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1
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Gaitán-González P, Sánchez-Hernández R, Arias-Montaño JA, Rueda A. Tale of two kinases: Protein kinase A and Ca 2+/calmodulin-dependent protein kinase II in pre-diabetic cardiomyopathy. World J Diabetes 2021; 12:1704-1718. [PMID: 34754372 PMCID: PMC8554373 DOI: 10.4239/wjd.v12.i10.1704] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/25/2021] [Revised: 07/28/2021] [Accepted: 08/30/2021] [Indexed: 02/06/2023] Open
Abstract
Metabolic syndrome is a pre-diabetic state characterized by several biochemical and physiological alterations, including insulin resistance, visceral fat accumulation, and dyslipidemias, which increase the risk for developing cardiovascular disease. Metabolic syndrome is associated with augmented sympathetic tone, which could account for the etiology of pre-diabetic cardiomyopathy. This review summarizes the current knowledge of the pathophysiological consequences of enhanced and sustained β-adrenergic response in pre-diabetes, focusing on cardiac dysfunction reported in diet-induced experimental models of pre-diabetic cardiomyopathy. The research reviewed indicates that both protein kinase A and Ca2+/calmodulin-dependent protein kinase II play important roles in functional responses mediated by β1-adrenoceptors; therefore, alterations in the expression or function of these kinases can be deleterious. This review also outlines recent information on the role of protein kinase A and Ca2+/calmodulin-dependent protein kinase II in abnormal Ca2+ handling by cardiomyocytes from diet-induced models of pre-diabetic cardiomyopathy.
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Affiliation(s)
- Pamela Gaitán-González
- Department of Biochemistry, Centro de Investigación y de Estudios Avanzados del Instituto Politécnico Nacional, Ciudad de México 07360, Mexico
| | - Rommel Sánchez-Hernández
- Department of Physiology, Biophysics and Neurosciences, Centro de Investigación y de Estudios Avanzados del Instituto Politécnico Nacional, Ciudad de México 07360, Mexico
| | - José-Antonio Arias-Montaño
- Department of Physiology, Biophysics and Neurosciences, Centro de Investigación y de Estudios Avanzados del Instituto Politécnico Nacional, Ciudad de México 07360, Mexico
| | - Angélica Rueda
- Department of Biochemistry, Centro de Investigación y de Estudios Avanzados del Instituto Politécnico Nacional, Ciudad de México 07360, Mexico
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2
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Ng YH, Okolo CA, Erickson JR, Baldi JC, Jones PP. Protein O-GlcNAcylation in the heart. Acta Physiol (Oxf) 2021; 233:e13696. [PMID: 34057811 DOI: 10.1111/apha.13696] [Citation(s) in RCA: 20] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/17/2021] [Revised: 05/25/2021] [Accepted: 05/27/2021] [Indexed: 12/30/2022]
Abstract
O-GlcNAcylation is a ubiquitous post-translational modification that is extremely labile and plays a significant role in physiology, including the heart. Sustained activation of cardiac O-GlcNAcylation is frequently associated with alterations in cellular metabolism, leading to detrimental effects on cardiovascular function. This is particularly true during conditions such as diabetes, hypertension, cardiac remodelling, heart failure and arrhythmogenesis. Paradoxically, transient elevation of cardiac protein O-GlcNAcylation can also exert beneficial effects in the heart. There is compelling evidence to suggest that a complex interaction between O-GlcNAcylation and phosphorylation also exists in the heart. Beyond direct functional consequences on cardiomyocytes, O-GlcNAcylation also acts indirectly by altering the function of transcription factors that affect downstream signalling. This review focuses on the potential cardioprotective role of protein O-GlcNAcylation during ischaemia-reperfusion injury, the deleterious consequences of chronically elevated O-GlcNAc levels, the interplay between O-GlcNAcylation and phosphorylation in the cardiomyocytes and the effects of O-GlcNAcylation on other major non-myocyte cell types in the heart.
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Affiliation(s)
- Yann Huey Ng
- Department of Medicine and HeartOtago University of Otago Dunedin New Zealand
| | - Chidinma A. Okolo
- Department of Physiology and HeartOtago University of Otago Dunedin New Zealand
- Life Sciences Division Diamond Light Source LtdHarwell Science and Innovation Campus Didcot UK
| | - Jeffrey R. Erickson
- Department of Physiology and HeartOtago University of Otago Dunedin New Zealand
| | - James C. Baldi
- Department of Medicine and HeartOtago University of Otago Dunedin New Zealand
| | - Peter P. Jones
- Department of Physiology and HeartOtago University of Otago Dunedin New Zealand
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3
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Frisk M, Le C, Shen X, Røe ÅT, Hou Y, Manfra O, Silva GJJ, van Hout I, Norden ES, Aronsen JM, Laasmaa M, Espe EKS, Zouein FA, Lambert RR, Dahl CP, Sjaastad I, Lunde IG, Coffey S, Cataliotti A, Gullestad L, Tønnessen T, Jones PP, Altara R, Louch WE. Etiology-Dependent Impairment of Diastolic Cardiomyocyte Calcium Homeostasis in Heart Failure With Preserved Ejection Fraction. J Am Coll Cardiol 2021; 77:405-419. [PMID: 33509397 PMCID: PMC7840890 DOI: 10.1016/j.jacc.2020.11.044] [Citation(s) in RCA: 67] [Impact Index Per Article: 16.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/25/2020] [Revised: 10/26/2020] [Accepted: 11/16/2020] [Indexed: 12/11/2022]
Abstract
BACKGROUND Whereas heart failure with reduced ejection fraction (HFrEF) is associated with ventricular dilation and markedly reduced systolic function, heart failure with preserved ejection fraction (HFpEF) patients exhibit concentric hypertrophy and diastolic dysfunction. Impaired cardiomyocyte Ca2+ homeostasis in HFrEF has been linked to disruption of membrane invaginations called t-tubules, but it is unknown if such changes occur in HFpEF. OBJECTIVES This study examined whether distinct cardiomyocyte phenotypes underlie the heart failure entities of HFrEF and HFpEF. METHODS T-tubule structure was investigated in left ventricular biopsies obtained from HFrEF and HFpEF patients, whereas cardiomyocyte Ca2+ homeostasis was studied in rat models of these conditions. RESULTS HFpEF patients exhibited increased t-tubule density in comparison with control subjects. Super-resolution imaging revealed that higher t-tubule density resulted from both tubule dilation and proliferation. In contrast, t-tubule density was reduced in patients with HFrEF. Augmented collagen deposition within t-tubules was observed in HFrEF but not HFpEF hearts. A causative link between mechanical stress and t-tubule disruption was supported by markedly elevated ventricular wall stress in HFrEF patients. In HFrEF rats, t-tubule loss was linked to impaired systolic Ca2+ homeostasis, although diastolic Ca2+ removal was also reduced. In contrast, Ca2+ transient magnitude and release kinetics were largely maintained in HFpEF rats. However, diastolic Ca2+ impairments, including reduced sarco/endoplasmic reticulum Ca2+-ATPase activity, were specifically observed in diabetic HFpEF but not in ischemic or hypertensive models. CONCLUSIONS Although t-tubule disruption and impaired cardiomyocyte Ca2+ release are hallmarks of HFrEF, such changes are not prominent in HFpEF. Impaired diastolic Ca2+ homeostasis occurs in both conditions, but in HFpEF, this mechanism for diastolic dysfunction is etiology-dependent.
