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Manoj KM, Nirusimhan V, Parashar A, Edward J, Gideon DA. Murburn precepts for lactic-acidosis, Cori cycle, and Warburg effect: Interactive dynamics of dehydrogenases, protons, and oxygen. J Cell Physiol 2021; 237:1902-1922. [PMID: 34927737 DOI: 10.1002/jcp.30661] [Citation(s) in RCA: 16] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/15/2021] [Revised: 12/01/2021] [Accepted: 12/03/2021] [Indexed: 12/24/2022]
Abstract
It is unresolved why lactate is transported to the liver for further utilization within the physiological purview of Cori cycle, when muscles have more lactate dehydrogenase (LDH) than liver. We point out that the answer lies in thermodynamics/equilibriums. While the utilization of NADH for the reduction of pyruvate to lactate can be mediated via the classical mechanism, the oxidation of lactate (with/without the uphill reduction of NAD+ ) necessitates alternative physiological approaches. The latter pathway occurs via interactive equilibriums involving the enzyme, protons and oxygen or diffusible reactive oxygen species (DROS). Since liver has high DROS, the murburn activity at LDH would enable the cellular system to tide over the unfavorable energy barriers of the forward reaction (~476 kJ/mol; earlier miscalculated as ~26 kJ/mole). Further, the new mechanism does not necessitate any "smart decision-making" or sophisticated control by/of proteins. The DROS-based murburn theory explains the invariant active-site structure of LDH isozymes and their multimeric nature. The theoretical insights, in silico evidence and analyses of literature herein also enrich our understanding of the underpinnings of "lactic acidosis" (lowering of physiological pH accompanied by lactate production), Warburg effect (increased lactate production at high pO2 by cancer cells) and approach for cancer therapy.
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Affiliation(s)
- Kelath Murali Manoj
- Department of Biochemistry, Satyamjayatu: The Science & Ethics Foundation, Palakkad, Kerala, India
| | - Vijay Nirusimhan
- Department of Biochemistry, Satyamjayatu: The Science & Ethics Foundation, Palakkad, Kerala, India
| | - Abhinav Parashar
- Department of Biochemistry, Satyamjayatu: The Science & Ethics Foundation, Palakkad, Kerala, India
| | - Jesucastin Edward
- Department of Biochemistry, Satyamjayatu: The Science & Ethics Foundation, Palakkad, Kerala, India
| | - Daniel Andrew Gideon
- Department of Biochemistry, Satyamjayatu: The Science & Ethics Foundation, Palakkad, Kerala, India
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2
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Wu H, Wang Y, Ying M, Jin C, Li J, Hu X. Lactate dehydrogenases amplify reactive oxygen species in cancer cells in response to oxidative stimuli. Signal Transduct Target Ther 2021; 6:242. [PMID: 34176927 PMCID: PMC8236487 DOI: 10.1038/s41392-021-00595-3] [Citation(s) in RCA: 54] [Impact Index Per Article: 13.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/27/2020] [Revised: 03/11/2021] [Accepted: 03/30/2021] [Indexed: 12/21/2022] Open
Abstract
Previous studies demonstrated that superoxide could initiate and amplify LDH-catalyzed hydrogen peroxide production in aqueous phase, but its physiological relevance is unknown. Here we showed that LDHA and LDHB both exhibited hydrogen peroxide-producing activity, which was significantly enhanced by the superoxide generated from the isolated mitochondria from HeLa cells and patients' cholangiocarcinoma specimen. After LDHA or LDHB were knocked out, hydrogen peroxide produced by Hela or 4T1 cancer cells were significantly reduced. Re-expression of LDHA in LDHA-knockout HeLa cells partially restored hydrogen peroxide production. In HeLa and 4T1 cells, LDHA or LDHB knockout or LDH inhibitor FX11 significantly decreased ROS induction by modulators of the mitochondrial electron transfer chain (antimycin, oligomycin, rotenone), hypoxia, and pharmacological ROS inducers piperlogumine (PL) and phenethyl isothiocyanate (PEITC). Moreover, the tumors formed by LDHA or LDHB knockout HeLa or 4T1 cells exhibited a significantly less oxidative state than those formed by control cells. Collectively, we provide a mechanistic understanding of a link between LDH and cellular hydrogen peroxide production or oxidative stress in cancer cells in vitro and in vivo.
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Grants
- This work has been supported in part by the China National 973 project (2013CB911303), China Natural Sciences Foundation projects (81470126), a key project (2018C03009) funded by Zhejiang Provincial Department of Sciences and Technologies, and the Fundamental Research Funds for the Central Universities (2017XZZX001-012019FZJD009), National Ministry of Education, China, to XH, and Zhejiang Provincial Natural Science Foundation of China (LY17H160036), the Fundamental Research Funds for the Central Universities (2017FZA7010) and China Natural Sciences Foundation project (81301707), to HW.
- Zhejiang Provincial Natural Science Foundation of China (LY17H160036), the Fundamental Research Funds for the Central Universities and China Natural Sciences Foundation project 2017FZA7010, to HW.
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Affiliation(s)
- Hao Wu
- Cancer Institute (Key Laboratory for Cancer Intervention and Prevention, China National Ministry of Education, Zhejiang Provincial Key Laboratory of Molecular Biology in Medical Sciences), The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
| | - Yuqi Wang
- Cancer Institute (Key Laboratory for Cancer Intervention and Prevention, China National Ministry of Education, Zhejiang Provincial Key Laboratory of Molecular Biology in Medical Sciences), The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
| | - Minfeng Ying
- Cancer Institute (Key Laboratory for Cancer Intervention and Prevention, China National Ministry of Education, Zhejiang Provincial Key Laboratory of Molecular Biology in Medical Sciences), The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
| | - Chengmeng Jin
- Cancer Institute (Key Laboratory for Cancer Intervention and Prevention, China National Ministry of Education, Zhejiang Provincial Key Laboratory of Molecular Biology in Medical Sciences), The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
| | - Jiangtao Li
- Department of Surgery, The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
| | - Xun Hu
- Cancer Institute (Key Laboratory for Cancer Intervention and Prevention, China National Ministry of Education, Zhejiang Provincial Key Laboratory of Molecular Biology in Medical Sciences), The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China.
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Abstract
Reductive stress is defined as a condition characterized by excess accumulation of reducing equivalents (e.g., NADH, NADPH, GSH), surpassing the activity of endogenous oxidoreductases. Excessive reducing equivalents can perturb cell signaling pathways, change the formation of disulfide bonding in proteins, disturb mitochondrial homeostasis or decrease metabolism. Reductive stress is influenced by cellular antioxidant load, its flux and a subverted homeostasis that paradoxically can result in excess ROS induction. Balanced reducing equivalents and antioxidant enzymes that contribute to reductive stress can be regulated by Nrf2, typically considered as an oxidative stress induced transcription factor. Cancer cells may coordinate distinct pools of redox couples under reductive stress and these may link to biological consequences from both molecular and translational standpoints. In cancer, there is recent interest in understanding how selective induction of reductive stress may influence therapeutic management and disease progression.
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Affiliation(s)
- Leilei Zhang
- Department of Cell and Molecular Pharmacology and Experimental Therapeutics, Medical University of South Carolina, Charleston, SC, United States.
| | - Kenneth D Tew
- Department of Cell and Molecular Pharmacology and Experimental Therapeutics, Medical University of South Carolina, Charleston, SC, United States
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Nikooie R, Moflehi D, Zand S. Lactate regulates autophagy through ROS-mediated activation of ERK1/2/m-TOR/p-70S6K pathway in skeletal muscle. J Cell Commun Signal 2021; 15:107-123. [PMID: 33398722 DOI: 10.1007/s12079-020-00599-8] [Citation(s) in RCA: 22] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/08/2020] [Accepted: 11/26/2020] [Indexed: 12/09/2022] Open
Abstract
The role of autophagy and lysosomal degradation pathway in the regulation of skeletal muscle metabolism was previously studied. However, underlying molecular mechanisms are poorly understood. L-lactate which is utilized as an energetic substrate by skeletal muscle can also augment genes expression related to metabolism and up-regulate those being responsive to reactive oxygen species (ROS). Since ROS is the most important regulator of autophagy in skeletal muscle, we tested if there is a link between cellular lactate metabolism and autophagy in differentiated C2C12 myotubes and the gastrocnemius muscle of male wistar rats. C2C12 mouse skeletal muscle was exposed to 2, 6, 10, and 20 mM lactate and evaluated for lactate autophagic effects. Lactate dose-dependently increased autophagy and augmented ROS generation in differentiated C2C12 myotubes. The autophagic effect of lactate deterred in N-acetylcysteine presence (NAC, a ROS scavenger) indicated lactate regulates autophagy with ROS participation. Lactate-induced up-regulation of extracellular signal-regulated kinase 1/2 (ERK1/2) through ROS was required to regulate the autophagy by lactate. Further analysis about ERK1/2 up- and downstream indicated that lactate regulates autophagy through ROS-mediated the activation of ERK1/2/mTOR/p70S6K pathway in skeletal muscle. The in vitro effects of lactate on autophagy also occurred in the gastrocnemius muscle of male Wistar rats. In conclusion, we provided the lactate-associated regulation evidence of autophagy in skeletal muscle by activating ROS-mediated ERK1/2/mTOR/p70S6K pathway. Since the increase in cellular lactate concentration is a hallmark of energy deficiency, the results provide insight into a skeletal muscle mechanism to fulfill its enhanced energy requirement.
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Affiliation(s)
- Rohollah Nikooie
- Department of Exercise physiology, Faculty of Physical Education and Sport Sciences, Shahid Bahonar University of Kerman, Kerman, Iran. .,Neuroscience Research Center, Institute of Neuropharmacology, Kerman University of Medical Sciences, Kerman, Iran.
| | - Daruosh Moflehi
- Department of Exercise physiology, Faculty of Physical Education and Sport Sciences, Shahid Bahonar University of Kerman, Kerman, Iran
| | - Samira Zand
- Department of Exercise physiology, Faculty of Physical Education and Sport Sciences, Shahid Bahonar University of Kerman, Kerman, Iran
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Zaidi Y, Aguilar EG, Troncoso M, Ilatovskaya DV, DeLeon-Pennell KY. Immune regulation of cardiac fibrosis post myocardial infarction. Cell Signal 2021; 77:109837. [PMID: 33207261 PMCID: PMC7720290 DOI: 10.1016/j.cellsig.2020.109837] [Citation(s) in RCA: 44] [Impact Index Per Article: 11.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/16/2020] [Revised: 11/11/2020] [Accepted: 11/12/2020] [Indexed: 12/24/2022]
Abstract
Pathological changes resulting from myocardial infarction (MI) include extracellular matrix alterations of the left ventricle, which can lead to cardiac stiffness and impair systolic and diastolic function. The signals released from necrotic tissue initiate the immune cascade, triggering an extensive inflammatory response followed by reparative fibrosis of the infarct area. Immune cells such as neutrophils, monocytes, macrophages, mast cells, T-cells, and dendritic cells play distinct roles in orchestrating this complex pathological condition, and regulate the balance between pro-fibrotic and anti-fibrotic responses. This review discusses how molecular signals between fibroblasts and immune cells mutually regulate fibrosis post-MI, and outlines the emerging pharmacological targets and therapies for modulating inflammation and cardiac fibrosis associated with MI.
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Affiliation(s)
- Yusra Zaidi
- Department of Medicine, Division of Cardiology, Medical University of South Carolina, 30 Courtenay Drive, Charleston, SC 29425, USA
| | - Eslie G Aguilar
- Department of Medicine, Division of Cardiology, Medical University of South Carolina, 30 Courtenay Drive, Charleston, SC 29425, USA
| | - Miguel Troncoso
- Department of Medicine, Division of Cardiology, Medical University of South Carolina, 30 Courtenay Drive, Charleston, SC 29425, USA
| | - Daria V Ilatovskaya
- Division of Nephrology, Department of Medicine, Medical University of South Carolina, Charleston, SC 29425, USA
| | - Kristine Y DeLeon-Pennell
- Department of Medicine, Division of Cardiology, Medical University of South Carolina, 30 Courtenay Drive, Charleston, SC 29425, USA; Ralph H. Johnson Veterans Affairs Medical Center, 109 Bee Street, Charleston, SC 29401, USA.
