9NH, United Kingdom.
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3
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Empagliflozin activates JAK2/STAT3 signaling and protects cardiomyocytes from hypoxia/reoxygenation injury under high glucose conditions. J Thromb Thrombolysis 2023; 55:116-125. [PMID: 36396837 DOI: 10.1007/s11239-022-02719-0] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 10/13/2022] [Indexed: 11/18/2022]
Abstract
The morbidity and mortality rates of cardiovascular disease are markedly higher in patients with diabetes than in non-diabetic patients, including patients with ischemia-reperfusion injury (IRI). However, the cardiovascular protective effects of Empagliflozin (EMPA) on IRI in diabetes mellitus have rarely been studied. In this study, we established a cardiomyocyte hypoxia/reoxygenation (H/R) injury model to mimic myocardial I/R injuries that occur in vivo. H9C2 cells were subjected to high glucose (HG) treatment plus H/R injury to mimic myocardial I/R injuries that occur in diabetes mellitus. Next, different concentrations of EMPA were added to the H9C2 cells and its protective effect was detected. STAT3 knockdown with recombinant plasmids was used to determine its roles. Our results showed that H/R injury-induced cell apoptosis, necroptosis, oxidative stress, and endoplasmic reticulum stress were further promoted by HG conditions, and HG treatment plus an H/R injury inhibited the activation of JAK2/STAT3 signaling. EMPA was found to protect against H/R-induced cardiomyocyte injury under HG conditions and activate JAK2/STAT3 signaling, while down-regulation of STAT3 reversed the protective effect of EMPA. When taken together, these findings indicate that EMPA protects against I/R-induced cardiomyocyte injury by activating JAK2/STAT3 signaling under HG conditions. Our results clarified the mechanisms that underlie the cardiovascular protective effects of EMPA in diabetes mellitus and provide new therapeutic targets for IRI in diabetes mellitus.
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4
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Recent Experimental Studies of Maternal Obesity, Diabetes during Pregnancy and the Developmental Origins of Cardiovascular Disease. Int J Mol Sci 2022; 23:ijms23084467. [PMID: 35457285 PMCID: PMC9027277 DOI: 10.3390/ijms23084467] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/16/2022] [Revised: 04/14/2022] [Accepted: 04/15/2022] [Indexed: 12/14/2022] Open
Abstract
Globally, cardiovascular disease remains the leading cause of death. Most concerning is the rise in cardiovascular risk factors including obesity, diabetes and hypertension among youth, which increases the likelihood of the development of earlier and more severe cardiovascular disease. While lifestyle factors are involved in these trends, an increasing body of evidence implicates environmental exposures in early life on health outcomes in adulthood. Maternal obesity and diabetes during pregnancy, which have increased dramatically in recent years, also have profound effects on fetal growth and development. Mounting evidence is emerging that maternal obesity and diabetes during pregnancy have lifelong effects on cardiovascular risk factors and heart disease development. However, the mechanisms responsible for these observations are unknown. In this review, we summarize the findings of recent experimental studies, showing that maternal obesity and diabetes during pregnancy affect energy metabolism and heart disease development in the offspring, with a focus on the mechanisms involved. We also evaluate early proof-of-concept studies for interventions that could mitigate maternal obesity and gestational diabetes-induced cardiovascular disease risk in the offspring.
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5
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La Favor JD, Pierre CJ, Bivalacqua TJ, Burnett AL. Rapamycin Suppresses Penile NADPH Oxidase Activity to Preserve Erectile Function in Mice Fed a Western Diet. Biomedicines 2021; 10:biomedicines10010068. [PMID: 35052748 PMCID: PMC8773370 DOI: 10.3390/biomedicines10010068] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/03/2021] [Revised: 12/23/2021] [Accepted: 12/29/2021] [Indexed: 11/16/2022] Open
Abstract
The mechanistic target of rapamycin (mTOR) is a nutrient-sensitive cellular signaling kinase that has been implicated in the excess production of reactive oxygen species (ROS). NADPH oxidase-derived ROS have been implicated in erectile dysfunction pathogenesis. The objective of this study was to determine if mTOR is an activator of NADPH oxidase in the penis and to determine the functional relevance of this pathway in a translationally relevant model of diet-induced erectile dysfunction. Male mice were fed a control diet or a high-fat, high-sucrose Western style diet (WD) for 12 weeks and treated with vehicle or rapamycin for the final 4 weeks of the dietary intervention. Following the intervention, erectile function was assessed by cavernous nerve-stimulated intracavernous pressure measurement, in vivo ROS production was measured in the penis using a microdialysis approach, and relative protein contents from the corpus cavernosum were determined by Western blot. Erectile function was impaired in vehicle treated WD-mice and was preserved in rapamycin treated WD-mice. Penile NADPH oxidase-mediated ROS were elevated in WD-mice and suppressed by rapamycin treatment. Western blot analysis suggests mTOR activation with WD by increased active site phosphorylation of mTOR and p70S6K, and increased expression of NADPH oxidase subunits, all of which were suppressed by rapamycin. These data suggest that mTOR is an upstream mediator of NADPH oxidase in the corpus cavernosum in response to a chronic Western diet, which has an adverse effect on erectile function.