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Affiliation(s)
- Michael Frisk
- Institute for Experimental Medical Research, Oslo University Hospital and University of Oslo, Oslo, Norway; K.G. Jebsen Center for Cardiac Research, University of Oslo, Oslo, Norway. https://twitter.com/IEMRLouch
| | - Christopher Le
- Institute for Experimental Medical Research, Oslo University Hospital and University of Oslo, Oslo, Norway; K.G. Jebsen Center for Cardiac Research, University of Oslo, Oslo, Norway
| | - Xin Shen
- Institute for Experimental Medical Research, Oslo University Hospital and University of Oslo, Oslo, Norway; K.G. Jebsen Center for Cardiac Research, University of Oslo, Oslo, Norway
| | - Åsmund T Røe
- Institute for Experimental Medical Research, Oslo University Hospital and University of Oslo, Oslo, Norway; K.G. Jebsen Center for Cardiac Research, University of Oslo, Oslo, Norway
| | - Yufeng Hou
- Institute for Experimental Medical Research, Oslo University Hospital and University of Oslo, Oslo, Norway; K.G. Jebsen Center for Cardiac Research, University of Oslo, Oslo, Norway
| | - Ornella Manfra
- Institute for Experimental Medical Research, Oslo University Hospital and University of Oslo, Oslo, Norway; K.G. Jebsen Center for Cardiac Research, University of Oslo, Oslo, Norway
| | - Gustavo J J Silva
- Institute for Experimental Medical Research, Oslo University Hospital and University of Oslo, Oslo, Norway; K.G. Jebsen Center for Cardiac Research, University of Oslo, Oslo, Norway
| | - Isabelle van Hout
- Department of Physiology, HeartOtago, University of Otago, Otago, New Zealand
| | - Einar S Norden
- Institute for Experimental Medical Research, Oslo University Hospital and University of Oslo, Oslo, Norway; K.G. Jebsen Center for Cardiac Research, University of Oslo, Oslo, Norway; Bjørknes College, Oslo, Norway
| | - J Magnus Aronsen
- Institute of Basic Medical Sciences, University of Oslo, Oslo, Norway
| | - Martin Laasmaa
- Institute for Experimental Medical Research, Oslo University Hospital and University of Oslo, Oslo, Norway; K.G. Jebsen Center for Cardiac Research, University of Oslo, Oslo, Norway
| | - Emil K S Espe
- Institute for Experimental Medical Research, Oslo University Hospital and University of Oslo, Oslo, Norway; K.G. Jebsen Center for Cardiac Research, University of Oslo, Oslo, Norway
| | - Fouad A Zouein
- Department of Pharmacology and Toxicology, American University of Beirut Medical Center, Faculty of Medicine, Riad El-Solh, Beirut, Lebanon
| | - Regis R Lambert
- Department of Physiology, HeartOtago, University of Otago, Otago, New Zealand
| | - Christen P Dahl
- Department of Cardiology, Oslo University Hospital, Rikshospitalet, Oslo, Norway; Research Institute for Internal Medicine, Oslo University Hospital, Rikshospitalet, Oslo, Norway
| | - Ivar Sjaastad
- Institute for Experimental Medical Research, Oslo University Hospital and University of Oslo, Oslo, Norway; K.G. Jebsen Center for Cardiac Research, University of Oslo, Oslo, Norway; Department of Cardiology, Oslo University Hospital, Ullevål, Oslo, Norway
| | - Ida G Lunde
- Institute for Experimental Medical Research, Oslo University Hospital and University of Oslo, Oslo, Norway; K.G. Jebsen Center for Cardiac Research, University of Oslo, Oslo, Norway
| | - Sean Coffey
- Department of Medicine and HeartOtago, Dunedin School of Medicine, University of Otago, Dunedin, New Zealand
| | - Alessandro Cataliotti
- Institute for Experimental Medical Research, Oslo University Hospital and University of Oslo, Oslo, Norway; K.G. Jebsen Center for Cardiac Research, University of Oslo, Oslo, Norway
| | - Lars Gullestad
- Department of Cardiology, Oslo University Hospital, Rikshospitalet, Oslo, Norway; Research Institute for Internal Medicine, Oslo University Hospital, Rikshospitalet, Oslo, Norway
| | - Theis Tønnessen
- Institute for Experimental Medical Research, Oslo University Hospital and University of Oslo, Oslo, Norway; K.G. Jebsen Center for Cardiac Research, University of Oslo, Oslo, Norway; Department of Cardiothoracic Surgery, Oslo University Hospital Ullevål, Oslo, Norway
| | - Peter P Jones
- Department of Physiology, HeartOtago, University of Otago, Otago, New Zealand
| | - Raffaele Altara
- Institute for Experimental Medical Research, Oslo University Hospital and University of Oslo, Oslo, Norway; K.G. Jebsen Center for Cardiac Research, University of Oslo, Oslo, Norway. https://twitter.com/IEMRLouch
| | - William E Louch
- Institute for Experimental Medical Research, Oslo University Hospital and University of Oslo, Oslo, Norway; K.G. Jebsen Center for Cardiac Research, University of Oslo, Oslo, Norway
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Cross-Talk Between the Adenylyl Cyclase/cAMP Pathway and Ca 2+ Homeostasis. Rev Physiol Biochem Pharmacol 2021; 179:73-116. [PMID: 33398503 DOI: 10.1007/112_2020_55] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
Cyclic AMP and Ca2+ are the first second or intracellular messengers identified, unveiling the cellular mechanisms activated by a plethora of extracellular signals, including hormones. Cyclic AMP generation is catalyzed by adenylyl cyclases (ACs), which convert ATP into cAMP and pyrophosphate. By the way, Ca2+, as energy, can neither be created nor be destroyed; Ca2+ can only be transported, from one compartment to another, or chelated by a variety of Ca2+-binding molecules. The fine regulation of cytosolic concentrations of cAMP and free Ca2+ is crucial in cell function and there is an intimate cross-talk between both messengers to fine-tune the cellular responses. Cancer is a multifactorial disease resulting from a combination of genetic and environmental factors. Frequent cases of cAMP and/or Ca2+ homeostasis remodeling have been described in cancer cells. In those tumoral cells, cAMP and Ca2+ signaling plays a crucial role in the development of hallmarks of cancer, including enhanced proliferation and migration, invasion, apoptosis resistance, or angiogenesis. This review summarizes the cross-talk between the ACs/cAMP and Ca2+ intracellular pathways with special attention to the functional and reciprocal regulation between Orai1 and AC8 in normal and cancer cells.
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Erdogan BR, Michel MC, Arioglu-Inan E. Expression and Signaling of β-Adrenoceptor Subtypes in the Diabetic Heart. Cells 2020; 9:cells9122548. [PMID: 33256212 PMCID: PMC7759850 DOI: 10.3390/cells9122548] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/28/2020] [Revised: 11/20/2020] [Accepted: 11/24/2020] [Indexed: 12/18/2022] Open
Abstract
Diabetes is a chronic, endocrine disorder that effects millions of people worldwide. Cardiovascular complications are the major cause of diabetes-related morbidity and mortality. Cardiac β1- and β2-adrenoceptor (AR) stimulation mediates positive inotropy and chronotropy, whereas β3-AR mediates negative inotropic effect. Changes in β-AR responsiveness are thought to be an important factor that contributes to the diabetic cardiac dysfunction. Diabetes related changes in β-AR expression, signaling, and β-AR mediated cardiac function have been studied by several investigators for many years. In the present review, we have screened PubMed database to obtain relevant articles on this topic. Our search has ended up with wide range of different findings about the effect of diabetes on β-AR mediated changes both in molecular and functional level. Considering these inconsistent findings, the effect of diabetes on cardiac β-AR still remains to be clarified.