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Svedung Wettervik T, Engquist H, Howells T, Rostami E, Hillered L, Enblad P, Lewén A. Arterial lactate in traumatic brain injury - Relation to intracranial pressure dynamics, cerebral energy metabolism and clinical outcome. J Crit Care 2020; 60:218-225. [PMID: 32882604 DOI: 10.1016/j.jcrc.2020.08.014] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/19/2019] [Revised: 04/21/2020] [Accepted: 08/13/2020] [Indexed: 10/23/2022]
Abstract
PURPOSE High arterial lactate is associated with disturbed systemic physiology. Lactate can also be used as alternative cerebral fuel and it is involved in regulating cerebral blood flow. This study explored the relation of endogenous arterial lactate to systemic physiology, pressure autoregulation, cerebral energy metabolism, and clinical outcome in traumatic brain injury (TBI). METHOD A retrospective study including 115 patients (consent given) with severe TBI treated in the neurointensive care unit, Uppsala university hospital, Sweden, 2008-2018. Data from cerebral microdialysis, arterial blood gases, hemodynamics and intracranial pressure were analyzed the first ten days post-injury. RESULTS Arterial lactate peaked on day 1 post-injury (mean 1.7 ± 0.7 mM) and gradually decreased. Higher arterial lactate correlated with lower age (p-value < 0.05), higher Marshall score (p-value < 0.05) and higher arterial glucose (p-value < 0.001) in a multiple regression analysis. Higher arterial lactate was associated with poor pressure autoregulation (p-value < 0.01), but not to worse cerebral energy metabolism. Higher arterial lactate was also associated with unfavorable clinical outcome (p-value < 0.05). CONCLUSIONS High endogenous arterial lactate is a biomarker of poor systemic physiology and may disturb cerebral blood flow autoregulation.
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Affiliation(s)
- Teodor Svedung Wettervik
- Department of Neuroscience, Section of Neurosurgery, Uppsala University, Uppsala SE-751 85, Sweden.
| | - Henrik Engquist
- Department of Surgical Sciences/Anesthesia and Intensive Care, Uppsala University, Uppsala SE-751 85, Sweden
| | - Timothy Howells
- Department of Neuroscience, Section of Neurosurgery, Uppsala University, Uppsala SE-751 85, Sweden
| | - Elham Rostami
- Department of Neuroscience, Section of Neurosurgery, Uppsala University, Uppsala SE-751 85, Sweden
| | - Lars Hillered
- Department of Neuroscience, Section of Neurosurgery, Uppsala University, Uppsala SE-751 85, Sweden
| | - Per Enblad
- Department of Neuroscience, Section of Neurosurgery, Uppsala University, Uppsala SE-751 85, Sweden
| | - Anders Lewén
- Department of Neuroscience, Section of Neurosurgery, Uppsala University, Uppsala SE-751 85, Sweden
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7
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Bellezza I, Riuzzi F, Chiappalupi S, Arcuri C, Giambanco I, Sorci G, Donato R. Reductive stress in striated muscle cells. Cell Mol Life Sci 2020; 77:3547-3565. [PMID: 32072237 PMCID: PMC11105111 DOI: 10.1007/s00018-020-03476-0] [Citation(s) in RCA: 26] [Impact Index Per Article: 5.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/15/2019] [Revised: 01/17/2020] [Accepted: 02/03/2020] [Indexed: 12/11/2022]
Abstract
Reductive stress is defined as a condition of sustained increase in cellular glutathione/glutathione disulfide and NADH/NAD+ ratios. Reductive stress is emerging as an important pathophysiological event in several diseased states, being as detrimental as is oxidative stress. Occurrence of reductive stress has been documented in several cardiomyopathies and is an important pathophysiological factor particularly in coronary artery disease and myocardial infarction. Excess activation of the transcription factor, Nrf2-the master regulator of the antioxidant response-, consequent in most cases to defective autophagy, can lead to reductive stress. In addition, hyperglycemia-induced activation of the polyol pathway can lead to increased NADH/NAD+ ratio, which might translate into increased levels of hydrogen sulfide-via enhanced activity of cystathionine β-synthase-that would fuel reductive stress through inhibition of mitochondrial complex I. Reductive stress may be either a potential weapon against cancer priming tumor cells to apoptosis or a cancer's ally promoting tumor cell proliferation and making tumor cells resistant to reactive oxygen species-inducing drugs. In non-cancer pathological states reductive stress is definitely harmful paradoxically leading to reactive oxygen species overproduction via excess NADPH oxidase 4 activity. In face of the documented occurrence of reductive stress in several heart diseases, there is much less information about the occurrence and effects of reductive stress in skeletal muscle tissue. In the present review we describe relevant results emerged from studies of reductive stress in the heart and review skeletal muscle conditions in which reductive stress has been experimentally documented and those in which reductive stress might have an as yet unrecognized pathophysiological role. Establishing whether reductive stress has a (patho)physiological role in skeletal muscle will hopefully contribute to answer the question whether antioxidant supplementation to the general population, athletes, and a large cohort of patients (e.g. heart, sarcopenic, dystrophic, myopathic, cancer, and bronco-pulmonary patients) is harmless or detrimental.
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Affiliation(s)
- Ilaria Bellezza
- Department of Experimental Medicine, Medical School, University of Perugia, Piazza Lucio Severi 1, 06132, Perugia, Italy
| | - Francesca Riuzzi
- Department of Experimental Medicine, Medical School, University of Perugia, Piazza Lucio Severi 1, 06132, Perugia, Italy
- Interuniversity Institute of Myology (IIM), University of Perugia, 06132, Perugia, Italy
| | - Sara Chiappalupi
- Department of Experimental Medicine, Medical School, University of Perugia, Piazza Lucio Severi 1, 06132, Perugia, Italy
- Interuniversity Institute of Myology (IIM), University of Perugia, 06132, Perugia, Italy
| | - Cataldo Arcuri
- Department of Experimental Medicine, Medical School, University of Perugia, Piazza Lucio Severi 1, 06132, Perugia, Italy
| | - Ileana Giambanco
- Department of Experimental Medicine, Medical School, University of Perugia, Piazza Lucio Severi 1, 06132, Perugia, Italy
| | - Guglielmo Sorci
- Department of Experimental Medicine, Medical School, University of Perugia, Piazza Lucio Severi 1, 06132, Perugia, Italy
- Interuniversity Institute of Myology (IIM), University of Perugia, 06132, Perugia, Italy
- Centro Universitario Di Ricerca Sulla Genomica Funzionale, University of Perugia, 06132, Perugia, Italy
| | - Rosario Donato
- Department of Experimental Medicine, Medical School, University of Perugia, Piazza Lucio Severi 1, 06132, Perugia, Italy.
- Interuniversity Institute of Myology (IIM), University of Perugia, 06132, Perugia, Italy.
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Radiological assessment of effectiveness of soluble RAGE in attenuating Angiotensin II-induced LVH mouse model using in vivo 9.4T MRI. Sci Rep 2019; 9:8475. [PMID: 31186521 PMCID: PMC6559980 DOI: 10.1038/s41598-019-44933-6] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/11/2018] [Accepted: 01/30/2019] [Indexed: 01/11/2023] Open
Abstract
We investigated the effectiveness of soluble Receptor for Advanced Glycation Endproducts (sRAGE) in attenuating angiotensin II (AngII)-induced left ventricular hypertrophy (LVH) using in vivo 9.4T cine-magnetic resonance imaging (CINE-MRI). Mice were divided into four groups: AngII (n = 9), saline (n = 10), sRAGE (n = 10), and AngII + sRAGE (n = 10). CINE-MRI was performed in each group after administration of the AngII or sRAGE, and CINE-MR images were analyzed to obtain parameters indicating cardiac anatomical and functional changes including end-diastolic and end-systolic blood volume, end-diastolic and end-systolic myocardial volume, ejection fraction, end-diastolic and end-systolic myocardial mass, and LV wall thickness. LVH observed in AngII group was significantly attenuated by sRAGE. These trends were also observed in histological analysis, demonstrating that cardiac function tracking using in vivo and real-time 9.4T MR imaging provides valuable information about the cardiac remodeling induced by AngII and sRAGE in an AngII-induced LV hypertrophy mice model.
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9
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Xu MJ, Cai Y, Qu A, Shyy JYJ, Li W, Wang X. Immediate Early Response Gene X-1 (IEX-1) Mediates Ischemic Preconditioning-Induced Cardioprotection in Rats. OXIDATIVE MEDICINE AND CELLULAR LONGEVITY 2017; 2017:6109061. [PMID: 29213350 PMCID: PMC5682079 DOI: 10.1155/2017/6109061] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 06/13/2017] [Accepted: 08/24/2017] [Indexed: 11/18/2022]
Abstract
Reversible myocardial ischemia/reperfusion (I/R) or ischemic preconditioning (IPC) is associated with an immediate genomic response; IPC-induced immediate early genes are associated with reduced infarct size. Because the immediate early response gene X-1 (IEX-1) plays a central role in cell apoptosis, we examine whether IEX-1 exerts protective effects against I/R injury. We found that the IEX-1 mRNA level was increased in the IPC-imposed rat heart. However, it was downregulated in the I/R rat heart, which was prevented by in situ IPC. When IEX-1 was knocked down, the protective effects imposed by IPC were lessened. Local gene delivery of Ad-IEX-1 to the left ventricle greatly diminished cardiac infarct size and improved systolic functions of I/R hearts in rats. In contrast, knocking down IEX-1 expression exacerbates myocardial infarction. Overexpression of IEX-1 in neonatal rat cardiomyocytes significantly reduced hypoxia-reoxygenation-induced intracellular and mitochondrial ROS accumulation and cell apoptosis. Furthermore, IPC-induced phosphorylation and particle translocation of PKCε were impaired by knocking down IEX-1 in vivo, and overexpressing IEX-1 showed similar cardioprotection imposed by IPC. Our results demonstrate that IPC increases IEX-1 expression, which may promote phosphorylation and particle translocation of PKCε and thus reduce intracellular ROS accumulation. These beneficial effects reduce cardiomyocyte apoptosis and necrosis to alleviate cardiac infarction.
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Affiliation(s)
- Ming-Jiang Xu
- Department of Physiology and Pathophysiology, School of Basic Medical Science, Peking University Health Science Center, Key Laboratory of Molecular Cardiovascular Science, Ministry of Education, Beijing, China
- Basic Medical School, Wuhan University, Wuhan, China
| | - Yan Cai
- Department of Physiology and Pathophysiology, School of Basic Medical Science, Peking University Health Science Center, Key Laboratory of Molecular Cardiovascular Science, Ministry of Education, Beijing, China
| | - Aijuan Qu
- Department of Physiology and Pathophysiology, School of Basic Medical Science, Capital Medical University, Key Laboratory of Remodeling-Related Cardiovascular Diseases, Ministry of Education, Beijing, China
| | - John Y.-J. Shyy
- Department of Medicine, University of California, San Diego, San Diego, CA 92093, USA
| | - Wenjing Li
- Department of Physiology and Pathophysiology, School of Basic Medical Science, Peking University Health Science Center, Key Laboratory of Molecular Cardiovascular Science, Ministry of Education, Beijing, China
| | - Xian Wang
- Department of Physiology and Pathophysiology, School of Basic Medical Science, Peking University Health Science Center, Key Laboratory of Molecular Cardiovascular Science, Ministry of Education, Beijing, China
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Acharya S, Stark TD, Oh ST, Jeon S, Pak SC, Kim M, Hur J, Matsutomo T, Hofmann T, Hill RA, Balemba OB. (2R,3S,2″R,3″R)-Manniflavanone Protects Proliferating Skeletal Muscle Cells against Oxidative Stress and Stimulates Myotube Formation. JOURNAL OF AGRICULTURAL AND FOOD CHEMISTRY 2017; 65:3636-3646. [PMID: 28430433 DOI: 10.1021/acs.jafc.6b05161] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 06/07/2023]
Abstract
We investigated the antioxidative properties of (2R,3S,2″R,3″R)-manniflavanone (MF) using in vitro assays and examined its effects on myogenesis and lactate-induced oxidative stress in C2C12 cells. MF was purified from Garcinia buchananii stem bark. H2O2 and oxygen radical absorbance capacity assays demonstrated that MF is a powerful antioxidant. This finding was supported by diphenylpicrylhydrazine radical scavenging activity of MF. MF was less cytotoxic to C2C12 cells compared to ascorbic acid and myricetin. Moreover, MF accelerated myotube formation in the differentiated C2C12 cells by up-regulating myogenic proteins such as MyoG and myosin heavy chain. Furthermore, MF rescued late differentiation of myoblast suppressed by lactate treatment and up-regulated the expression levels of Nrf2 in lactate-induced oxidative stress, indicating that MF stimulates antioxidative activity inside C2C12 cells. Collectively, MF is a potent antioxidant with a higher safety profile than ascorbic acid and myricetin. It reduces oxidative stress-induced delaying of skeletal muscle differentiation by scavenging reactive oxygen species and regulating myogenic proteins factors.