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Affiliation(s)
- Justin D. La Favor
- Department of Nutrition and Integrative Physiology, Florida State University, Tallahassee, FL 32306, USA;
- Correspondence: ; Tel.: +1-850-644-3149
| | - Clifford J. Pierre
- Department of Nutrition and Integrative Physiology, Florida State University, Tallahassee, FL 32306, USA;
| | - Trinity J. Bivalacqua
- Department of Urology, The James Buchanan Brady Urological Institute, The Johns Hopkins School of Medicine, Baltimore, MD 21287, USA; (T.J.B.); (A.L.B.)
| | - Arthur L. Burnett
- Department of Urology, The James Buchanan Brady Urological Institute, The Johns Hopkins School of Medicine, Baltimore, MD 21287, USA; (T.J.B.); (A.L.B.)
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6
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Higa R, Leonardi ML, Jawerbaum A. Intrauterine Programming of Cardiovascular Diseases in Maternal Diabetes. Front Physiol 2021; 12:760251. [PMID: 34803741 PMCID: PMC8595320 DOI: 10.3389/fphys.2021.760251] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/17/2021] [Accepted: 10/11/2021] [Indexed: 11/13/2022] Open
Abstract
Maternal diabetes is a prevalent pathology that increases the risk of cardiovascular diseases in the offspring, the heart being one of the main target organs affected from the fetal stage until the adult life. Metabolic, pro-oxidant, and proinflammatory alterations in the fetal heart constitute the first steps in the adverse fetal programming of cardiovascular disease in the context of maternal diabetes. This review discusses both human and experimental studies addressing putative mechanisms involved in this fetal programming of heart damage in maternal diabetes. These include cardiac epigenetic changes, alterations in cardiac carbohydrate and lipid metabolism, damaging effects caused by a pro-oxidant and proinflammatory environment, alterations in the cardiac extracellular matrix remodeling, and specific signaling pathways. Putative actions to prevent cardiovascular impairments in the offspring of mothers with diabetes are also discussed.
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Affiliation(s)
- Romina Higa
- Facultad de Medicina, Universidad de Buenos Aires, Buenos Aires, Argentina.,Laboratory of Reproduction and Metabolism, CONICET-Universidad de Buenos Aires, CEFYBO, Buenos Aires, Argentina
| | - María Laura Leonardi
- Facultad de Medicina, Universidad de Buenos Aires, Buenos Aires, Argentina.,Laboratory of Reproduction and Metabolism, CONICET-Universidad de Buenos Aires, CEFYBO, Buenos Aires, Argentina
| | - Alicia Jawerbaum
- Facultad de Medicina, Universidad de Buenos Aires, Buenos Aires, Argentina.,Laboratory of Reproduction and Metabolism, CONICET-Universidad de Buenos Aires, CEFYBO, Buenos Aires, Argentina
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Exosomes Released from CaSR-Stimulated PMNs Reduce Ischaemia/Reperfusion Injury. OXIDATIVE MEDICINE AND CELLULAR LONGEVITY 2021; 2021:3010548. [PMID: 33505580 PMCID: PMC7815400 DOI: 10.1155/2021/3010548] [Citation(s) in RCA: 14] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 06/24/2020] [Revised: 11/30/2020] [Accepted: 12/25/2020] [Indexed: 12/31/2022]
Abstract