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Affiliation(s)
- Betul R. Erdogan
- Department of Pharmacology, Faculty of Pharmacy, Ankara University, 06560 Ankara, Turkey;
- Department of Pharmacology, Faculty of Pharmacy, Izmir Katip Celebi University, 35620 Izmir, Turkey
| | - Martin C. Michel
- Department of Pharmacology, Johannes Gutenberg University, 55131 Mainz, Germany;
| | - Ebru Arioglu-Inan
- Department of Pharmacology, Faculty of Pharmacy, Ankara University, 06560 Ankara, Turkey;
- Correspondence:
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Li S, Chopra A, Keung W, Chan CWY, Costa KD, Kong CW, Hajjar RJ, Chen CS, Li RA. Sarco/endoplasmic reticulum Ca2+-ATPase is a more effective calcium remover than sodium-calcium exchanger in human embryonic stem cell-derived cardiomyocytes. Am J Physiol Heart Circ Physiol 2019; 317:H1105-H1115. [DOI: 10.1152/ajpheart.00540.2018] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/14/2023]
Abstract
Human pluripotent stem cell (hPSCs)-derived ventricular (V) cardiomyocytes (CMs) display immature Ca2+–handing properties with smaller transient amplitudes and slower kinetics due to such differences in crucial Ca2+-handling proteins as the poor sarco/endoplasmic reticulum Ca2+-ATPase (SERCA) pump but robust Na+-Ca2+ exchanger (NCX) activities in human embryonic stem cell (ESC)-derived VCMs compared with adult. Despite their fundamental importance in excitation-contraction coupling, the relative contribution of SERCA and NCX to Ca2+-handling of hPSC-VCMs remains unexplored. We systematically altered the activities of SERCA and NCX in human embryonic stem cell-derived ventricular cardiomyocytes (hESC-VCMs) and their engineered microtissues, followed by examining the resultant phenotypic consequences. SERCA overexpression in hESC-VCMs shortened the decay of Ca2+ transient at low frequencies (0.5 Hz) without affecting the amplitude, SR Ca2+ content and Ca2+ baseline. Interestingly, short hairpin RNA-based NCX suppression did not prolong the transient decay, indicating a compensatory response for Ca2+ removal. Although hESC-VCMs and their derived microtissues exhibited negative frequency-transient/force responses, SERCA overexpression rendered them less negative at high frequencies (>2 Hz) by accelerating Ca2+ sequestration. We conclude that for hESC-VCMs and their microtissues, SERCA, rather than NCX, is the main Ca2+ remover during diastole; poor SERCA expression is the leading cause for immature negative-frequency/force responses, which can be partially reverted by forced expression. Combinatorial approach to mature calcium handling in hESC-VCMs may help shed further mechanistic insights. NEW & NOTEWORTHY In this study of human pluripotent stem cell-derived cardiomyocytes, we studied the role of sarco/endoplasmic reticulum Ca2+-ATPase (SERCA) and Na+-Ca2+ exchanger (NCX) in Ca2+ handling. Our data support the notion that SERCA is more effective in cytosolic calcium removal than the NCX.
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Affiliation(s)
- Sen Li
- Dr. Li Dak-Sum Research Centre, The University of Hong Kong, Pokfulam, Hong Kong
- Stem Cell and Regenerative Medicine Consortium, Li Ka Shing Faculty of Medicine, University of Hong Kong, Hong Kong
| | - Anant Chopra
- Department of Bioengineering, Boston University, Boston, Massachusetts
- Harvard Wyss Institute for Biologically Inspired Engineering, Boston, Massachusetts
| | - Wendy Keung
- Dr. Li Dak-Sum Research Centre, The University of Hong Kong, Pokfulam, Hong Kong
- Stem Cell and Regenerative Medicine Consortium, Li Ka Shing Faculty of Medicine, University of Hong Kong, Hong Kong
| | - Camie W. Y. Chan
- Stem Cell and Regenerative Medicine Consortium, Li Ka Shing Faculty of Medicine, University of Hong Kong, Hong Kong
| | - Kevin D. Costa
- Cardiovascular Research Center, Icahn School of Medicine at Mount Sinai, Manhattan, New York
| | - Chi-Wing Kong
- Dr. Li Dak-Sum Research Centre, The University of Hong Kong, Pokfulam, Hong Kong
- Stem Cell and Regenerative Medicine Consortium, Li Ka Shing Faculty of Medicine, University of Hong Kong, Hong Kong
| | - Roger J. Hajjar
- Cardiovascular Research Center, Icahn School of Medicine at Mount Sinai, Manhattan, New York
| | - Christopher S. Chen
- Department of Bioengineering, Boston University, Boston, Massachusetts
- Harvard Wyss Institute for Biologically Inspired Engineering, Boston, Massachusetts
| | - Ronald A. Li
- Dr. Li Dak-Sum Research Centre, The University of Hong Kong, Pokfulam, Hong Kong
- Stem Cell and Regenerative Medicine Consortium, Li Ka Shing Faculty of Medicine, University of Hong Kong, Hong Kong
- Ming-Wai Lau Centre for Reparative Medicine, Karolinska Institutet, Hong Kong
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7
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Guo Y, Zhang Z, Wu HE, Luo ZD, Hogan QH, Pan B. Increased thrombospondin-4 after nerve injury mediates disruption of intracellular calcium signaling in primary sensory neurons. Neuropharmacology 2017; 117:292-304. [PMID: 28232180 DOI: 10.1016/j.neuropharm.2017.02.019] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/27/2016] [Revised: 01/31/2017] [Accepted: 02/18/2017] [Indexed: 12/14/2022]
Abstract
Painful nerve injury disrupts Ca2+ signaling in primary sensory neurons by elevating plasma membrane Ca2+-ATPase (PMCA) function and depressing sarco-endoplasmic reticulum Ca2+-ATPase (SERCA) function, which decreases endoplasmic reticulum (ER) Ca2+ stores and stimulates store-operated Ca2+ entry (SOCE). The extracellular matrix glycoprotein thrombospondin-4 (TSP4), which is increased after painful nerve injury, decreases Ca2+ current (ICa) through high-voltage-activated Ca2+ channels and increases ICa through low-voltage-activated Ca2+ channels in dorsal root ganglion neurons, which are events similar to the effect of nerve injury. We therefore examined whether TSP4 plays a critical role in injury-induced disruption of intracellular Ca2+ signaling. We found that TSP4 increases PMCA activity, inhibits SERCA, depletes ER Ca2+ stores, and enhances store-operated Ca2+ influx. Injury-induced changes of SERCA and PMCA function are attenuated in TSP4 knock-out mice. Effects of TSP4 on intracellular Ca2+ signaling are attenuated in voltage-gated Ca2+ channel α2δ1 subunit (Cavα2δ1) conditional knock-out mice and are also Protein Kinase C (PKC) signaling dependent. These findings suggest that TSP4 elevation may contribute to the pathogenesis of chronic pain following nerve injury by disrupting intracellular Ca2+ signaling via interacting with the Cavα2δ1 and the subsequent PKC signaling pathway. Controlling TSP4 mediated intracellular Ca2+ signaling in peripheral sensory neurons may be a target for analgesic drug development for neuropathic pain.
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Affiliation(s)
- Yuan Guo
- Department of Anesthesiology, Medical College of Wisconsin, 8701 Watertown Plank Road, Milwaukee, WI 53226, United States
| | - Zhiyong Zhang
- Department of Anesthesiology, Medical College of Wisconsin, 8701 Watertown Plank Road, Milwaukee, WI 53226, United States
| | - Hsiang-En Wu
- Department of Anesthesiology, Medical College of Wisconsin, 8701 Watertown Plank Road, Milwaukee, WI 53226, United States
| | - Z David Luo
- Department of Anesthesiology & Perioperative Care, University of California Irvine, Irvine, CA 92697, United States; Department of Pharmacology, University of California Irvine, Irvine, CA 92697, United States
| | - Quinn H Hogan
- Department of Anesthesiology, Medical College of Wisconsin, 8701 Watertown Plank Road, Milwaukee, WI 53226, United States
| | - Bin Pan
- Department of Anesthesiology, Medical College of Wisconsin, 8701 Watertown Plank Road, Milwaukee, WI 53226, United States.