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Affiliation(s)
- Suresh Acharya
- Department of Animal and Veterinary Science, University of Idaho , Moscow, Idaho 83844, United States
| | - Timo D Stark
- Chair of Food Chemistry and Molecular Sensory Science, Technische Universität München , Lise-Meitner Strasse 34, D-85354 Freising, Germany
| | - Seung Tack Oh
- Research Institute, Dongkwang Pharmaceutical Company, Ltd. , Toegye-ro, Jung-gu, Seoul 04535, Republic of Korea
| | - Songhee Jeon
- Department of Biomedical Sciences, Center for Creative Biomedical Scientists at Chonnam National University , Gwangju 61469, Republic of Korea
| | - Sok Cheon Pak
- School of Biomedical Sciences, Charles Sturt University , Bathurst, New South Wales 2795, Australia
| | - Mina Kim
- Korea Food Research Institute , Sungnamsi 13539, Republic of Korea
| | - Jinyoung Hur
- Korea Food Research Institute , Sungnamsi 13539, Republic of Korea
| | - Toshiaki Matsutomo
- Chair of Food Chemistry and Molecular Sensory Science, Technische Universität München , Lise-Meitner Strasse 34, D-85354 Freising, Germany
| | - Thomas Hofmann
- Chair of Food Chemistry and Molecular Sensory Science, Technische Universität München , Lise-Meitner Strasse 34, D-85354 Freising, Germany
| | - Rodney A Hill
- Department of Animal and Veterinary Science, University of Idaho , Moscow, Idaho 83844, United States
- School of Biomedical Sciences, Charles Sturt University , Bathurst, New South Wales 2795, Australia
| | - Onesmo B Balemba
- Department of Biological Sciences, University of Idaho , Moscow, Idaho 83844, United States
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11
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Ma MW, Wang J, Zhang Q, Wang R, Dhandapani KM, Vadlamudi RK, Brann DW. NADPH oxidase in brain injury and neurodegenerative disorders. Mol Neurodegener 2017; 12:7. [PMID: 28095923 PMCID: PMC5240251 DOI: 10.1186/s13024-017-0150-7] [Citation(s) in RCA: 313] [Impact Index Per Article: 39.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/03/2016] [Accepted: 01/05/2017] [Indexed: 12/11/2022] Open
Abstract
Oxidative stress is a common denominator in the pathology of neurodegenerative disorders such as Alzheimer’s disease, Parkinson’s disease, Huntington’s disease, amyotrophic lateral sclerosis, and multiple sclerosis, as well as in ischemic and traumatic brain injury. The brain is highly vulnerable to oxidative damage due to its high metabolic demand. However, therapies attempting to scavenge free radicals have shown little success. By shifting the focus to inhibit the generation of damaging free radicals, recent studies have identified NADPH oxidase as a major contributor to disease pathology. NADPH oxidase has the primary function to generate free radicals. In particular, there is growing evidence that the isoforms NOX1, NOX2, and NOX4 can be upregulated by a variety of neurodegenerative factors. The majority of recent studies have shown that genetic and pharmacological inhibition of NADPH oxidase enzymes are neuroprotective and able to reduce detrimental aspects of pathology following ischemic and traumatic brain injury, as well as in chronic neurodegenerative disorders. This review aims to summarize evidence supporting the role of NADPH oxidase in the pathology of these neurological disorders, explores pharmacological strategies of targeting this major oxidative stress pathway, and outlines obstacles that need to be overcome for successful translation of these therapies to the clinic.
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Affiliation(s)
- Merry W Ma
- Charlie Norwood VA Medical Center, One Freedom Way, Augusta, GA, 30904, USA.,Department of Neuroscience and Regenerative Medicine, Medical College of Georgia, 1120 Fifteenth Street, Augusta, GA, 30912, USA
| | - Jing Wang
- Charlie Norwood VA Medical Center, One Freedom Way, Augusta, GA, 30904, USA.,Department of Neuroscience and Regenerative Medicine, Medical College of Georgia, 1120 Fifteenth Street, Augusta, GA, 30912, USA
| | - Quanguang Zhang
- Charlie Norwood VA Medical Center, One Freedom Way, Augusta, GA, 30904, USA.,Department of Neuroscience and Regenerative Medicine, Medical College of Georgia, 1120 Fifteenth Street, Augusta, GA, 30912, USA
| | - Ruimin Wang
- Charlie Norwood VA Medical Center, One Freedom Way, Augusta, GA, 30904, USA.,Department of Neuroscience and Regenerative Medicine, Medical College of Georgia, 1120 Fifteenth Street, Augusta, GA, 30912, USA
| | - Krishnan M Dhandapani
- Charlie Norwood VA Medical Center, One Freedom Way, Augusta, GA, 30904, USA.,Department of Neurosurgery, Medical College of Georgia, Augusta University, 1120 Fifteenth Street, Augusta, GA, 30912, USA
| | - Ratna K Vadlamudi
- Department of Obstetrics and Gynecology, University of Texas Health Science Center, 7703 Medical Drive, San Antonio, TX, 78229, USA
| | - Darrell W Brann
- Charlie Norwood VA Medical Center, One Freedom Way, Augusta, GA, 30904, USA. .,Department of Neuroscience and Regenerative Medicine, Medical College of Georgia, 1120 Fifteenth Street, Augusta, GA, 30912, USA.
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12
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Parker L, Shaw CS, Stepto NK, Levinger I. Exercise and Glycemic Control: Focus on Redox Homeostasis and Redox-Sensitive Protein Signaling. Front Endocrinol (Lausanne) 2017; 8:87. [PMID: 28529499 PMCID: PMC5418238 DOI: 10.3389/fendo.2017.00087] [Citation(s) in RCA: 34] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/31/2017] [Accepted: 04/04/2017] [Indexed: 12/16/2022] Open
Abstract
Physical inactivity, excess energy consumption, and obesity are associated with elevated systemic oxidative stress and the sustained activation of redox-sensitive stress-activated protein kinase (SAPK) and mitogen-activated protein kinase signaling pathways. Sustained SAPK activation leads to aberrant insulin signaling, impaired glycemic control, and the development and progression of cardiometabolic disease. Paradoxically, acute exercise transiently increases oxidative stress and SAPK signaling, yet postexercise glycemic control and skeletal muscle function are enhanced. Furthermore, regular exercise leads to the upregulation of antioxidant defense, which likely assists in the mitigation of chronic oxidative stress-associated disease. In this review, we explore the complex spatiotemporal interplay between exercise, oxidative stress, and glycemic control, and highlight exercise-induced reactive oxygen species and redox-sensitive protein signaling as important regulators of glucose homeostasis.
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Affiliation(s)
- Lewan Parker
- Institute of Sport, Exercise and Active Living (ISEAL), College of Sport and Exercise Science, Victoria University, Melbourne, VIC, Australia
- *Correspondence: Lewan Parker, ,
| | - Christopher S. Shaw
- Institute for Physical Activity and Nutrition, School of Exercise and Nutrition Sciences, Deakin University, Geelong, VIC, Australia
| | - Nigel K. Stepto
- Institute of Sport, Exercise and Active Living (ISEAL), College of Sport and Exercise Science, Victoria University, Melbourne, VIC, Australia
- Monash Centre for Health Research and Implementation, School of Public Health and Preventative Medicine, Monash University, Clayton, VIC, Australia
- Australian Institute for Musculoskeletal Science (AIMSS), Victoria University and Western Health, St. Albans, VIC, Australia
| | - Itamar Levinger
- Institute of Sport, Exercise and Active Living (ISEAL), College of Sport and Exercise Science, Victoria University, Melbourne, VIC, Australia
- Australian Institute for Musculoskeletal Science (AIMSS), Victoria University and Western Health, St. Albans, VIC, Australia
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13
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Pterostilbene protects against myocardial ischemia/reperfusion injury via suppressing oxidative/nitrative stress and inflammatory response. Int Immunopharmacol 2016; 43:7-15. [PMID: 27936461 DOI: 10.1016/j.intimp.2016.11.018] [Citation(s) in RCA: 50] [Impact Index Per Article: 5.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/30/2016] [Revised: 11/17/2016] [Accepted: 11/18/2016] [Indexed: 12/21/2022]
Abstract
Recent studies have shown that pterostilbene (Pte) confers protection against myocardial ischemia/reperfusion injury. The oxidative/nitrative stress and inflammation induce injury after myocardial ischemia/reperfusion. The present study was designed to evaluate whether treatment with Pte attenuates oxidative/nitrative stress and inflammation in myocardial ischemia/reperfusion (MI/R). Rats were subjected to 30min of myocardial ischemia and 3h of reperfusion, and the rats were administered with vehicle or Pte. The results showed that Pte (10mg/kg) dramatically improved cardiac function and reduced myocardial infarction and myocardial apoptosis following MI/R. As an indicator of oxidative/nitrative stress, myocardial ONOO- content was markedly reduced after Pte treatment. And, Pte led to a dramatic decrease in superoxide generation and malondialdehyde (MDA) content and a dramatic increase in superoxide dismutase (SOD) activity. In addition, Pte treatment significantly reduced p38 MAPK activation and the expression of iNOS and gp91phox and increased phosphorylated eNOS expression. Pte treatment dramatically decreased myocardial TNF-α, and IL-1β levels and myeloperoxidase (MPO) activity. Furthermore, ONOO- suppression by either Pte or uric acid (UA), an ONOO- scavenger, reduced myocardial injury. In conclusion, Pte exerts a protective effect against MI/R injury by suppressing oxidative/nitrative stress. These results provide evidence that Pte might be a therapeutic approach for the treatment of MI/R injury.
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Natoli R, Rutar M, Lu YZ, Chu-Tan JA, Chen Y, Saxena K, Madigan M, Valter K, Provis JM. The Role of Pyruvate in Protecting 661W Photoreceptor-Like Cells Against Light-Induced Cell Death. Curr Eye Res 2016; 41:1473-1481. [PMID: 27217092 DOI: 10.3109/02713683.2016.1139725] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/10/2015] [Accepted: 01/05/2016] [Indexed: 12/31/2022]
Abstract
PURPOSE Light is a requirement for the function of photoreceptors in visual processing. However, prolonged light exposure can be toxic to photoreceptors, leading to increased reactive oxygen species (ROS), lipid peroxidation, and photoreceptor cell death. We used the 661W mouse cone photoreceptor-like cell line to study the effects of pyruvate in protecting these cells from light-induced toxicity. METHODS 661W cells were exposed to 15,000 lux continuous bright light for 5 hours and incubated in Dulbecco's modified eagle medium (DMEM) with various concentrations of pyruvate. Following light damage, cells were assessed for changes in morphology, cell toxicity, viability, and ROS production. Mitochondrial respiration and anaerobic glycolysis were also assessed using a Seahorse Xfe96 extracellular flux analyzer. RESULTS We found that cell death caused by light damage in 661W cells was dramatically reduced in the presence of pyruvate. Cells with pyruvate-supplemented media also showed attenuation of oxidative stress and maintained normal levels of ATP. We also found that alterations in the concentrations of pyruvate had no effect on mitochondrial respiration or glycolysis in light-damaged cells. CONCLUSIONS Taken together, the results show that pyruvate is protective against light damage but does not alter the metabolic output of the cells, indicating an alternative role for pyruvate in reducing oxidative stress. Thus, sodium pyruvate is a possible candidate for the treatment against the oxidative stress component of retinal degenerations.