Ischemia-reperfusion (I/R) injury caused by acute myocardial infarction (AMI) can initiate a strong inflammatory response. Polymorphonuclear cells (PMNs) are the most important inflammatory cells. Our previous studies found that the calcium-sensing receptor (CaSR) regulates the proinflammatory effects of PMNs. However, the role and mechanism of CaSR-regulated PMNs in I/R injury remain uncertain. A rat AMI model was developed in this study and showed that the expression of CaSR on PMNs increased in AMI; however, the levels of Bcl-xl and SOD in myocardial tissue decreased, while Bax and MDA levels increased. Then, after coculture with CaSR-stimulated PMNs, the expression of Bcl-xl in cardiomyocytes significantly increased, Bax expression and the apoptotic rate decreased, and ROS production was significantly inhibited. At the same time, the cardiomyocyte damage caused by hypoxia-reoxygenation was reduced. Furthermore, we found that exosomes derived from PMNs could be taken up by cardiomyocytes. Additionally, the exosomes secreted by CaSR-stimulated PMNs had the same effect on cardiomyocytes as CaSR-stimulated PMNs, while the increased phosphorylation level of AKT in cardiomyocytes could be revered by AKT transduction pathway inhibitors. Subsequently, we identified the exosomes derived from CaSR-stimulated PMNs by second-generation sequencing technology, and increased expression of lncRNA ENSRNOT00000039868 was noted. The data show that this lncRNA can prevent the hypoxia-reoxygenation injury by upregulating the expression of PDGFD in cardiomyocytes. In vivo, exosomes from CaSR-stimulated PMNs played a significant role against AMI and reperfusion injury in myocardial tissue. Thus, we propose that exosomes derived from CaSR-stimulated PMNs can reduce I/R injury in AMI, and this effect may be related to the AKT signaling pathway.
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8
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Kumar V, Kurth T, Zheleznova NN, Yang C, Cowley AW. NOX4/H 2O 2/mTORC1 Pathway in Salt-Induced Hypertension and Kidney Injury. Hypertension 2020; 76:133-143. [PMID: 32475313 PMCID: PMC10629473 DOI: 10.1161/hypertensionaha.120.15058] [Citation(s) in RCA: 24] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/12/2020] [Accepted: 04/27/2020] [Indexed: 11/16/2022]
Abstract
We have reported that a high-salt (4.0% NaCl) dietary intake activates mTORC1 and inhibition of this pathway with rapamycin blunts the chronic phase of salt-induced hypertension and renal injury in Dahl salt-sensitive (SS) rats. In SS rats, high-salt intake is known to increase the renal production of H2O2 by NOX4, the most abundant NOX isoform in the kidney, and the global knockout of NOX4 blunts salt-sensitivity in these rats. Here, we explored the hypothesis that elevations of H2O2 by NOX4 in high-salt fed SS rat stimulate mTORC1 for the full development of salt-induced hypertension and renal injury. Our in vitro studies found that H2O2 activates mTORC1 independent of PI3K/AKT and AMPK pathways. To determine the in vivo relevance of NOX4/H2O2/mTORC1 in the salt-induced hypertension, SS-Nox4 knockout (SSNox4-/-) rats were daily administrated with vehicle/rapamycin fed a high-salt diet for 21 days. Rapamycin treatment of SSNox4-/- rats had shown no augmented effect on the salt-induced hypertension nor upon indices of renal injury. Significant reductions of renal T lymphocyte and macrophage together with inhibition of cell proliferation were observed in rapamycin treated rats suggesting a role of mTORC1 independent of NOX4 in the proliferation of immune cell. Given the direct activation of mTORC1 by H2O2 and absence of any further protection from salt-induced hypertension in rapamycin-treated SSNox4-/- rats, we conclude that NOX4-H2O2 is a major upstream activator of mTORC1 that contributes importantly to salt-induced hypertension and renal injury in the SS rat model.