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8
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Das PN, Kumar A, Bairagi N, Chatterjee S. Restoring calcium homeostasis in diabetic cardiomyocytes: an investigation through mathematical modelling. MOLECULAR BIOSYSTEMS 2017; 13:2056-2068. [PMID: 28795720 DOI: 10.1039/c7mb00264e] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/09/2023]
Abstract
Regulated calcium flux from sarcoplasmic reticulum could be a possible therapeutic strategy in diabetic cardiomyocyte problem.
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Affiliation(s)
| | - Ajay Kumar
- Drug Discovery Research Center
- Translational Health Science and Technology Institute
- Faridabad-121001
- India
| | | | - Samrat Chatterjee
- Drug Discovery Research Center
- Translational Health Science and Technology Institute
- Faridabad-121001
- India
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9
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Qin CX, Sleaby R, Davidoff AJ, Bell JR, De Blasio MJ, Delbridge LM, Chatham JC, Ritchie RH. Insights into the role of maladaptive hexosamine biosynthesis and O-GlcNAcylation in development of diabetic cardiac complications. Pharmacol Res 2016; 116:45-56. [PMID: 27988387 DOI: 10.1016/j.phrs.2016.12.016] [Citation(s) in RCA: 49] [Impact Index Per Article: 5.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/08/2016] [Revised: 10/28/2016] [Accepted: 12/13/2016] [Indexed: 12/21/2022]
Abstract
Diabetes mellitus significantly increases the risk of heart failure, independent of coronary artery disease. The mechanisms implicated in the development of diabetic heart disease, commonly termed diabetic cardiomyopathy, are complex, but much of the impact of diabetes on the heart can be attributed to impaired glucose handling. It has been shown that the maladaptive nutrient-sensing hexosamine biosynthesis pathway (HBP) contributes to diabetic complications in many non-cardiac tissues. Glucose metabolism by the HBP leads to enzymatically-regulated, O-linked attachment of a sugar moiety molecule, β-N-acetylglucosamine (O-GlcNAc), to proteins, affecting their biological activity (similar to phosphorylation). In normal physiology, transient activation of HBP/O-GlcNAc mechanisms is an adaptive, protective means to enhance cell survival; interventions that acutely suppress this pathway decrease tolerance to stress. Conversely, chronic dysregulation of HBP/O-GlcNAc mechanisms has been shown to be detrimental in certain pathological settings, including diabetes and cancer. Most of our understanding of the impact of sustained maladaptive HBP and O-GlcNAc protein modifications has been derived from adipose tissue, skeletal muscle and other non-cardiac tissues, as a contributing mechanism to insulin resistance and progression of diabetic complications. However, the long-term consequences of persistent activation of cardiac HBP and O-GlcNAc are not well-understood; therefore, the goal of this timely review is to highlight current understanding of the role of the HBP pathway in development of diabetic cardiomyopathy.
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Affiliation(s)
- Cheng Xue Qin
- Heart Failure Pharmacology, Baker IDI Heart & Diabetes Institute, Melbourne VIC 3004, Australia; Department of Pharmacology, University of Melbourne, VIC 3010, Australia
| | - Rochelle Sleaby
- Heart Failure Pharmacology, Baker IDI Heart & Diabetes Institute, Melbourne VIC 3004, Australia; Department of Physiology, University of Melbourne, VIC 3010, Australia
| | - Amy J Davidoff
- University of New England, Biddeford, ME, 04072, United States
| | - James R Bell
- Department of Physiology, University of Melbourne, VIC 3010, Australia
| | - Miles J De Blasio
- Heart Failure Pharmacology, Baker IDI Heart & Diabetes Institute, Melbourne VIC 3004, Australia; School of BioSciences, University of Melbourne, VIC 3010, Australia
| | | | - John C Chatham
- University of Alabama at Birmingham, Birmingham, AL, 35233, United States
| | - Rebecca H Ritchie
- Heart Failure Pharmacology, Baker IDI Heart & Diabetes Institute, Melbourne VIC 3004, Australia; Department of Pharmacology, University of Melbourne, VIC 3010, Australia; Department of Medicine, Monash University, Clayton 3800, VIC, Australia.
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10
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Neviere R, Delguste F, Durand A, Inamo J, Boulanger E, Preau S. Abnormal Mitochondrial cAMP/PKA Signaling Is Involved in Sepsis-Induced Mitochondrial and Myocardial Dysfunction. Int J Mol Sci 2016; 17:ijms17122075. [PMID: 27973394 PMCID: PMC5187875 DOI: 10.3390/ijms17122075] [Citation(s) in RCA: 25] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/14/2016] [Revised: 11/18/2016] [Accepted: 12/06/2016] [Indexed: 12/11/2022] Open
Abstract
Adrenergic receptors couple to Gs-proteins leading to transmembrane adenylyl cyclase activation and cytosolic cyclic adenosine monophosphate (cAMP) production. Cyclic AMP is also produced in the mitochondrial matrix, where it regulates respiration through protein kinase A (PKA)-dependent phosphorylation of respiratory chain complexes. We hypothesized that a blunted mitochondrial cAMP-PKA pathway would participate in sepsis-induced heart dysfunction. Adult male mice were subjected to intra-abdominal sepsis. Mitochondrial respiration of cardiac fibers and myocardial contractile performance were evaluated in response to 8Br-cAMP, PKA inhibition (H89), soluble adenylyl cyclase inhibition (KH7), and phosphodiesterase inhibition (IBMX; BAY60-7550). Adenosine diphosphate (ADP)-stimulated respiratory rates of cardiac fibers were reduced in septic mice. Compared with controls, stimulatory effects of 8Br-cAMP on respiration rates were enhanced in septic fibers, whereas inhibitory effects of H89 were reduced. Ser-58 phosphorylation of cytochrome c oxidase subunit IV-1 was reduced in septic hearts. In vitro, incubation of septic cardiac fibers with BAY60-7550 increased respiratory control ratio and improved cardiac MVO2 efficiency in isolated septic heart. In vivo, BAY60-7550 pre-treatment of septic mice have limited impact on myocardial function. Mitochondrial cAMP-PKA signaling is impaired in the septic myocardium. PDE2 phosphodiesterase inhibition by BAY60-7550 improves mitochondrial respiration and cardiac MVO2 efficiency in septic mice.
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Affiliation(s)
- Remi Neviere
- Département de Physiologie, Faculté de Médecine, Université Lille, 1 Place de Verdun, F-59000 Lille CEDEX 59045, France.
- INSERM LIRIC U995/Team "Glycation: From Inflammation to Aging", Université Lille, F-59000 Lille, France.
| | - Florian Delguste
- INSERM LIRIC U995/Team "Glycation: From Inflammation to Aging", Université Lille, F-59000 Lille, France.
| | - Arthur Durand
- INSERM LIRIC U995/Team "Glycation: From Inflammation to Aging", Université Lille, F-59000 Lille, France.
- Pôle Réanimation Médicale, CHU Lille, Bd Pr Leclercq, F-59000 Lille, France.
| | - Jocelyn Inamo
- Département de Cardiologie, CHU Martinique, Faculté de Médecine, Université des Antilles, F-97200 Fort de France, France.
| | - Eric Boulanger
- INSERM LIRIC U995/Team "Glycation: From Inflammation to Aging", Université Lille, F-59000 Lille, France.
| | - Sebastien Preau
- INSERM LIRIC U995/Team "Glycation: From Inflammation to Aging", Université Lille, F-59000 Lille, France.