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Affiliation(s)
- Riccardo Natoli
- a John Curtin School of Medical Research, Australian National University , Canberra , Australia
- b ANU Medical School, The Australian National University , Canberra , Australia
| | - Matt Rutar
- a John Curtin School of Medical Research, Australian National University , Canberra , Australia
| | - Yen-Zhen Lu
- a John Curtin School of Medical Research, Australian National University , Canberra , Australia
| | - Joshua A Chu-Tan
- a John Curtin School of Medical Research, Australian National University , Canberra , Australia
| | - Yuwei Chen
- a John Curtin School of Medical Research, Australian National University , Canberra , Australia
| | - Kartik Saxena
- a John Curtin School of Medical Research, Australian National University , Canberra , Australia
| | - Michele Madigan
- c School of Optometry and Vision Sciences, University of New South Wales , Sydney , Australia
- d The Save Sight Institute, University of Sydney , Sydney , Australia
| | - Krisztina Valter
- a John Curtin School of Medical Research, Australian National University , Canberra , Australia
- b ANU Medical School, The Australian National University , Canberra , Australia
| | - Jan M Provis
- a John Curtin School of Medical Research, Australian National University , Canberra , Australia
- b ANU Medical School, The Australian National University , Canberra , Australia
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15
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Mancinelli R, Di Filippo ES, Verratti V, Fulle S, Toniolo L, Reggiani C, Pietrangelo T. The Regenerative Potential of Female Skeletal Muscle upon Hypobaric Hypoxic Exposure. Front Physiol 2016; 7:303. [PMID: 27471475 PMCID: PMC4943944 DOI: 10.3389/fphys.2016.00303] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/16/2016] [Accepted: 06/30/2016] [Indexed: 11/23/2022] Open
Abstract
Aim: The aim of this study was to determine whether a 14-day trekking expeditions, in high altitude hypoxic environment, triggers redox disturbance at the level of satellite cells (adult stem cells) in young women. Methods: We collected muscle biopsies from Vastus Lateralis muscle for both single fiber analysis and satellite cells isolation. The samples collected before (PRE-Hypoxia) and after (POST-Hypoxia) the trekking in the Himalayas were compared. Satellite cells were investigated for oxidative stress (oxidant production, antioxidant enzyme activity, and lipid damage), mitochondrial potential variation, gene profile of HIF, and myogenic transcription factors (Pax7, MyoD, myogenin), and miRNA expression (miR-1, miR-133, miR-206). Results: The nuclear domain analysis showed a significant fusion and consequent reduction of the Pax7+ satellite cells in the single mature fibers. The POST-Hypoxia myoblasts obtained by two out of six volunteers showed high superoxide anion production and lipid peroxidation along with impaired dismutase and catalase and mitochondrial potential. The transcription profile and miRNA expression were different for oxidized and non-oxidized cells. Conclusions: The present study supports the phenomenon of hypobaric-hypoxia-induced oxidative stress and its role in the impairment of the regenerative capacity of satellite cells derived from the V. Lateralis muscle of young adult female subjects.
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Affiliation(s)
- Rosa Mancinelli
- Department of Neuroscience, Imaging and Clinical Sciences, G. d'Annunzio University of Chieti-PescaraChieti, Italy; Laboratory of Functional Evaluation, University 'G. d'Annunzio', Chieti-PescaraChieti, Italy; Interuniversity Institute of MyologyChieti, Italy
| | - Ester S Di Filippo
- Department of Neuroscience, Imaging and Clinical Sciences, G. d'Annunzio University of Chieti-PescaraChieti, Italy; Interuniversity Institute of MyologyChieti, Italy
| | - Vittore Verratti
- Department of Neuroscience, Imaging and Clinical Sciences, G. d'Annunzio University of Chieti-PescaraChieti, Italy; Laboratory of Functional Evaluation, University 'G. d'Annunzio', Chieti-PescaraChieti, Italy
| | - Stefania Fulle
- Department of Neuroscience, Imaging and Clinical Sciences, G. d'Annunzio University of Chieti-PescaraChieti, Italy; Laboratory of Functional Evaluation, University 'G. d'Annunzio', Chieti-PescaraChieti, Italy; Interuniversity Institute of MyologyChieti, Italy
| | - Luana Toniolo
- Interuniversity Institute of MyologyChieti, Italy; Department of Anatomy and Physiology, University of PaduaPadua, Italy
| | - Carlo Reggiani
- Interuniversity Institute of MyologyChieti, Italy; Department of Anatomy and Physiology, University of PaduaPadua, Italy
| | - Tiziana Pietrangelo
- Department of Neuroscience, Imaging and Clinical Sciences, G. d'Annunzio University of Chieti-PescaraChieti, Italy; Laboratory of Functional Evaluation, University 'G. d'Annunzio', Chieti-PescaraChieti, Italy; Interuniversity Institute of MyologyChieti, Italy
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16
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Neri M, Riezzo I, Pomara C, Schiavone S, Turillazzi E. Oxidative-Nitrosative Stress and Myocardial Dysfunctions in Sepsis: Evidence from the Literature and Postmortem Observations. Mediators Inflamm 2016; 2016:3423450. [PMID: 27274621 PMCID: PMC4870364 DOI: 10.1155/2016/3423450] [Citation(s) in RCA: 53] [Impact Index Per Article: 5.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/08/2016] [Accepted: 04/11/2016] [Indexed: 01/14/2023] Open
Abstract
BACKGROUND Myocardial depression in sepsis is common, and it is associated with higher mortality. In recent years, the hypothesis that the myocardial dysfunction during sepsis could be mediated by ischemia related to decreased coronary blood flow waned and a complex mechanism was invoked to explain cardiac dysfunction in sepsis. Oxidative stress unbalance is thought to play a critical role in the pathogenesis of cardiac impairment in septic patients. AIM In this paper, we review the current literature regarding the pathophysiology of cardiac dysfunction in sepsis, focusing on the possible role of oxidative-nitrosative stress unbalance and mitochondria dysfunction. We discuss these mechanisms within the broad scenario of cardiac involvement in sepsis. CONCLUSIONS Findings from the current literature broaden our understanding of the role of oxidative and nitrosative stress unbalance in the pathophysiology of cardiac dysfunction in sepsis, thus contributing to the establishment of a relationship between these settings and the occurrence of oxidative stress. The complex pathogenesis of septic cardiac failure may explain why, despite the therapeutic strategies, sepsis remains a big clinical challenge for effectively managing the disease to minimize mortality, leading to consideration of the potential therapeutic effects of antioxidant agents.
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Affiliation(s)
- M. Neri
- Institute of Forensic Pathology, Department of Clinical and Experimental Medicine, University of Foggia, Ospedale Colonnello D'Avanzo, Viale degli Aviatori 1, 71100 Foggia, Italy
| | - I. Riezzo
- Institute of Forensic Pathology, Department of Clinical and Experimental Medicine, University of Foggia, Ospedale Colonnello D'Avanzo, Viale degli Aviatori 1, 71100 Foggia, Italy
| | - C. Pomara
- Institute of Forensic Pathology, Department of Clinical and Experimental Medicine, University of Foggia, Ospedale Colonnello D'Avanzo, Viale degli Aviatori 1, 71100 Foggia, Italy
| | - S. Schiavone
- Institute of Pharmacology, Department of Clinical and Experimental Medicine, University of Foggia, Via L. Pinto 1, 71100 Foggia, Italy
| | - E. Turillazzi
- Institute of Forensic Pathology, Department of Clinical and Experimental Medicine, University of Foggia, Ospedale Colonnello D'Avanzo, Viale degli Aviatori 1, 71100 Foggia, Italy
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Lubrano V, Balzan S. Enzymatic antioxidant system in vascular inflammation and coronary artery disease. World J Exp Med 2015; 5:218-224. [PMID: 26618108 PMCID: PMC4655251 DOI: 10.5493/wjem.v5.i4.218] [Citation(s) in RCA: 99] [Impact Index Per Article: 9.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/16/2015] [Revised: 08/07/2015] [Accepted: 11/04/2015] [Indexed: 02/06/2023] Open
Abstract
In biological systems there is a balance between the production and neutralization of reactive oxygen species (ROS). This balance is maintained by the presence of natural antioxidants and antioxidant enzymes such as superoxide dismutase (SOD), catalase and glutathione peroxidase. The enhancement of lipid peroxidation or the decrease of antioxidant protection present in metabolic diseases or bad lifestyle can induce endothelial dysfunction and atherosclerosis. Clinical studies have shown that oxidative stress can increase ROS reducing the formation of antioxidant defences, especially in subjects with coronary artery disease (CAD). Some observation indicated that in the early stages of the disease there is a homeostatic up-regulation of the antioxidant enzyme system in response to increased free radicals to prevent vascular damage. As soon as free radicals get to chronically elevated levels, this compensation ceases. Therefore, SOD and the other enzymes may represent a good therapeutic target against ROS, but they are not useful markers for the diagnosis of CAD. In conclusion antioxidant enzymes are reduced in presence of metabolic disease and CAD. However the existence of genes that promote their enzymatic activity could contribute to create new drugs for the treatment of damage caused by metabolic diseases or lifestyle that increases the plasma ROS levels.
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18
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Song S, Kertowidjojo E, Ojaimi C, Martin-Fernandez B, Kandhi S, Wolin M, Hintze TH. Long-term methionine-diet induced mild hyperhomocysteinemia associated cardiac metabolic dysfunction in multiparous rats. Physiol Rep 2015; 3:3/5/e12292. [PMID: 26009634 PMCID: PMC4463811 DOI: 10.14814/phy2.12292] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/19/2023] Open
Abstract
Mild hyperhomocysteinemia (HHcy, clinically defined as less than 30 μmol/L) is an independent cardiovascular disease (CVD) risk factor, and is associated with many complications during pregnancy, such as preeclampsia (PE). The aim of this study was to assess the effect of long-term mild HHcy on cardiac metabolic function of multiparous rats. Female rats were mated 3 to 4 times and were fed with methionine in drinking water to increase plasma Hcy (2.9 ± 0.3 to 10.5 ± 2.3 μmol/L) until termination. This caused significant increase of heart weight/body weight (0.24 ± 0.01 to 0.27 ± 0.01 g/100 g) and left ventricle weight (0.69 ± 0.03 to 0.78 ± 0.01 g). Superoxide production was increased by 2.5-fold in HHcy hearts using lucigenin chemiluminescence. The ability of bradykinin and carbachol to regulate myocardial oxygen consumption (MVO2) in vitro was impaired by 59% and 66% in HHcy heart, and it was restored by ascorbic acid (AA), tempol, or apocynin (Apo). Protein expression of p22phox subunit of NAD(P)H oxidase was increased by 2.6-fold, but there were no changes in other NAD(P)H oxidase subunits, NOSs or SODs. Microarray revealed 1518 genes to be differentially regulated (P < 0.05). The mRNA level of NAD(P)H oxidase subunits, NOSs or SODs remained unchanged. In conclusion, long-term mild HHcy increases cardiac superoxide mainly through regulation of p22phox component of the NAD(P)H oxidase and impairs the ability of NO to regulate MVO2 in heart of multiparous mothers.
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Affiliation(s)
- Su Song
- Department of Physiology, New York Medical College, Valhalla, New York, 10595, USA
| | | | - Caroline Ojaimi
- Department of Physiology, New York Medical College, Valhalla, New York, 10595, USA
| | | | - Sharath Kandhi
- Department of Physiology, New York Medical College, Valhalla, New York, 10595, USA
| | - Michael Wolin
- Department of Physiology, New York Medical College, Valhalla, New York, 10595, USA
| | - Thomas H Hintze
- Department of Physiology, New York Medical College, Valhalla, New York, 10595, USA
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19
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Gabriel-Costa D, da Cunha TF, Bechara LRG, Fortunato RS, Bozi LHM, Coelho MDA, Barreto-Chaves ML, Brum PC. Lactate up-regulates the expression of lactate oxidation complex-related genes in left ventricular cardiac tissue of rats. PLoS One 2015; 10:e0127843. [PMID: 25996919 PMCID: PMC4440754 DOI: 10.1371/journal.pone.0127843] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/15/2014] [Accepted: 04/20/2015] [Indexed: 11/18/2022] Open
Abstract
Background Besides its role as a fuel source in intermediary metabolism, lactate has been considered a signaling molecule modulating lactate-sensitive genes involved in the regulation of skeletal muscle metabolism. Even though the flux of lactate is significantly high in the heart, its role on regulation of cardiac genes regulating lactate oxidation has not been clarified yet. We tested the hypothesis that lactate would increase cardiac levels of reactive oxygen species and up-regulate the expression of genes related to lactate oxidation complex. Methods/Principal Findings Isolated hearts from male adult Wistar rats were perfused with control, lactate or acetate (20mM) added Krebs-Henseleit solution during 120 min in modified Langendorff apparatus. Reactive oxygen species (O2●-/H2O2) levels, and NADH and NADPH oxidase activities (in enriched microsomal or plasmatic membranes, respectively) were evaluated by fluorimetry while SOD and catalase activities were evaluated by spectrophotometry. mRNA levels of lactate oxidation complex and energetic enzymes MCT1, MCT4, HK, LDH, PDH, CS, PGC1α and COXIV were quantified by real time RT-PCR. Mitochondrial DNA levels were also evaluated. Hemodynamic parameters were acquired during the experiment. The key findings of this work were that lactate elevated cardiac NADH oxidase activity but not NADPH activity. This response was associated with increased cardiac O2●-/H2O2 levels and up-regulation of MCT1, MCT4, LDH and PGC1α with no changes in HK, PDH, CS, COXIV mRNA levels and mitochondrial DNA levels. Lactate increased NRF-2 nuclear expression and SOD activity probably as counter-regulatory responses to increased O2●-/H2O2. Conclusions Our results provide evidence for lactate-induced up-regulation of lactate oxidation complex associated with increased NADH oxidase activity and cardiac O2●-/H2O2 driving to an anti-oxidant response. These results unveil lactate as an important signaling molecule regulating components of the lactate oxidation complex in cardiac muscle.