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Affiliation(s)
- Vikash Kumar
- From the Department of Physiology, Medical College of Wisconsin, Milwaukee
| | - Theresa Kurth
- From the Department of Physiology, Medical College of Wisconsin, Milwaukee
| | | | - Chun Yang
- From the Department of Physiology, Medical College of Wisconsin, Milwaukee
| | - Allen W Cowley
- From the Department of Physiology, Medical College of Wisconsin, Milwaukee
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9
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Wang J, Toan S, Zhou H. New insights into the role of mitochondria in cardiac microvascular ischemia/reperfusion injury. Angiogenesis 2020; 23:299-314. [PMID: 32246225 DOI: 10.1007/s10456-020-09720-2] [Citation(s) in RCA: 208] [Impact Index Per Article: 41.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/04/2020] [Accepted: 03/30/2020] [Indexed: 12/19/2022]
Abstract
As reperfusion therapies have become more widely used in acute myocardial infarction patients, ischemia-induced myocardial damage has been markedly reduced, but reperfusion-induced cardiac injury has become increasingly evident. The features of cardiac ischemia-reperfusion (I/R) injury include microvascular perfusion defects, platelet activation and sequential cardiomyocyte death due to additional ischemic events at the reperfusion stage. Microvascular obstruction, defined as a no-reflow phenomenon, determines the infarct zone, myocardial function and peri-operative mortality. Cardiac microvascular endothelial cell injury may occur much earlier and with much greater severity than cardiomyocyte injury. Endothelial cells contain fewer mitochondria than other cardiac cells, and several of the pathological alterations during cardiac microvascular I/R injury involve mitochondria, such as increased mitochondrial reactive oxygen species (mROS) levels and disturbed mitochondrial dynamics. Although mROS are necessary physiological second messengers, high mROS levels induce oxidative stress, endothelial senescence and apoptosis. Mitochondrial dynamics, including fission, fusion and mitophagy, determine the shape, distribution, size and function of mitochondria. These adaptive responses modify extracellular signals and orchestrate intracellular processes such as cell proliferation, migration, metabolism, angiogenesis, permeability transition, adhesive molecule expression, endothelial barrier function and anticoagulation. In this review, we discuss the involvement of mROS and mitochondrial morphofunction in cardiac microvascular I/R injury.
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Affiliation(s)
- Jin Wang
- Chinese PLA General Hospital, Medical School of Chinese PLA, Beijing, 100853, China
| | - Sam Toan
- Department of Chemical Engineering, University of Minnesota-Duluth, Duluth, MN, 55812, USA
| | - Hao Zhou
- Chinese PLA General Hospital, Medical School of Chinese PLA, Beijing, 100853, China. .,Department of Cardiology, The First Medical Center, Chinese PLA General Hospital, Beijing, 100853, China.
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10
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Dong Y, Xu W, Liu C, Liu P, Li P, Wang K. Reactive Oxygen Species Related Noncoding RNAs as Regulators of Cardiovascular Diseases. Int J Biol Sci 2019; 15:680-687. [PMID: 30745854 PMCID: PMC6367576 DOI: 10.7150/ijbs.30464] [Citation(s) in RCA: 23] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/07/2018] [Accepted: 12/19/2018] [Indexed: 12/12/2022] Open
Abstract
Reactive oxygen species (ROS) are a class of reactive molecules that have been implicated in a variety of cardiovascular diseases, accompanied by disorder of multiple signaling events. As cardiomyocytes maintain abundant of mitochondria, which supply the major source of endogenous ROS, oxidative damage to mitochondria often drives apoptotic cell death and initiates cardiac pathology. In recent years, non-coding RNAs (ncRNAs) have received much attention to uncover their roles in regulating gene expression during those pathological events in the heart, such as myocardial infarction, cardiac hypertrophy, and heart failure. Emerging evidences have highlighted that different ROS levels in response to diverse cardiac stresses result in differential expression of ncRNAs, subsequently altering the expression of pathogenetic genes. However, the knowledge about the ncRNA-linked ROS regulatory mechanisms in cardiac pathologies is still largely unexplored. In this review, we summarize the connections that exist among ROS, ncRNAs, and cardiac diseases to understand the interactions among the molecular entities underlying cardiac pathological events in the hopes of guiding novel therapies for heart diseases in the future.