- Pôle Réanimation Médicale, CHU Lille, Bd Pr Leclercq, F-59000 Lille, France.
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11
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Okatan EN, Durak AT, Turan B. Electrophysiological basis of metabolic-syndrome-induced cardiac dysfunction. Can J Physiol Pharmacol 2016; 94:1064-1073. [DOI: 10.1139/cjpp-2015-0531] [Citation(s) in RCA: 26] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/20/2022]
Abstract
Myocardial contractility is controlled by intracellular Ca2+ cycling with the contribution of sarcoplasmic reticulum (SR). In this study, we aimed to investigate the role of altered SR function in defective regulation of intracellular Ca2+ levels in rats with metabolic syndrome (MetS) induced by a 16-week high-sucrose drinking-water diet. Electric-field stimulated transient intracellular Ca2+ changes in MetS cardiomyocytes exhibited significantly reduced amplitude (∼30%) and prolonged time courses (2-fold), as well as depressed SR Ca2+ loading (∼55%) with increased basal Ca2+ level. Consistent with these data, altered ryanodine receptor (RyR2) function and SERCA2a activity were found in MetS cardiomyocytes through Ca2+ spark measurements and caffeine application assay in a state in which sodium calcium exchanger was inhibited. Furthermore, tetracaine application assay results and hyperphosphorylated level of RyR2 also support the “leaky RyR2” hypothesis. Moreover, altered phosphorylation levels of phospholamban (PLN) support the depressed SERCA2a-activity thesis and these alterations in the phosphorylation of Ca2+-handling proteins are correlated with altered protein kinase and phosphatase activity in MetS cardiomyocytes. In conclusion, MetS-rat heart exhibits altered Ca2+ signaling largely due to altered SR function via changes in RyR2 and SERCA2a activity. These results point to RyR2 and SERCA2a as potential pharmacological targets for restoring intracellular Ca2+ homeostasis and, thereby, combatting dysfunction in MetS-rat heart.
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Affiliation(s)
- Esma N. Okatan
- Department of Biophysics, Ankara University, Faculty of Medicine, 06100 Ankara, Turkey
- Department of Biophysics, Ankara University, Faculty of Medicine, 06100 Ankara, Turkey
| | - Aysegul Toy Durak
- Department of Biophysics, Ankara University, Faculty of Medicine, 06100 Ankara, Turkey
- Department of Biophysics, Ankara University, Faculty of Medicine, 06100 Ankara, Turkey
| | - Belma Turan
- Department of Biophysics, Ankara University, Faculty of Medicine, 06100 Ankara, Turkey
- Department of Biophysics, Ankara University, Faculty of Medicine, 06100 Ankara, Turkey
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12
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Marsh SA, Collins HE, Chatham JC. Protein O-GlcNAcylation and cardiovascular (patho)physiology. J Biol Chem 2014; 289:34449-56. [PMID: 25336635 DOI: 10.1074/jbc.r114.585984] [Citation(s) in RCA: 66] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/06/2022] Open
Abstract
Our understanding of the role of protein O-GlcNAcylation in the regulation of the cardiovascular system has increased rapidly in recent years. Studies have linked increased O-GlcNAc levels to glucose toxicity and diabetic complications; conversely, acute activation of O-GlcNAcylation has been shown to be cardioprotective. However, it is also increasingly evident that O-GlcNAc turnover plays a central role in the delicate regulation of the cardiovascular system. Therefore, the goals of this minireview are to summarize our current understanding of how changes in O-GlcNAcylation influence cardiovascular pathophysiology and to highlight the evidence that O-GlcNAc cycling is critical for normal function of the cardiovascular system.
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Affiliation(s)
- Susan A Marsh
- From the Section of Experimental and Systems Pharmacology, College of Pharmacy, Washington State University, Spokane, Washington 99210-1495 and
| | - Helen E Collins
- the Division of Molecular and Cellular Pathology, Department of Pathology, University of Alabama at Birmingham, Birmingham, Alabama 35294-0019
| | - John C Chatham
- the Division of Molecular and Cellular Pathology, Department of Pathology, University of Alabama at Birmingham, Birmingham, Alabama 35294-0019
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13
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Myslicki JP, Belke DD, Shearer J. Role of O-GlcNAcylation in nutritional sensing, insulin resistance and in mediating the benefits of exercise. Appl Physiol Nutr Metab 2014; 39:1205-13. [PMID: 25203141 DOI: 10.1139/apnm-2014-0122] [Citation(s) in RCA: 20] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/22/2022]
Abstract
The purpose of this review is to highlight the role of O-linked β-N-acetylglucosamine (O-GlcNAc) protein modification in metabolic disease states and to summarize current knowledge of how exercise affects this important post-translational signalling pathway. O-GlcNAc modification is an intracellular tool capable of integrating energy supply with demand. The accumulation of excess energy associated with obesity and insulin resistance is mediated, in part, by the hexosamine biosynthetic pathway (HBP), which results in the O-GlcNAcylation of a myriad of proteins, thereby affecting their respective function, stability, and localization. Insulin resistance is related to the excessive O-GlcNAcylation of key metabolic proteins causing a chronic blunting of insulin signalling pathways and precipitating the accompanying pathologies, such as heart and kidney disease. Lifestyle modifications such as diet and exercise also modify the pathway. Exercise is a front-line and cost-effective therapeutic approach for insulin resistance, and recent work shows that the intervention can alter O-GlcNAc gene expression, signalling, and protein modification. However, there is currently no consensus on the effect of frequency, intensity, type, and duration of exercise on O-GlcNAc modification, the HBP, and its related enzymes. On one end of the spectrum, mild, prolonged swim training reduces O-GlcNAcylation, while on the other end, higher intensity treadmill running increases cardiac protein O-GlcNAc modification. Clearly, a balance between acute and chronic stress of exercise is needed to reap the benefits of the intervention on O-GlcNAc signalling.
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Affiliation(s)
- Jason P Myslicki
- a Faculty of Kinesiology, University of Calgary, Calgary, AB T2N 1N4, Canada
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14
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Huynh K, Bernardo BC, McMullen JR, Ritchie RH. Diabetic cardiomyopathy: mechanisms and new treatment strategies targeting antioxidant signaling pathways. Pharmacol Ther 2014; 142:375-415. [PMID: 24462787 DOI: 10.1016/j.pharmthera.2014.01.003] [Citation(s) in RCA: 425] [Impact Index Per Article: 38.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/06/2014] [Accepted: 01/08/2014] [Indexed: 12/14/2022]
Abstract
Cardiovascular disease is the primary cause of morbidity and mortality among the diabetic population. Both experimental and clinical evidence suggest that diabetic subjects are predisposed to a distinct cardiomyopathy, independent of concomitant macro- and microvascular disorders. 'Diabetic cardiomyopathy' is characterized by early impairments in diastolic function, accompanied by the development of cardiomyocyte hypertrophy, myocardial fibrosis and cardiomyocyte apoptosis. The pathophysiology underlying diabetes-induced cardiac damage is complex and multifactorial, with elevated oxidative stress as a key contributor. We now review the current evidence of molecular disturbances present in the diabetic heart, and their role in the development of diabetes-induced impairments in myocardial function and structure. Our focus incorporates both the contribution of increased reactive oxygen species production and reduced antioxidant defenses to diabetic cardiomyopathy, together with modulation of protein signaling pathways and the emerging role of protein O-GlcNAcylation and miRNA dysregulation in the progression of diabetic heart disease. Lastly, we discuss both conventional and novel therapeutic approaches for the treatment of left ventricular dysfunction in diabetic patients, from inhibition of the renin-angiotensin-aldosterone-system, through recent evidence favoring supplementation of endogenous antioxidants for the treatment of diabetic cardiomyopathy. Novel therapeutic strategies, such as gene therapy targeting the phosphoinositide 3-kinase PI3K(p110α) signaling pathway, and miRNA dysregulation, are also reviewed. Targeting redox stress and protective protein signaling pathways may represent a future strategy for combating the ever-increasing incidence of heart failure in the diabetic population.