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Affiliation(s)
| | | | | | - Rodrigo Soares Fortunato
- Carlos Chagas Filho Institute of Biophysics, Federal University of Rio de Janeiro, Rio de Janeiro, Brazil
| | | | | | | | - Patricia Chakur Brum
- School of physical Education and Sport, University of São Paulo, São Paulo, Brazil
- * E-mail:
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20
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Garza MA, Wason EA, Zhang JQ. Cardiac remodeling and physical training post myocardial infarction. World J Cardiol 2015; 7:52-64. [PMID: 25717353 PMCID: PMC4325302 DOI: 10.4330/wjc.v7.i2.52] [Citation(s) in RCA: 66] [Impact Index Per Article: 6.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/29/2014] [Revised: 12/22/2014] [Accepted: 01/19/2015] [Indexed: 02/06/2023] Open
Abstract
After myocardial infarction (MI), the heart undergoes extensive myocardial remodeling through the accumulation of fibrous tissue in both the infarcted and noninfarcted myocardium, which distorts tissue structure, increases tissue stiffness, and accounts for ventricular dysfunction. There is growing clinical consensus that exercise training may beneficially alter the course of post-MI myocardial remodeling and improve cardiac function. This review summarizes the present state of knowledge regarding the effect of post-MI exercise training on infarcted hearts. Due to the degree of difficulty to study a viable human heart at both protein and molecular levels, most of the detailed studies have been performed by using animal models. Although there are some negative reports indicating that post-MI exercise may further cause deterioration of the wounded hearts, a growing body of research from both human and animal experiments demonstrates that post-MI exercise may beneficially alter the course of wound healing and improve cardiac function. Furthermore, the improved function is likely due to exercise training-induced mitigation of renin-angiotensin-aldosterone system, improved balance between matrix metalloproteinase-1 and tissue inhibitor of matrix metalloproteinase-1, favorable myosin heavy chain isoform switch, diminished oxidative stress, enhanced antioxidant capacity, improved mitochondrial calcium handling, and boosted myocardial angiogenesis. Additionally, meta-analyses revealed that exercise-based cardiac rehabilitation has proven to be effective, and remains one of the least expensive therapies for both the prevention and treatment of cardiovascular disease, and prevents re-infarction.
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Abstract
SIGNIFICANCE Oxygen plays a key role in cellular metabolism and function. Oxygen delivery to cells is crucial, and a lack of oxygen such as that which occurs during myocardial infarction can be lethal. Cells should, therefore, be able to respond to changes in oxygen tension. RECENT ADVANCES Since the first studies examining the acute cellular effect of hypoxia on activation of transmitter release from glomus or type I chemoreceptor cells, it is now known that virtually all cells are able to respond to changes in oxygen tension. CRITICAL ISSUES Despite advances made in characterizing hypoxic responses, the identity of the "oxygen sensor" remains debated. Recently, more evidence has evolved as to how cardiac myocytes sense acute changes in oxygen. This review will examine the available evidence in support of acute oxygen-sensing mechanisms providing a brief historical perspective and then more detailed insights into the heart and the role of cardiac ion channels in hypoxic responses. FUTURE DIRECTIONS A further understanding of these cellular processes should result in interventions that assist in preventing the deleterious effects of acute changes in oxygen tension such as alterations in contractile function and cardiac arrhythmia.
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Affiliation(s)
- Livia C Hool
- School of Anatomy, Physiology, and Human Biology, The University of Western Australia , Crawley, Australia
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22
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Golub AS, Pittman RN. Bang-bang model for regulation of local blood flow. Microcirculation 2014; 20:455-83. [PMID: 23441827 DOI: 10.1111/micc.12051] [Citation(s) in RCA: 26] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/03/2013] [Accepted: 02/19/2013] [Indexed: 11/27/2022]
Abstract
The classical model of metabolic regulation of blood flow in muscle tissue implies the maintenance of basal tone in arterioles of resting muscle and their dilation in response to exercise and/or tissue hypoxia via the evoked production of vasodilator metabolites by myocytes. A century-long effort to identify specific metabolites responsible for explaining active and reactive hyperemia has not been successful. Furthermore, the metabolic theory is not compatible with new knowledge on the role of physiological radicals (e.g., nitric oxide, NO, and superoxide anion, O2 (-) ) in the regulation of microvascular tone. We propose a model of regulation in which muscle contraction and active hyperemia are considered the physiologically normal state. We employ the "bang-bang" or "on/off" regulatory model which makes use of a threshold and hysteresis; a float valve to control the water level in a tank is a common example of this type of regulation. Active bang-bang regulation comes into effect when the supply of oxygen and glucose exceeds the demand, leading to activation of membrane NADPH oxidase, release of O2 (-) into the interstitial space and subsequent neutralization of the interstitial NO. Switching arterioles on/off when local blood flow crosses the threshold is realized by a local cell circuit with the properties of a bang-bang controller, determined by its threshold, hysteresis, and dead-band. This model provides a clear and unambiguous interpretation of the mechanism to balance tissue demand with a sufficient supply of nutrients and oxygen.
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Affiliation(s)
- Aleksander S Golub
- Department of Physiology and Biophysics, Medical College of Virginia Campus, Virginia Commonwealth University, Richmond, VA, USA.
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Qin C, Yap S, Woodman OL. Antioxidants in the prevention of myocardial ischemia/reperfusion injury. Expert Rev Clin Pharmacol 2014; 2:673-95. [DOI: 10.1586/ecp.09.41] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/25/2023]
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Liu T, O'Rourke B. Regulation of the Na+/Ca2+ exchanger by pyridine nucleotide redox potential in ventricular myocytes. J Biol Chem 2013; 288:31984-92. [PMID: 24045952 DOI: 10.1074/jbc.m113.496588] [Citation(s) in RCA: 23] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/01/2023] Open
Abstract
The cardiac Na(+)/Ca(2+) exchanger (NCX) is the major Ca(2+) efflux pathway on the sarcolemma, counterbalancing Ca(2+) influx via L-type Ca(2+) current during excitation-contraction coupling. Altered NCX activity modulates the sarcoplastic reticulum Ca(2+) load and can contribute to abnormal Ca(2+) handling and arrhythmias. NADH/NAD(+) is the main redox couple controlling mitochondrial energy production, glycolysis, and other redox reactions. Here, we tested whether cytosolic NADH/NAD(+) redox potential regulates NCX activity in adult cardiomyocytes. NCX current (INCX), measured with whole cell patch clamp, was inhibited in response to cytosolic NADH loaded directly via pipette or increased by extracellular lactate perfusion, whereas an increase of mitochondrial NADH had no effect. Reactive oxygen species (ROS) accumulation was enhanced by increasing cytosolic NADH, and NADH-induced INCX inhibition was abolished by the H2O2 scavenger catalase. NADH-induced ROS accumulation was independent of mitochondrial respiration (rotenone-insensitive) but was inhibited by the flavoenzyme blocker diphenylene iodonium. NADPH oxidase was ruled out as the effector because INCX was insensitive to cytosolic NADPH, and NADH-induced ROS and INCX inhibition were not abrogated by the specific NADPH oxidase inhibitor gp91ds-tat. This study reveals a novel mechanism of NCX regulation by cytosolic NADH/NAD(+) redox potential through a ROS-generating NADH-driven flavoprotein oxidase. The mechanism is likely to play a key role in Ca(2+) homeostasis and the response to alterations in the cytosolic pyridine nucleotide redox state during ischemia-reperfusion or other cardiovascular diseases.
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Affiliation(s)
- Ting Liu
- From the Division of Cardiology, Department of Medicine, The Johns Hopkins University, Baltimore, Maryland 21205
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25
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Horáková L, Strosova MK, Spickett CM, Blaskovic D. Impairment of calcium ATPases by high glucose and potential pharmacological protection. Free Radic Res 2013; 47 Suppl 1:81-92. [PMID: 23710650 DOI: 10.3109/10715762.2013.807923] [Citation(s) in RCA: 23] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/04/2023]
Abstract
The review deals with impairment of Ca(2+)-ATPases by high glucose or its derivatives in vitro, as well as in human diabetes and experimental animal models. Acute increases in glucose level strongly correlate with oxidative stress. Dysfunction of Ca(2+)-ATPases in diabetic and in some cases even in nondiabetic conditions may result in nitration of and in irreversible modification of cysteine-674. Nonenyzmatic protein glycation might lead to alteration of Ca(2+)-ATPase structure and function contributing to Ca(2+) imbalance and thus may be involved in development of chronic complications of diabetes. The susceptibility to glycation is probably due to the relatively high percentage of lysine and arginine residues at the ATP binding and phosphorylation domains. Reversible glycation may develop into irreversible modifications (advanced glycation end products, AGEs). Sites of SERCA AGEs are depicted in this review. Finally, several mechanisms of prevention of Ca(2+)-pump glycation, and their advantages and disadvantages are discussed.
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Affiliation(s)
- L Horáková
- Institute of Experimental Pharmacology and Toxicology, SAS, Bratislava, Slovakia.
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Wang C, Liu N, Luan R, Li Y, Wang D, Zou W, Xing Y, Tao L, Cao F, Wang H. Apelin protects sarcoplasmic reticulum function and cardiac performance in ischaemia-reperfusion by attenuating oxidation of sarcoplasmic reticulum Ca2+-ATPase and ryanodine receptor. Cardiovasc Res 2013; 100:114-24. [DOI: 10.1093/cvr/cvt160] [Citation(s) in RCA: 32] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/29/2022] Open
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Cytosolic malate dehydrogenase regulates senescence in human fibroblasts. Biogerontology 2012; 13:525-36. [PMID: 22971926 DOI: 10.1007/s10522-012-9397-0] [Citation(s) in RCA: 50] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/03/2012] [Accepted: 08/21/2012] [Indexed: 10/27/2022]
Abstract
Carbohydrate metabolism changes during cellular senescence. Cytosolic malate dehydrogenase (MDH1) catalyzes the reversible reduction of oxaloacetate to malate at the expense of reduced nicotinamide adenine dinucleotide (NADH). Here, we show that MDH1 plays a critical role in the cellular senescence of human fibroblasts. We observed that the activity of MDH1 was reduced in old human dermal fibroblasts (HDFs) [population doublings (PD) 56], suggesting a link between decreased MDH1 protein levels and aging. Knockdown of MDH1 in young HDFs (PD 20) and the IMR90 human fibroblast cell line resulted in the appearance of significant cellular senescence features, including senescence-associated β-galactosidase staining, flattened and enlarged morphology, increased population doubling time, and elevated p16(INK4A) and p21(CIP1) protein levels. Cytosolic NAD/NADH ratios were decreased in old HDFs to the same extent as in MDH1 knockdown HDFs, suggesting that cytosolic NAD depletion is related to cellular senescence. We found that AMP-activated protein kinase, a sensor of cellular energy, was activated in MDH1 knockdown cells. We also found that sirtuin 1 (SIRT1) deacetylase, a controller of cellular senescence, was decreased in MDH1 knockdown cells. These results indicate that the decrease in MDH1 and subsequent reduction in NAD/NADH ratio, which causes SIRT1 inhibition, is a likely carbohydrate metabolism-controlled cellular senescence mechanism.