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Affiliation(s)
- Yanhan Dong
- Qingdao University, Deng Zhou Road 38, Qingdao 266021, China
| | - Wenhua Xu
- Qingdao University, Deng Zhou Road 38, Qingdao 266021, China
| | - Cuiyun Liu
- Qingdao University, Deng Zhou Road 38, Qingdao 266021, China
| | - Peijun Liu
- Biochemistry Department No.2 Middle School Qingdao Shandong P.R. China 266000
| | - Peifeng Li
- Qingdao University, Deng Zhou Road 38, Qingdao 266021, China
| | - Kun Wang
- Qingdao University, Deng Zhou Road 38, Qingdao 266021, China
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11
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Fauzia E, Barbhuyan TK, Shrivastava AK, Kumar M, Garg P, Khan MA, Robertson AAB, Raza SS. Chick Embryo: A Preclinical Model for Understanding Ischemia-Reperfusion Mechanism. Front Pharmacol 2018; 9:1034. [PMID: 30298003 PMCID: PMC6160536 DOI: 10.3389/fphar.2018.01034] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/04/2018] [Accepted: 08/27/2018] [Indexed: 12/19/2022] Open
Abstract
Ischemia-reperfusion (I/R)-related disorders, such as stroke, myocardial infarction, and peripheral vascular disease, are among the most frequent causes of disease and death. Tissue injury or death may result from the initial ischemic insult, primarily determined by the magnitude and duration of the interruption in blood supply and then by the subsequent reperfusion-induced damage. Various in vitro and in vivo models are currently available to study I/R mechanism in the brain and other tissues. However, thus far, no in ovo I/R model has been reported for understanding the I/R mechanisms and for faster drug screening. Here, we developed an in ovo Hook model of I/R by occluding and releasing the right vitelline artery of a chick embryo at 72 h of development. To validate the model and elucidate various underlying survival and death mechanisms, we employed imaging (Doppler blood flow imaging), biochemical, and blotting techniques and evaluated the cell death mechanism: autophagy and inflammation caused by I/R. In conclusion, the present model is useful in parallel with established in vitro and in vivo I/R models to understand the mechanisms of I/R development and its treatment.
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Affiliation(s)
- Eram Fauzia
- Laboratory for Stem Cell and Restorative Neurology, Department of Biotechnology, Era's Lucknow Medical College and Hospital, Era University, Lucknow, India
| | - Tarun Kumar Barbhuyan
- Laboratory for Stem Cell and Restorative Neurology, Department of Biotechnology, Era's Lucknow Medical College and Hospital, Era University, Lucknow, India
| | - Amit Kumar Shrivastava
- Laboratory for Stem Cell and Restorative Neurology, Department of Biotechnology, Era's Lucknow Medical College and Hospital, Era University, Lucknow, India
| | - Manish Kumar
- Laboratory for Stem Cell and Restorative Neurology, Department of Biotechnology, Era's Lucknow Medical College and Hospital, Era University, Lucknow, India
| | - Paarth Garg
- Laboratory for Stem Cell and Restorative Neurology, Department of Biotechnology, Era's Lucknow Medical College and Hospital, Era University, Lucknow, India
| | - Mohsin Ali Khan
- Era's Lucknow Medical College and Hospital, Era University, Lucknow, India
| | - Avril A B Robertson
- School of Chemistry and Molecular Biosciences, The University of Queensland, Brisbane, QLD, Australia
| | - Syed Shadab Raza
- Laboratory for Stem Cell and Restorative Neurology, Department of Biotechnology, Era's Lucknow Medical College and Hospital, Era University, Lucknow, India.,Department of Stem Cell Biology and Regenerative Medicine, Era University, Lucknow, India
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12
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Baicalein Rescues Delayed Cooling via Preservation of Akt Activation and Akt-Mediated Phospholamban Phosphorylation. Int J Mol Sci 2018; 19:ijms19040973. [PMID: 29587364 PMCID: PMC5979521 DOI: 10.3390/ijms19040973] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/15/2018] [Revised: 03/20/2018] [Accepted: 03/22/2018] [Indexed: 12/26/2022] Open
Abstract
Cooling reduces the ischemia/reperfusion (I/R) injury seen in sudden cardiac arrest (SCA) by decreasing the burst of reactive oxygen species (ROS). Its cardioprotection is diminished when delay in reaching the target temperature occurs. Baicalein, a flavonoid derived from the root of Scutellaria baicalensis Georgi, possesses antioxidant properties. Therefore, we hypothesized that baicalein can rescue cooling cardioprotection when cooling is delayed. Two murine cardiomyocyte models, an I/R model (90 min ischemia/3 h reperfusion) and stunning model (30 min ischemia/90 min reperfusion), were used to assess cell survival and contractility, respectively. Cooling (32 °C) was initiated either during ischemia or during reperfusion. Cell viability and ROS generation were measured. Cell contractility was evaluated by real-time phase-contrast imaging. Our results showed that cooling reduced cell death and ROS generation, and this effect was diminished when cooling was delayed. Baicalein (25 µM), given either at the start of reperfusion or start of cooling, resulted in a comparable reduction of cell death and ROS production. Baicalein improved phospholamban phosphorylation, contractility recovery, and cell survival. These effects were Akt-dependent. In addition, no synergistic effect was observed with the combined treatments of cooling and baicalein. Our data suggest that baicalein may serve as a novel adjunct therapeutic strategy for SCA resuscitation.
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