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Affiliation(s)
- Karina Huynh
- Baker IDI Heart & Diabetes Institute, Melbourne, Australia; Department of Medicine, Monash University, Clayton, Victoria, Australia
| | | | - Julie R McMullen
- Baker IDI Heart & Diabetes Institute, Melbourne, Australia; Department of Medicine, Monash University, Clayton, Victoria, Australia; Department of Physiology, Monash University, Clayton, Victoria, Australia.
| | - Rebecca H Ritchie
- Baker IDI Heart & Diabetes Institute, Melbourne, Australia; Department of Medicine, Monash University, Clayton, Victoria, Australia.
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15
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Balderas-Villalobos J, Molina-Muñoz T, Mailloux-Salinas P, Bravo G, Carvajal K, Gómez-Viquez NL. Oxidative stress in cardiomyocytes contributes to decreased SERCA2a activity in rats with metabolic syndrome. Am J Physiol Heart Circ Physiol 2013; 305:H1344-53. [PMID: 23997093 DOI: 10.1152/ajpheart.00211.2013] [Citation(s) in RCA: 68] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/01/2023]
Abstract
Ca(+) mishandling due to impaired activity of cardiac sarco(endo)plasmic reticulum Ca(2+) ATPase (SERCA2a) has been associated with the development of left ventricular diastolic dysfunction in insulin-resistant cardiomyopathy. However, the molecular causes underlying SERCA2a alterations induced by insulin resistance and related metabolic disorders, such as metabolic syndrome (MetS), are not completely understood. In this study, we used a sucrose-fed rat model of MetS to test the hypothesis that decreased SERCA2a activity is mediated by elevated oxidative stress produced in the MetS heart. Production of ROS and cytosolic Ca(2+) concentration were recorded in left ventricular myocytes using confocal imaging. The level of SERCA2a oxidation was determined in left ventricular homogenates by biotinylated iodoacetamide labeling. Compared with control rats, sucrose-fed rats exhibited several characteristics of MetS, including central obesity, insulin resistance, hyperinsulinemia, and hypertriglyceridemia. Moreover, relative to myocytes from control rats, myocytes from MetS rats exhibited elevated basal production of ROS accompanied by slowed cytosolic Ca(2+) removal, reflected by prolonged Ca(2+) transients. The slowed cytosolic Ca(2+) removal was associated with a significant decrease in SERCA2a-mediated Ca(2+) reuptake and increased SERCA2a oxidation. Importantly, myocytes from MetS rats treated with the antioxidant N-acetylcysteine showed normal ROS levels and SERCA2a-mediated Ca(2+) reuptake as well as accelerated cytosolic Ca(2+) removal. These data suggest that elevated oxidative stress may induce oxidative modifications on SERCA2a leading to abnormal function of this protein in the MetS heart.
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Affiliation(s)
- Jaime Balderas-Villalobos
- Departamento de Farmacobiología, Centro de Investigación y de Estudios Avanzados-Instituto Politécnico Nacional, Mexico City, Mexico; and
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16
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Younce CW, Burmeister MA, Ayala JE. Exendin-4 attenuates high glucose-induced cardiomyocyte apoptosis via inhibition of endoplasmic reticulum stress and activation of SERCA2a. Am J Physiol Cell Physiol 2013; 304:C508-18. [PMID: 23302777 DOI: 10.1152/ajpcell.00248.2012] [Citation(s) in RCA: 105] [Impact Index Per Article: 8.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/17/2022]
Abstract
Hyperglycemia-induced cardiomyocyte apoptosis contributes to diabetic cardiomyopathy. Glucagon-like peptide-1 (Glp1) receptor (Glp1r) agonists improve cardiac function and survival in response to ischemia-reperfusion and myocardial infarction. The present studies assessed whether Glp1r activation exerts direct cardioprotective effects in response to hyperglycemia. Treatment with the Glp1r agonist Exendin-4 attenuated apoptosis in neonatal rat ventricular cardiomyocytes cultured in high (33 mM) glucose. This protective effect was mimicked by the cAMP inducer forskolin. The Exendin-4 protective effect was blocked by the Glp1r antagonist Exendin(9-39) or the PKA antagonist H-89. Exendin-4 also protected cardiomyocytes from hydrogen peroxide (H2O2)-induced cell death. Cardiomyocyte protection by Exendin-4 was not due to reduced reactive oxygen species levels. Instead, Exendin-4 treatment reduced endoplasmic reticulum (ER) stress, demonstrated by decreased expression of glucose-regulated protein-78 (GRP78) and CCAT/enhancer-binding homologous protein (CHOP). Reduced ER stress was not due to activation of the unfolded protein response, indicating that Exendin-4 directly prevents ER stress. Exendin-4 treatment selectively protected cardiomyocytes from thapsigargin- but not tunicamycin-induced death. This suggests that Exendin-4 attenuates thapsigargin-mediated inhibition of the sarco/endoplasmic reticulum Ca(2+) ATPase-2a (SERCA2a). High glucose attenuates SERCA2a function by reducing SERCA2a mRNA and protein levels, but Exendin-4 treatment prevented this reduction. Exendin-4 treatment also enhanced phosphorylation of the SERCA2a regulator phospholamban (PLN), which would be expected to stimulate SERCA2a activity. In sum, Glp1r activation attenuates high glucose-induced cardiomyocyte apoptosis in association with decreased ER stress and markers of enhanced SERCA2a activity. These findings identify a novel mechanism whereby Glp1-based therapies could be used as treatments for diabetic cardiomyopathy.
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Affiliation(s)
- Craig W Younce
- Metabolic Signaling and Disease Program, Diabetes and Obesity Research Center, Sanford Burnham Medical Research Institute at Lake Nona, 6400 Sanger Rd., Orlando, FL 32837, USA
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17
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Lima VV, Giachini FRC, Carneiro FS, Carneiro ZN, Fortes ZB, Carvalho MHC, Webb RC, Tostes RC. Increased vascular O-GlcNAcylation augments reactivity to constrictor stimuli - VASOACTIVE PEPTIDE SYMPOSIUM. ACTA ACUST UNITED AC 2012; 2:410-7. [PMID: 19884969 DOI: 10.1016/j.jash.2008.06.001] [Citation(s) in RCA: 25] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/26/2023]
Abstract
BACKGROUND O-Linked N-acetylglucosaminylation (O-GlcNAcylation) plays a role in many aspects of protein function. Whereas elevated O-GlcNAc levels contribute to diabetes related end-organ damage, O-GlcNAcylation is also physiologically important. Because proteins that play a role in vascular tone regulation can be O-GlcNAcylated, we hypothesized that O-GlcNAcylation increases vascular reactivity to constrictor stimuli. METHODS AND RESULTS Aortas from male Sprague-Dawley rats and C57BL/6 mice were incubated for 24 h with vehicle or PugNAc (O-GlcNAcase inhibitor, 100muM). PugNAc incubation significantly increased O-GlcNAc-proteins, as determined by Western blot. PugNAc also increased vascular contractions to phenylephrine and serotonin, an effect not observed in the presence of L-NAME or in endothelium-denuded vessels. Acetylcholine-induced relaxation, but not that to sodium nitroprusside was decreased by PugNAc treatment, an effect accompanied by decreased levels of phosphorylated eNOS(Ser-1177) and Akt(Ser-473). CONCLUSION Augmented O-GlcNAcylation increases vascular reactivity to constrictor stimuli, possibly due to its effects on eNOS expression and activity, reinforcing the concept that O-GlcNAcylation modulates vascular reactivity and may play a role in pathological conditions associated with abnormal vascular function.