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Echigoya Y, Morita S, Itou T, Sakai T. Effects of extracellular lactate on production of reactive oxygen species by equine polymorphonuclear leukocytes in vitro. Am J Vet Res 2012; 73:1290-8. [DOI: 10.2460/ajvr.73.8.1290] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/20/2022]
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Liu D, Huang L, Wang Y, Wang W, Wehrens XH, Belousova T, Abdelrahim M, DiMattia G, Sheikh-Hamad D. Human stanniocalcin-1 suppresses angiotensin II-induced superoxide generation in cardiomyocytes through UCP3-mediated anti-oxidant pathway. PLoS One 2012; 7:e36994. [PMID: 22693564 PMCID: PMC3365029 DOI: 10.1371/journal.pone.0036994] [Citation(s) in RCA: 26] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/08/2012] [Accepted: 04/11/2012] [Indexed: 01/30/2023] Open
Abstract
Rationale We have previously shown increased cardiac stanniocalcin-1 (STC1) in patients with idiopathic dilated cardiomyopathy. STC1 localizes to the inner mitochondrial membrane and transgenic over-expression of STC1 is associated with increased energy utilization. Objective We examined the hypothesis that STC1 uncouples mitochondrial oxidative phosphorylation - to suppress superoxide generation and modulate neurohormonal effects on cardiomyocytes. Methods and Results Compared to WT mouse heart, STC1 Tg heart displays: 2-fold higher uncoupling protein 3 (UCP3) levels, but no effect on UCP2 protein; 40% lower ATP levels; but similar activities of respiratory chain complexes I-IV. In cultured adult rat and freshly-isolated mouse cardiomyocytes, rSTC1 induces UCP3, but not UCP2. Treatment of cardiomyocytes with STC1 decreases mitochondrial membrane potential and suppresses baseline and angiotensin II (Ang II)-induced superoxide generation. Furthermore, baseline superoxide generation is higher in freshly-isolated adult UCP3−/− mouse cardiomyocytes compared to WT, suggesting an important role for UCP3 in regulating cardiomyocyte ROS under physiologic conditions. Treatment of UCP3−/− cardiomyocytes with rSTC1 failed to suppress superoxide generation, suggesting that the effects of STC1 on superoxide generation in cardiomyocytes are UCP3-dependent. Conclusion STC1 activates a novel anti-oxidant pathway in cardiac myocytes through induction of UCP3, and may play an important role in suppressing ROS in the heart under normal physiologic conditions and ameliorate the deleterious effects of Ang II-mediated cardiac injury. Importantly, our data point to a critical role for the mitochondria in regulating ROS generation in response to Ang II.
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Affiliation(s)
- Dajun Liu
- Division of Nephrology/Department of Medicine, Baylor College of Medicine, Houston, Texas, United States of America
| | - Luping Huang
- Division of Nephrology/Department of Medicine, Baylor College of Medicine, Houston, Texas, United States of America
- * E-mail: (DSH); (LH)
| | - Yanlin Wang
- Division of Nephrology/Department of Medicine, Baylor College of Medicine, Houston, Texas, United States of America
| | - Wei Wang
- Department of Molecular Physiology and Biophysics, Baylor College of Medicine, Houston, Texas, United States of America
| | - Xander H.T. Wehrens
- Department of Molecular Physiology and Biophysics, Baylor College of Medicine, Houston, Texas, United States of America
| | - Tatiana Belousova
- Division of Nephrology/Department of Medicine, Baylor College of Medicine, Houston, Texas, United States of America
| | - Maen Abdelrahim
- Cancer Research Institute, MD Anderson Cancer Center Orlando, Orlando, Florida, United States of America
| | - Gabriel DiMattia
- Departments of Oncology and Biochemistry, The University of Western Ontario, London, Ontario, Canada
| | - David Sheikh-Hamad
- Division of Nephrology/Department of Medicine, Baylor College of Medicine, Houston, Texas, United States of America
- * E-mail: (DSH); (LH)
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Novel role of NADPH oxidase in ischemic myocardium: a study with Nox2 knockout mice. Funct Integr Genomics 2011; 12:501-14. [DOI: 10.1007/s10142-011-0256-x] [Citation(s) in RCA: 18] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/25/2011] [Revised: 09/13/2011] [Accepted: 10/03/2011] [Indexed: 10/15/2022]
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Zuo L, Youtz DJ, Wold LE. Particulate matter exposure exacerbates high glucose-induced cardiomyocyte dysfunction through ROS generation. PLoS One 2011; 6:e23116. [PMID: 21850256 PMCID: PMC3151271 DOI: 10.1371/journal.pone.0023116] [Citation(s) in RCA: 46] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/12/2011] [Accepted: 07/10/2011] [Indexed: 12/24/2022] Open
Abstract
Diabetes mellitus and fine particulate matter from diesel exhaust (DEP) are both important contributors to the development of cardiovascular disease (CVD). Diabetes mellitus is a progressive disease with a high mortality rate in patients suffering from CVD, resulting in diabetic cardiomyopathy. Elevated DEP levels in the air are attributed to the development of various CVDs, presumably since fine DEP (<2.5 µm in diameter) can be inhaled and gain access to the circulatory system. However, mechanisms defining how DEP affects diabetic or control cardiomyocyte function remain poorly understood. The purpose of the present study was to evaluate cardiomyocyte function and reactive oxygen species (ROS) generation in isolated rat ventricular myocytes exposed overnight to fine DEP (0.1 µg/ml), and/or high glucose (HG, 25.5 mM). Our hypothesis was that DEP exposure exacerbates contractile dysfunction via ROS generation in cardiomyocytes exposed to HG. Ventricular myocytes were isolated from male adult Sprague-Dawley rats cultured overnight and sarcomeric contractile properties were evaluated, including: peak shortening normalized to baseline (PS), time-to-90% shortening (TPS90), time-to-90% relengthening (TR90) and maximal velocities of shortening/relengthening (±dL/dt), using an IonOptix field-stimulator system. ROS generation was determined using hydroethidine/ethidium confocal microscopy. We found that DEP exposure significantly increased TR90, decreased PS and ±dL/dt, and enhanced intracellular ROS generation in myocytes exposed to HG. Further studies indicated that co-culture with antioxidants (0.25 mM Tiron and 0.5 mM N-Acetyl-L-cysteine) completely restored contractile function in DEP, HG and HG+DEP-treated myocytes. ROS generation was blocked in HG-treated cells with mitochondrial inhibition, while ROS generation was blocked in DEP-treated cells with NADPH oxidase inhibition. Our results suggest that DEP exacerbates myocardial dysfunction in isolated cardiomyocytes exposed to HG-containing media, which is potentially mediated by various ROS generation pathways.
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Affiliation(s)
- Li Zuo
- Center for Cardiovascular and Pulmonary Research, The Research Institute at Nationwide Children's Hospital, Columbus, Ohio, United States of America
- Department of Pediatrics, The Ohio State University College of Medicine, Columbus, Ohio, United States of America
| | - Dane J. Youtz
- Center for Cardiovascular and Pulmonary Research, The Research Institute at Nationwide Children's Hospital, Columbus, Ohio, United States of America
| | - Loren E. Wold
- Center for Cardiovascular and Pulmonary Research, The Research Institute at Nationwide Children's Hospital, Columbus, Ohio, United States of America
- Department of Pediatrics, The Ohio State University College of Medicine, Columbus, Ohio, United States of America
- Department of Physiology and Cell Biology, The Ohio State University College of Medicine, Columbus, Ohio, United States of America
- * E-mail:
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Arias-Loza PA, Hu K, Frantz S, Dienesch C, Bayer B, Wu R, Ertl G, Pelzer T. Medroxyprogesterone acetate aggravates oxidative stress and left ventricular dysfunction in rats with chronic myocardial infarction. Toxicol Pathol 2011; 39:867-878. [PMID: 21670166 DOI: 10.1177/0192623311410441] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/13/2023]
Abstract
The role of estrogens during myocardial ischemia has been extensively studied. However, effects of a standard hormone replacement therapy including 17β-estradiol (E2) combined with medroxyprogesterone acetate (MPA) have not been assessed, and this combination could have contributed to the negative outcomes of the clinical studies on hormone replacement. We hypothesized that adding MPA to an E2 treatment would aggravate chronic heart failure after experimental myocardial infarction (MI). To address this issue, we evaluated clinical signs of heart failure as well as left ventricular (LV) dysfunction and remodeling in ovariectomized rats subjected to chronic MI receiving E2 or E2 plus MPA. After eight weeks MI E2 showed no effects. Adding MPA to E2 aggravated LV remodeling and dysfunction as judged by increased heart weight, elevated myocyte cross-sectional areas, increased elevated left ventricle end diastolic pressure, and decreased LV fractional shortening. Impaired LV function in rats receiving MPA plus E2 was associated with increased cardiac reactive oxygen species generation and myocardial expression levels of NADPH oxidase subunits. These results support the interpretation that adding MPA to an E2 treatment complicates cardiovascular injury damage post-MI and therefore contributes to explain the adverse outcome of prospective clinical studies.
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Lee TM, Chen CC, Hsu YJ. Differential effects of NADPH oxidase and xanthine oxidase inhibition on sympathetic reinnervation in postinfarct rat hearts. Free Radic Biol Med 2011; 50:1461-70. [PMID: 21295134 DOI: 10.1016/j.freeradbiomed.2011.01.031] [Citation(s) in RCA: 28] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/27/2010] [Revised: 01/11/2011] [Accepted: 01/25/2011] [Indexed: 01/16/2023]
Abstract
Superoxide has been shown to play a major role in ventricular remodeling and arrhythmias after myocardial infarction. However, the source of increased myocardial superoxide production and the role of superoxide in sympathetic innervation remain to be further characterized. Male Wistar rats, after coronary artery ligation, were randomized to vehicle, allopurinol, or apocynin for 4weeks. To determine the role of peroxynitrite in sympathetic reinnervation, we also used 3-morpholinosydnonimine (a peroxynitrite generator). The postinfarction period was associated with increased oxidative stress, as measured by myocardial superoxide, nitrotyrosine, xanthine oxidase activity, NADPH oxidase activity, and dihydroethidium fluorescent staining. Measurement of myocardial norepinephrine levels revealed a significant elevation in vehicle-treated infarcted rats compared with sham. Sympathetic hyperinnervation was blunted after administration of allopurinol. Arrhythmic scores in the allopurinol-treated infarcted rats were significantly lower than those in vehicle. For similar levels of ventricular remodeling, apocynin had no beneficial effects on oxidative stress, sympathetic hyperinnervation, or arrhythmia vulnerability. Allopurinol-treated hearts had significantly decreased nerve growth factor expression, which was substantially increased after coadministration of 3-morpholinosydnonimine. These results indicate that xanthine oxidase but not NADPH oxidase largely mediates superoxide production after myocardial infarction. Xanthine oxidase inhibition ameliorates sympathetic innervation and arrhythmias possibly via inhibition of the peroxynitrite-mediated nerve growth factor pathway.
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Affiliation(s)
- Tsung-Ming Lee
- Department of Medicine, Cardiology Section, Chi-Mei Medical Center, Tainan, Taiwan.
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Wang CZ, Mehendale SR, Calway T, Yuan CS. Botanical flavonoids on coronary heart disease. THE AMERICAN JOURNAL OF CHINESE MEDICINE 2011; 39:661-71. [PMID: 21721147 PMCID: PMC3277260 DOI: 10.1142/s0192415x1100910x] [Citation(s) in RCA: 60] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Subscribe] [Scholar Register] [Indexed: 01/08/2023]
Abstract
Ischemic heart disease (IHD) is one of the leading causes of death in Western countries. Prevention rather than treatment of heart disease can significantly improve patients' quality of life and reduce health care costs. Flavonoids are widely distributed in vegetables, fruits and herbal medicines. Regularly consuming botanicals, especially those containing flavonoids, has been associated with a reduction in cardiovascualar disease; thus, it is important to investigate how flavonoids improve cardiac resistance to heart disease and their related mechanisms of action. It has been shown that cardiomyocyte injury and death can result from ischemia-reperfusion, which is pathognomonic of ischemic heart disease. Massive reactive oxygen species (ROS) release at the onset of reperfusion produces cell injury and death. "Programming" the heart to either generate less ROS or to increase strategic ROS removal could reduce reperfusion response. Additionally, profuse nitric oxide (NO) release at reperfusion could be protective in "preconditioning" models. Botanical flavonoids induce preconditioning of the heart, thereby protecting against ischemia-reperfusion injury. In this article, we will discuss two herbs containing potent flavonoids, Scutellaria baicalensis and grape seed proanthocyanidin, which can potentially offer cardiac protection against ischemic heart disease.
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Affiliation(s)
- Chong-Zhi Wang
- Tang Center for Herbal Medicine Research and Departments of Anesthesia and Critical Care, The Pritzker School of Medicine, University of Chicago, Chicago, IL 60637, USA
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Zhang T, Feng Q. Nitric oxide and calcium signaling regulate myocardial tumor necrosis factor-α expression and cardiac function in sepsis. Can J Physiol Pharmacol 2010; 88:92-104. [PMID: 20237583 DOI: 10.1139/y09-097] [Citation(s) in RCA: 22] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/30/2023]
Abstract
Myocardial tumor necrosis factor-alpha (TNF-alpha), a proinflammatory cytokine, is a critical inducer of myocardial dysfunction in sepsis. The purpose of this review is to summarize the mechanisms through which TNF-alpha production is regulated in cardiomyocytes in response to lipopolysaccharide (LPS), a key pathogen-associated molecular pattern (PAMP) in sepsis. These mechanisms include Nox2-containing NAD(P)H oxidase, phospholipase C (PLC)gamma1, and Ca2+ signaling pathways. Activation of these pathways increases TNF-alpha expression via activation of extracellular signal-regulated kinases 1 and 2 (ERK1/2) and p38 mitogen-activated protein kinase (MAPK). Conversely, activation of c-Jun NH2-terminal kinase 1 (JNK1) negatively regulates TNF-alpha production through inhibition of ERK1/2 and p38 MAPK activity. Interestingly, endothelial nitric oxide synthase (eNOS) promotes TNF-alpha expression by enhancing p38 MAPK activation, whereas neuronal NOS (nNOS) inhibits TNF-alpha production by reducing Ca2+-dependent ERK1/2 activity. Therefore, the JNK1 and nNOS inhibitory pathways represent a "brake" that limits myocardial TNF-alpha expression in sepsis. Further understanding of these signal transduction mechanisms may lead to novel pharmacological therapies in sepsis.
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Affiliation(s)
- Ting Zhang
- Department of Physiology and Pharmacology, Schulich School of Medicine and Dentistry, University of Western Ontario, Lawson Health Research Institute, London, ON N6A 5C1, Canada
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Tang WH, Cheng WT, Kravtsov GM, Tong XY, Hou XY, Chung SK, Chung SSM. Cardiac contractile dysfunction during acute hyperglycemia due to impairment of SERCA by polyol pathway-mediated oxidative stress. Am J Physiol Cell Physiol 2010; 299:C643-53. [PMID: 20573996 DOI: 10.1152/ajpcell.00137.2010] [Citation(s) in RCA: 56] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/22/2022]
Abstract
Hyperglycemia is an indication of poor outcome for heart attack patients, even for nondiabetic patients with stress-induced hyperglycemia. Previous studies showed that inhibition of aldose reductase, the first and rate-limiting enzyme of the polyol pathway, attenuated contractile dysfunction in diabetic animals, but the mechanism is unclear. We therefore wanted to find out whether the polyol pathway also contributes to acute hyperglycemia-induced cardiac contractile dysfunction, and determine the mechanism involved. Rat hearts were isolated and retrogradely perfused with Krebs buffer containing either normal or high concentrations of glucose for 2 h. Short exposure to high-glucose medium led to contractile dysfunction as indicated by decreased -dP/dt(max), as well as elevation in left ventricular end-diastolic pressure. Cardiomyocytes incubated in high-glucose medium showed abnormal Ca2+ signaling, most likely because of decreased activity of sarco(endo)plasmic reticulum Ca2+-ATPase (SERCA) inactivated by oxidative stress. Inhibition of aldose reductase or sorbitol dehydrogenase, the second enzyme in the polyol pathway, ameliorated contractile dysfunction, attenuated oxidative stress, and normalized Ca2+ signaling and SERCA activity caused by high glucose, indicating that the polyol pathway is the major contributor to acute hyperglycemia-induced oxidative stress leading to the inactivation of SERCA and contractile dysfunction.
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Affiliation(s)
- Wai Ho Tang
- Department of Physiology, Faculty of Medicine, University of Hong Kong, Hong Kong, China
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Ji L, Fu F, Zhang L, Liu W, Cai X, Zhang L, Zheng Q, Zhang H, Gao F. Insulin attenuates myocardial ischemia/reperfusion injury via reducing oxidative/nitrative stress. Am J Physiol Endocrinol Metab 2010; 298:E871-80. [PMID: 20124508 DOI: 10.1152/ajpendo.00623.2009] [Citation(s) in RCA: 117] [Impact Index Per Article: 7.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/22/2022]
Abstract
It is well known that insulin possesses a cardioprotective effect and that insulin resistance is closely related to cardiovascular diseases. Peroxynitrite (ONOO(-)) formation may trigger oxidative/nitrative stress and represent a major cytotoxic effect in heart diseases. This study was designed to investigate whether insulin attenuates ONOO(-) generation and oxidative/nitrative stress in acute myocardial ischemia/reperfusion (MI/R). Adult male rats were subjected to 30 min of myocardial ischemia and 3 h of reperfusion. Rats randomly received vehicle, insulin, or insulin plus wortmannin. Arterial blood pressure and left ventricular pressure were monitored throughout the experiment. Insulin significantly improved cardiac functions and reduced myocardial infarction, apoptotic cell death, and blood creatine kinase/lactate dehydrogenase levels following MI/R. Myocardial ONOO(-) formation was significantly attenuated after insulin treatment. Moreover, insulin resulted in a significant increase in Akt and endothelial nitric oxide (NO) synthase (eNOS) phosphorylation, NO production, and antioxidant capacity in ischemic/reperfused myocardial tissue. On the other hand, insulin markedly reduced MI/R-induced inducible NOS (iNOS) and gp91(phox) expression in cardiac tissue. Inhibition of insulin signaling with wortmannin not only blocked the cardioprotection of insulin but also markedly attenuated insulin-induced antioxidative/antinitrative effect. Furthermore, the suppression on ONOO(-) formation by either insulin or an ONOO(-) scavenger uric acid reduced myocardial infarct size in rats subjected to MI/R. We concluded that insulin exerts a cardioprotective effect against MI/R injury by blocking ONOO(-) formation. Increased physiological NO production (via eNOS phosphorylation) and superoxide anion reduction contribute to the antioxidative/antinitrative effect of insulin, which can be reversed by inhibiting phosphatidylinositol 3'-kinase. These results provide important novel information on the mechanisms of cardiovascular actions of insulin.
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Affiliation(s)
- Lele Ji
- Dept. of Physiology, Tangdu Hospital, Fourth Military Medical University, Xi'an, China
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Polyol pathway impairs the function of SERCA and RyR in ischemic-reperfused rat hearts by increasing oxidative modifications of these proteins. J Mol Cell Cardiol 2009; 49:58-69. [PMID: 20025885 DOI: 10.1016/j.yjmcc.2009.12.003] [Citation(s) in RCA: 40] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/20/2009] [Revised: 12/04/2009] [Accepted: 12/05/2009] [Indexed: 11/23/2022]
Abstract
A number of studies have shown that the polyol pathway, consisting of aldose reductase (AR) and sorbitol dehydrogenase (SDH), contributes to ischemia-reperfusion (I/R)-induced myocardial infarction due to depletion of ATP. In this report we show that the polyol pathway in I/R heart also contributes to the impairment of sacro/endoplasmic reticulum Ca(2+)-ATPase (SERCA) and ryanodine receptor (RyR), two key players in Ca(2+) signaling that regulate cardiac contraction. Rat hearts were isolated and retrogradely perfused with either Krebs' buffer containing 1 microM AR inhibitor, zopolrestat, or 200 nM SDH inhibitor, CP-170,711, and challenged by 30 min of regional ischemia and 45 min of reperfusion. We found that post-ischemic contractile function of the isolated perfused hearts was improved by pharmacological inhibition of the polyol pathway. I/R-induced contractile dysfunction is most likely due to impairment in Ca(2+) signaling and the activities of SERCA and RyR. All these abnormalities were significantly ameliorated by treatment with ARI or SDI. We showed that the polyol pathway activities increase the level of peroxynitrite, which enhances the tyrosine nitration of SERCA and irreversibly modifies it to form SERCAC674-SO(3)H. This leads to reduced level of S-glutathiolated SERCA, contributing to its inactivation. The polyol pathway activities also deplete the level of GSH, leading to decreased active RyR, the S-glutathiolated RyR. Thus, in I/R heart, inhibition of polyol pathway improved the function of SERCA and RyR by protecting them from irreversible oxidation.
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Di Maria CA, Bogoyevitch MA, McKitrick DJ, Arnolda LF, Hool LC, Arthur PG. Changes in oxygen tension affect cardiac mitochondrial respiration rate via changes in the rate of mitochondrial hydrogen peroxide production. J Mol Cell Cardiol 2009; 47:49-56. [DOI: 10.1016/j.yjmcc.2009.03.010] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/04/2008] [Revised: 02/26/2009] [Accepted: 03/12/2009] [Indexed: 12/01/2022]
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Zhao W, Zhao D, Yan R, Sun Y. Cardiac oxidative stress and remodeling following infarction: role of NADPH oxidase. Cardiovasc Pathol 2009; 18:156-66. [PMID: 18402834 PMCID: PMC2693891 DOI: 10.1016/j.carpath.2007.12.013] [Citation(s) in RCA: 35] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/10/2007] [Revised: 09/18/2007] [Accepted: 12/20/2007] [Indexed: 01/30/2023] Open
Abstract
BACKGROUND There is growing recognition that oxidative stress plays a role in the pathogeneses of myocardial repair/remodeling following myocardial infarction (MI). Nicotinamide adenine denucleotide phosphate (NADPH) oxidase is a major source for cardiac reactive oxygen species production. Herein, we studied the importance of NADPH oxidase in development of cardiac oxidative stress and its induced molecular and cellular changes related to myocardial repair/remodeling. METHODS MI was created by coronary artery ligation in C57/BL (wild type) and NADPH oxidase (gp91(phox)) knockout mice. Cardiac oxidative stress, inflammatory/fibrogenic responses, apoptosis, and hypertrophy were detected by in situ hybridization, immunohistochemistry, terminal deoxynucleotidyl transferase biotin-dUTP nick end labeling (TUNEL), picrosirius red staining, and image analysis, respectively, at different stages post MI. RESULTS In wild-type mice with MI, and compared to sham-operated animals, we observed significantly increased gp91(phox) and 3-nitrotyrosine, a marker of oxidative stress, in the infarcted myocardium; accumulated macrophages and myofibroblasts at the infarct site; abundant apoptotic myocytes primarily at border zones on Day 3; and numerous apoptotic inflammatory/myofibroblasts in the later stages. In addition, we detected significantly increased transforming growth factor beta1, tissue inhibitor of metalloprotease 2, and type 1 collagen gene expression; continuously increasing collagen volume in the infarcted myocardium; and hypertrophy in noninfarcted myocardium. Compared to wild-type mice with MI, we did not observe significant difference in infarct size/thickness, cardiac hypertrophy, myocyte apoptosis, inflammatory/fibrogenic responses, as well as cardiac oxidative stress in gp91(phox) knockout mice. CONCLUSION Our findings indicate that during NADPH oxidase deficiency, superoxide production can be compensated by other sources, which leads to cardiac oxidative stress and its related molecular/cellular events in the infarcted heart.
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Affiliation(s)
- Wenyuan Zhao
- Department of Medicine, Division of Cardiovascular Diseases, University of Tennessee, Health Science Center, Memphis, TN 38163, USA
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Abstract
Heart failure is a global health problem, appearing most commonly in patients with previous myocardial infarction (MI). Cardiac remodelling, particularly fibrosis, seen in both the infarcted and non-infarcted myocardium is recognized to be a major determinant of the development of impaired ventricular function, leading to a poor prognosis. Elucidating cellular and molecular mechanisms responsible for the accumulation of extracellular matrix is essential for designing cardioprotective and reparative strategies that could regress fibrosis after infarction. Multiple factors contribute to left ventricular remodelling at different stages post-MI. This review will discuss the role of oxidative stress and locally produced angiotensin II in the pathogenesis of myocardial repair/remodelling after MI.
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Affiliation(s)
- Yao Sun
- Division of Cardiovascular Diseases, Department of Medicine, University of Tennessee Health Science Center, 956 Court Avenue, Box 20, Memphis, TN 38163, USA.
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Chen CH, Liu K, Chan JYH. Anesthetic preconditioning confers acute cardioprotection via up-regulation of manganese superoxide dismutase and preservation of mitochondrial respiratory enzyme activity. Shock 2008; 29:300-8. [PMID: 17693941 DOI: 10.1097/shk.0b013e3181454295] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/09/2023]
Abstract
The cellular and molecular mechanisms that underlie cardioprotection against I/R by anesthetic-induced preconditioning (APC) require further elucidation. Using isoflurane as a representative anesthetic, we evaluated the hypothesis that APC induces myocardial protection against I/R by attenuation of excessive reactive oxygen species and restoration of mitochondrial bioenergetics through postischemic up-regulation of manganese superoxide dismutase (MnSOD) expression and preservation of respiratory enzyme activity. Pentobarbital anesthetized open-chest Sprague-Dawley rats were subject to 30-min left coronary artery occlusion, followed by 120-min reperfusion. Before ischemia, rats were randomly assigned to receive 0.9% saline, two cycles of brief coronary artery occlusion and reperfusion, or a 30-min exposure to 1.0 minimum alveolar concentration isoflurane in the absence or presence of a specific mitochondrial adenosine triphosphate-sensitive potassium (KATP) channel blocker, 5-hydroxydecanoate; a membrane-permeable superoxide scavenger, 4-hydroxy-2,2,6,6-tetramethyl piperidinoxyl; or a NOS inhibitor, N(G)-nitro-L-arginine methyl ester. Isoflurane exposure induced an initial increase in myocardial superoxide (O2-), but not NO level. It also significantly decreased infarct size and restored mitochondrial respiratory enzyme activity or ATP production in I/R rat hearts, along with suppression of the O2- surge at reperfusion and increase in MnSOD expression or enzyme activity. These protective effects were abrogated by 5-hydroxydecanoate or 4-hydroxy-2,2,6,6-tetramethyl piperidinoxyl, but not by N(G)-nitro-L-arginine methyl ester pretreatment. These results suggest that opening of mitochondrial KATP channel, followed by O2- signaling, induces postischemic augmentation of MnSOD and preservation of mitochondrial respiratory enzyme activities, leading to attenuated cardiac O2- surge and restored ATP production during reperfusion, and underlie APC-induced cardioprotection.