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Affiliation(s)
- Victor V Lima
- Department of Physiology, Medical College of Georgia, Augusta, GA, 30912-3000, USA
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18
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Post-translational protein modification by O-linked N-acetyl-glucosamine: its role in mediating the adverse effects of diabetes on the heart. Life Sci 2012; 92:621-7. [PMID: 22985933 DOI: 10.1016/j.lfs.2012.08.006] [Citation(s) in RCA: 59] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/05/2012] [Revised: 07/16/2012] [Accepted: 08/02/2012] [Indexed: 11/20/2022]
Abstract
The post-translation attachment of O-linked N-acetylglucosamine, or O-GlcNAc, to serine and threonine residues of nuclear and cytoplasmic proteins is increasingly recognized as a key regulator of diverse cellular processes. O-GlcNAc synthesis is essential for cell survival and it has been shown that acute activation of pathways, which increase cellular O-GlcNAc levels is cytoprotective; however, prolonged increases in O-GlcNAcylation have been implicated in a number of chronic diseases. Glucose metabolism via the hexosamine biosynthesis pathway plays a central role in regulating O-GlcNAc synthesis; consequently, sustained increases in O-GlcNAc levels have been implicated in glucose toxicity and insulin resistance. Studies on the role of O-GlcNAc in regulating cardiomyocyte function have grown rapidly over the past decade and there is growing evidence that increased O-GlcNAc levels contribute to the adverse effects of diabetes on the heart, including impaired contractility, calcium handling, and abnormal stress responses. Recent evidence also suggests that O-GlcNAc plays a role in epigenetic control of gene transcription. The goal of this review is to provide an overview of our current knowledge about the regulation of protein O-GlcNAcylation and to explore in more detail O-GlcNAc-mediated responses in the diabetic heart.
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19
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Mekahli D, Bultynck G, Parys JB, De Smedt H, Missiaen L. Endoplasmic-reticulum calcium depletion and disease. Cold Spring Harb Perspect Biol 2011; 3:a004317. [PMID: 21441595 PMCID: PMC3098671 DOI: 10.1101/cshperspect.a004317] [Citation(s) in RCA: 355] [Impact Index Per Article: 25.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
Abstract
The endoplasmic reticulum (ER) as an intracellular Ca(2+) store not only sets up cytosolic Ca(2+) signals, but, among other functions, also assembles and folds newly synthesized proteins. Alterations in ER homeostasis, including severe Ca(2+) depletion, are an upstream event in the pathophysiology of many diseases. On the one hand, insufficient release of activator Ca(2+) may no longer sustain essential cell functions. On the other hand, loss of luminal Ca(2+) causes ER stress and activates an unfolded protein response, which, depending on the duration and severity of the stress, can reestablish normal ER function or lead to cell death. We will review these various diseases by mainly focusing on the mechanisms that cause ER Ca(2+) depletion.
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Affiliation(s)
- Djalila Mekahli
- Laboratory of Molecular and Cellular Signaling, Department of Molecular Cell Biology, KU Leuven Campus Gasthuisberg O&N I, Belgium
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20
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Lima VV, Giachini FR, Hardy DM, Webb RC, Tostes RC. O-GlcNAcylation: a novel pathway contributing to the effects of endothelin in the vasculature. Am J Physiol Regul Integr Comp Physiol 2010; 300:R236-50. [PMID: 21068200 DOI: 10.1152/ajpregu.00230.2010] [Citation(s) in RCA: 33] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/24/2023]
Abstract
Glycosylation with O-linked β-N-acetylglucosamine (O-GlcNAc) or O-GlcNAcylation on serine and threonine residues of nuclear and cytoplasmic proteins is a posttranslational modification that alters the function of numerous proteins important in vascular function, including kinases, phosphatases, transcription factors, and cytoskeletal proteins. O-GlcNAcylation is an innovative way to think about vascular signaling events both in physiological conditions and in disease states. This posttranslational modification interferes with vascular processes, mainly vascular reactivity, in conditions where endothelin-1 (ET-1) levels are augmented (e.g. salt-sensitive hypertension, ischemia/reperfusion, and stroke). ET-1 plays a crucial role in the vascular function of most organ systems, both in physiological and pathophysiological conditions. Recognition of ET-1 by the ET(A) and ET(B) receptors activates intracellular signaling pathways and cascades that result in rapid and long-term alterations in vascular activity and function. Components of these ET-1-activated signaling pathways (e.g., mitogen-activated protein kinases, protein kinase C, RhoA/Rho kinase) are also targets for O-GlcNAcylation. Recent experimental evidence suggests that ET-1 directly activates O-GlcNAcylation, and this posttranslational modification mediates important vascular effects of the peptide. This review focuses on ET-1-activated signaling pathways that can be modified by O-GlcNAcylation. A brief description of the O-GlcNAcylation biology is presented, and its role on vascular function is addressed. ET-1-induced O-GlcNAcylation and its implications for vascular function are then discussed. Finally, the interplay between O-GlcNAcylation and O-phosphorylation is addressed.
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Affiliation(s)
- Victor V Lima
- Department of Physiology, Medical College of Georgia, Augusta, Georgia, USA
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21
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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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22
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Yokoe S, Asahi M, Takeda T, Otsu K, Taniguchi N, Miyoshi E, Suzuki K. Inhibition of phospholamban phosphorylation by O-GlcNAcylation: implications for diabetic cardiomyopathy. Glycobiology 2010; 20:1217-26. [PMID: 20484118 DOI: 10.1093/glycob/cwq071] [Citation(s) in RCA: 70] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/13/2022] Open
Abstract
Cardiac-type sarco(endo)plasmic reticulum Ca(2)-ATPase (SERCA2a) plays a major role in cardiac muscle contractility. Phospholamban (PLN) regulates the function of SERCA2a via its Ser(16)-phosphorylation. Since it has been proposed that the Ser/Thr residues on cytoplasmic and nuclear proteins are modified by O-linked N-acetylglucosamine (O-GlcNAc), we examined the effect of O-GlcNAcylation on PLN function in rat adult cardiomyocytes. Studies using enzymatic labeling and co-immunoprecipitation of wild type and a series of mutants of PLN showed that PLN was O-GlcNAcylated and Ser(16) of PLN might be the site for O-GlcNAcylation. In cardiomyocytes treated with O-(2-acetamido-2-deoxy-D-glucopyranosylidene)amino-N-phenylcarbamate (PUGNAc), the O-GlcNAcylation was significantly increased compared to non-treated cells. Simultaneously, Ser(16)-phosphorylation of PLN was reduced. In Chinese hamster ovary cells where PLN cDNA and O-GlcNAc transferase siRNA were co-transfected, the Ser(16)-phosphorylation of PLN was significantly increased compared to controls. The same results were observed in heart homogenates from diabetic rats. In a co-immunoprecipitation of PLN with SERCA2a, the physical interaction between the two proteins was increased in PUGNAc-treated cardiomyocytes. Unlike non-treated cells, the activity of SERCA2a and the profiles of calcium transients in PUGNAc-treated cardiomyocytes were not significantly changed even after treatment with catecholamine. These data suggest that PLN is O-GlcNAcylated to induce the inhibition of its phosphorylation, which correlates to the deterioration of cardiac function. This might define a novel mechanism by which PLN regulation of SERCA2a is altered under conditions where O-GlcNAcylation is increased, such as those occurring in diabetes.