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Affiliation(s)
- Chen Hsiu Chen
- Department of Anesthesiology, Kaohsiung Veterans General Hospital, Kaohsiung, Taiwan, Republic of China
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Matveeva NS, Lyubitsky OB, Osipov AN, Vladimirov YA. Lucigenin-enhanced chemiluminescence of animal tissues. Biophysics (Nagoya-shi) 2008. [DOI: 10.1134/s0006350907060164] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/22/2022] Open
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Hayashi H, Kobara M, Abe M, Tanaka N, Gouda E, Toba H, Yamada H, Tatsumi T, Nakata T, Matsubara H. Aldosterone nongenomically produces NADPH oxidase-dependent reactive oxygen species and induces myocyte apoptosis. Hypertens Res 2008; 31:363-75. [PMID: 18360057 DOI: 10.1291/hypres.31.363] [Citation(s) in RCA: 88] [Impact Index Per Article: 5.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
Abstract
The roles of aldosterone in the progression of heart failure have not been fully elucidated. This study examined whether aldosterone nongenomically activates reactive oxygen species (ROS) production, causing myocyte apoptosis. Addition of aldosterone to neonatal rat cardiac myocytes caused the activation of NADPH oxidase and intracellular ROS production in a dose-dependent manner (10-(9)-10(-7) mol/L). NADPH oxidase activation was evident as soon as 5 min after aldosterone treatment. Neither an inhibitor for nuclear transcription (actinomycin D) nor an inhibitor of new protein synthesis (cycloheximide) blocked this rapid activation, and specific binding of aldosterone to plasma membrane fraction was inhibited by eplerenone, suggesting a nongenomic mechanism. Aldosterone did not affect the mRNA or protein levels of NOX2, which is a major subunit of NADPH oxidase in myocytes, after 48 h. Nuclear staining with DAPI showed that aldosterone (10(-7) mol/L) increased the myocyte apoptosis (2.3 fold, p<0.001), coincident with the activation of caspase-3 (1.4 fold, p<0.05), compared with the serum-deprived control after 48 h. Aldosterone also induced phosphorylation of apoptosis signal-regulating kinase 1 (ASK1). These effects of aldosterone on myocyte ROS accumulation, ASK1 activation, and apoptosis were abolished by eplerenone, a mineralocorticoid receptor (MR) antagonist, apocynin, an inhibitor of NADPH oxidase activation, and tempol, a free radical scavenger, but by neither RU486, a glucocorticoid receptor antagonist, nor butylated hydroxyanisol (BHA), a mitochondrial ROS scavenger. In conclusion, aldosterone-mediated ROS production is blocked by eplerenone and induced by the nongenomic activation of NADPH oxidase, leading to myocyte apoptosis associated with ASK1 activation. These proapoptotic actions of aldosterone may play a role in the progression of heart failure.
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Affiliation(s)
- Hironori Hayashi
- Department of Cardiovascular Medicine, Kyoto Prefectural University of Medicine, Kyoto, Japan
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Hayashi T, Yamashita C, Matsumoto C, Kwak CJ, Fujii K, Hirata T, Miyamura M, Mori T, Ukimura A, Okada Y, Matsumura Y, Kitaura Y. Role of gp91phox-containing NADPH oxidase in left ventricular remodeling induced by intermittent hypoxic stress. Am J Physiol Heart Circ Physiol 2008; 294:H2197-203. [PMID: 18326795 DOI: 10.1152/ajpheart.91496.2007] [Citation(s) in RCA: 50] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/05/2023]
Abstract
Intermittent hypoxia due to sleep apnea syndrome is associated with cardiovascular diseases. However, the precise mechanisms by which intermittent hypoxic stress accelerates cardiovascular diseases are largely unclear. The aim of this study was to investigate the role of gp91(phox)-containing NADPH oxidase in the development of left ventricular (LV) remodeling induced by intermittent hypoxic stress in mice. Male gp91(phox)-deficient (gp91(-/-)) mice (n = 26) and wild-type (n = 39) mice at 7-12 wk of age were exposed to intermittent hypoxia (30 s of 4.5-5.5% O(2) followed by 30 s of 21% O(2) for 8 h/day during daytime) or normoxia for 10 days. Mean blood pressure and LV systolic and diastolic function were not changed by intermittent hypoxia in wild-type or gp91(-/-) mice, although right ventricular systolic pressure tended to be increased. In wild-type mice, intermittent hypoxic stress significantly increased the diameter of cardiomyocytes and interstitial fibrosis in LV myocardium. Furthermore, intermittent hypoxic stress increased superoxide production, 4-hydroxy-2-nonenal protein, TNF-alpha and transforming growth factor-beta mRNA, and NF-kappaB binding activity in wild-type, but not gp91(-/-), mice. These results suggest that gp91(phox)-containing NADPH oxidase plays a crucial role in the pathophysiology of intermittent hypoxia-induced LV remodeling through an increase of oxidative stress.
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Affiliation(s)
- Tetsuya Hayashi
- Department of Internal Medicine III, Osaka Medical College, 2-7 Daigakumachi, Takatsuki, Osaka, Japan.
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Abstract
Ischemia/reperfusion (I/R) injury is a major contributory factor to cardiac dysfunction and infarct size that determines patient prognosis after acute myocardial infarction. Considerable interest exists in harnessing the heart's endogenous capacity to resist I/R injury, known as ischemic preconditioning (IPC). The IPC research has contributed to uncovering the pathophysiology of I/R injury on a molecular and cellular basis and to invent potential therapeutic means to combat such damage. However, the translation of basic research findings learned from IPC into clinical practice has often been inadequate because the majority of basic research findings have stemmed from young and healthy animals. Few if any successful implementations of IPC have occurred in the diseased hearts that are the primary target of viable therapies activating cardioprotective mechanisms to limit cardiac dysfunction and infarct size. Therefore, the first purpose of this review is to facilitate understanding of pathophysiology of I/R injury and the mechanisms of cardioprotection afforded by IPC in the normal heart. Then I focus on the problems and opportunities for successful bench-to-bedside translation of IPC in the diseased hearts.
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Affiliation(s)
- Hajime Otani
- Second Department of Internal Medicine, Division of Cardiology, Kansai Medical University, Moriguchi City, Japan.
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Cardiac capsaicin-sensitive sensory nerves regulate myocardial relaxation via S-nitrosylation of SERCA: role of peroxynitrite. Br J Pharmacol 2007; 153:488-96. [PMID: 18037908 DOI: 10.1038/sj.bjp.0707599] [Citation(s) in RCA: 37] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/17/2023] Open
Abstract
BACKGROUND AND PURPOSE Sensory neuropathy develops in the presence of cardiovascular risk factors (e.g. diabetes, dyslipidemia), but its pathological consequences in the heart are unclear. We have previously shown that systemic sensory chemodenervation by capsaicin leads to impaired myocardial relaxation and diminished cardiac nitric oxide (NO) content. Here we examined the mechanism of diminished NO formation and if it may lead to a reduction of peroxynitrite (ONOO(-))-induced S-nitrosylation of sarcoendoplasmic reticulum Ca(2+)-ATPase (SERCA2a). EXPERIMENTAL APPROACH Male Wistar rats were treated with capsaicin for 3 days to induce sensory chemodenervation. Seven days later, myocardial function and biochemical parameters were measured. KEY RESULTS Capsaicin pretreatment significantly increased left ventricular end-diastolic pressure (LVEDP) decreased cardiac NO level, Ca(2+)-dependent NO synthase (NOS) activity, and NOS-3 mRNA. Myocardial superoxide content, xanthine oxidoreductase and NADPH oxidase activities did not change, although superoxide dismutase (SOD) activity increased. Myocardial and serum ONOO(-) concentration and S-nitrosylation of SERCA2a were significantly decreased. CONCLUSIONS AND IMPLICATIONS Our results show that sensory chemodenervation decreases cardiac NO via decreased expression and activity of Ca(2+)-dependent NOS and increases SOD activity, thereby leading to decreased basal ONOO(-) formation and reduction of S-nitrosylation of SERCA2a, which causes impaired myocardial relaxation characterized by increased left ventricular end-diastolic pressure (LVEDP). This suggests that capsaicin sensitive sensory neurons regulate myocardial relaxation via maintaining basal ONOO(-) formation and SERCA S-nitrosylation.
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Gupte RS, Vijay V, Marks B, Levine RJ, Sabbah HN, Wolin MS, Recchia FA, Gupte SA. Upregulation of glucose-6-phosphate dehydrogenase and NAD(P)H oxidase activity increases oxidative stress in failing human heart. J Card Fail 2007; 13:497-506. [PMID: 17675065 DOI: 10.1016/j.cardfail.2007.04.003] [Citation(s) in RCA: 71] [Impact Index Per Article: 3.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/08/2006] [Revised: 04/05/2007] [Accepted: 04/09/2007] [Indexed: 02/07/2023]
Abstract
BACKGROUND We previously found that higher NADPH levels produced by glucose-6-phosphate dehydrogenase (G6PD) can enhance myocardial superoxide generation by NAD(P)H oxidase in a dog model of dilated cardiomyopathy. Therefore, we tested whether G6PD activity is elevated and enhances NADPH level and increases NAD(P)H oxidase-derived superoxide production in the myocardium from patients with heart failure from ischemic cardiomyopathy. METHODS AND RESULTS Surgical discards of left ventricle were collected from 8 congestive heart failure patients undergoing surgical ventricular restoration procedures, whereas control left ventricle tissue was obtained from 5 normal donor hearts deemed not suitable for transplantation. Biochemical assays were performed in tissue homogenates. We found that superoxide and hydrogen peroxide were elevated, respectively, by 9- and 3-fold in failing versus normal hearts (P < .05). The NAD(P)H oxidase inhibitors gp91(ds-tat), apocynin, and diphenyleneiodonium, significantly inhibited superoxide generation by approximately 75%, 89%, and 91%, respectively. Superoxide production by NAD(P)H oxidase increased 10- and 3-fold by adding NADPH (100 micromol/L) and NADH (100 micromol/L), respectively, in a DPI- and gp91(ds-tat)-inhibitable manner. Interestingly, chelerythrine, a PKC inhibitor, and PP2, a Src kinase family inhibitor, reduced G6PD activity (0.29 +/- 0.04 nM x min x mg protein) by 50% and 51% and these inhibitors also decreased myocardial superoxide by 99% and 79%, respectively. Furthermore, 6-aminonicotinamide, a G6PD inhibitor, decreased myocardial superoxide production by 71%. CONCLUSIONS These data suggest that high NAD(P)H oxidase, fueled by G6PD-derived NADPH, generates most of the superoxide in failing hearts of patients with ischemic cardiomyopathy. In addition, PKC-Src kinase signaling pathways seem to coordinate the activation of both G6PD and NAD(P)H oxidase in human cardiac muscle.
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Affiliation(s)
- Rakhee S Gupte
- Department of Physiology, New York Medical College, Valhalla, New York 10595, USA
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Abstract
Extensive cardiac remodeling after myocardial infarction (MI) contributes significantly to ventricular dysfunction. Factors regulating left ventricular remodeling at different stages after MI are under investigation. There is growing recognition and experimental evidence that oxidative stress mediated by reactive oxygen species plays a role in the pathogeneses of myocardial repair/remodeling in various cardiac diseases. After acute MI, oxidative stress is developed in both infarcted and noninfarcted myocardium. Accumulating evidence has demonstrated that oxidative stress participates in several aspects of cardiac repair/remodeling after infarction that include cardiomyocyte apoptosis, inflammatory/fibrogenic responses, and hypertrophy. The exact pathways on reactive oxygen species-mediated myocardial remodeling are under investigation. The therapeutic potential of oxidative stress-directed drugs in myocardial remodeling after infarction has not been fully realized.
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Affiliation(s)
- Yao Sun
- Division of Cardiovascular Diseases, Department of Medicine, University of Tennessee, Health Science Center, Memphis, Tennessee 38163, USA.
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