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Affiliation(s)
- Shunichi Yokoe
- Department of Biochemistry, Hyogo College of Medicine, 1-1 Mukogawa-cho, Nishinomiya, Hyogo, Japan
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23
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Takeda N. Cardiac disturbances in diabetes mellitus. PATHOPHYSIOLOGY 2010; 17:83-8. [DOI: 10.1016/j.pathophys.2009.03.012] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/29/2008] [Revised: 01/20/2009] [Accepted: 03/20/2009] [Indexed: 10/20/2022] Open
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24
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Gao YD, Zou JJ, Zheng JW, Shang M, Chen X, Geng S, Yang J. Promoting effects of IL-13 on Ca2+ release and store-operated Ca2+ entry in airway smooth muscle cells. Pulm Pharmacol Ther 2010; 23:182-9. [PMID: 20045483 DOI: 10.1016/j.pupt.2009.12.005] [Citation(s) in RCA: 39] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/18/2009] [Revised: 12/10/2009] [Accepted: 12/22/2009] [Indexed: 10/20/2022]
Abstract
Th2 cytokine interleukin (IL)-13 plays a central role in the pathogenesis of allergic asthma. IL-13 exhibits a direct effect on airway smooth muscle cells (ASMCs) to cause airway hyperresponsiveness. IL-13 has been demonstrated to regulate Ca(2+) signaling in ASMCs, but the underlying mechanisms are not fully understood. Store-operated Ca(2+) entry (SOCE) plays an important role in regulating Ca(2+) signaling and cellular responses of ASMCs, whether IL-13 affects SOCE in ASMCs has not been reported. In this study, by using confocal Ca(2+) fluorescence imaging, we found that IL-13 (10 ng/ml) treatment increased basal intracellular Ca(2+) ([Ca(2+)](i)) level, Ca(2+) release and SOCE induced by SERCA inhibitor thapsigargin in rat bronchial smooth muscle cells. The glucocorticoid dexamethasone and the short-acting beta2 adrenergic agonist (beta2 agonist) salbutamol suppressed IL-13-augumented basal [Ca(2+)](i), Ca(2+) release and SOCE, whereas the long-acting beta2 agonist salmeterol had no effect on altered Ca(2+) signaling in IL-13-treated ASMCs. Membrane-permeable cAMP analog dibutyryl-cAMP (db-cAMP) similarly decreased Ca(2+) release and SOCE induced by thapsigargin in IL-13-treated ASMCs, confirmed a role of cAMP/PKA signaling pathway in the regulation of SOCE. IL-13 promoted the proliferation of ASMCs stimulated by serum; this effect was inhibited by nonspecific Ca(2+) channel blockers SKF-96365 and NiCl(2), by salmeterol, but not by salbutamol and dexamethasone. IL-13 treatment did not change the expression of SOC channel-associated molecules STIM1, Orai1 and TRPC1 at mRNA level. Our findings identified a promoting effect of IL-13 on Ca(2+) release and SOCE in ASMCs, which partially contributes to its effect on the proliferation of ASMCs; the differences of glucocorticoids and beta2 agonists in inhibiting Ca(2+) signal and proliferation potentiated by IL-13 suggest that these therapies of asthma may have distinct effect on the relief of airway contraction and remodeling in bronchial asthma.
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Affiliation(s)
- Ya-dong Gao
- Department of Respiratory Medicine, Zhongnan Hospital, Wuhan University, Wuhan 430071, PR China
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25
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Karakikes I, Kim M, Hadri L, Sakata S, Sun Y, Zhang W, Chemaly ER, Hajjar RJ, Lebeche D. Gene remodeling in type 2 diabetic cardiomyopathy and its phenotypic rescue with SERCA2a. PLoS One 2009; 4:e6474. [PMID: 19649297 PMCID: PMC2714457 DOI: 10.1371/journal.pone.0006474] [Citation(s) in RCA: 29] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/19/2008] [Accepted: 07/03/2009] [Indexed: 12/31/2022] Open
Abstract
Background/Aim Diabetes-associated myocardial dysfunction results in altered gene expression in the heart. We aimed to investigate the changes in gene expression profiles accompanying diabetes-induced cardiomyopathy and its phenotypic rescue by restoration of SERCA2a expression. Methods/Results Using the Otsuka Long-Evans Tokushima Fatty rat model of type 2 diabetes and the Agilent rat microarray chip, we analyzed gene expression by comparing differential transcriptional changes in age-matched control versus diabetic hearts and diabetic hearts that received gene transfer of SERCA2a. Microarray expression profiles of selected genes were verified with real-time qPCR and immunoblotting. Our analysis indicates that diabetic cardiomyopathy is associated with a downregulation of transcripts. Diabetic cardiomyopathic hearts have reduced levels of SERCA2a. SERCA2a gene transfer in these hearts reduced diabetes-associated hypertrophy, and differentially modulated the expression of 76 genes and reversed the transcriptional profile induced by diabetes. In isolated cardiomyocytes in vitro, SERCA2a overexpression significantly modified the expression of a number of transcripts known to be involved in insulin signaling, glucose metabolism and cardiac remodeling. Conclusion This investigation provided insight into the pathophysiology of cardiac remodeling and the potential role of SERCA2a normalization in multiple pathways in diabetic cardiomyopathy.
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Affiliation(s)
- Ioannis Karakikes
- Cardiovascular Research Center, Mount Sinai School of Medicine, New York, New York, United States of America
| | - Maengjo Kim
- Cardiovascular Research Center, Mount Sinai School of Medicine, New York, New York, United States of America
| | - Lahouaria Hadri
- Cardiovascular Research Center, Mount Sinai School of Medicine, New York, New York, United States of America
| | - Susumu Sakata
- Department of Physiology II, Nara Medical University, Kashihara, Nara, Japan
| | - Yezhou Sun
- Bioinformatics Laboratory of Personalized Medicine Research Program, Mount Sinai School of Medicine, New York, New York, United States of America
| | - Weijia Zhang
- Bioinformatics Laboratory of Personalized Medicine Research Program, Mount Sinai School of Medicine, New York, New York, United States of America
| | - Elie R. Chemaly
- Cardiovascular Research Center, Mount Sinai School of Medicine, New York, New York, United States of America
| | - Roger J. Hajjar
- Cardiovascular Research Center, Mount Sinai School of Medicine, New York, New York, United States of America
| | - Djamel Lebeche
- Cardiovascular Research Center, Mount Sinai School of Medicine, New York, New York, United States of America
- * E-mail:
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26
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Laczy B, Hill BG, Wang K, Paterson AJ, White CR, Xing D, Chen YF, Darley-Usmar V, Oparil S, Chatham JC. Protein O-GlcNAcylation: a new signaling paradigm for the cardiovascular system. Am J Physiol Heart Circ Physiol 2009; 296:H13-28. [PMID: 19028792 PMCID: PMC2637779 DOI: 10.1152/ajpheart.01056.2008] [Citation(s) in RCA: 120] [Impact Index Per Article: 7.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/02/2008] [Accepted: 11/11/2008] [Indexed: 02/07/2023]
Abstract
The posttranslational modification of serine and threonine residues of nuclear and cytoplasmic proteins by the O-linked attachment of the monosaccharide beta-N-acetylglucosamine (O-GlcNAc) is a highly dynamic and ubiquitous protein modification. Protein O-GlcNAcylation is rapidly emerging as a key regulator of critical biological processes including nuclear transport, translation and transcription, signal transduction, cytoskeletal reorganization, proteasomal degradation, and apoptosis. Increased levels of O-GlcNAc have been implicated as a pathogenic contributor to glucose toxicity and insulin resistance, which are both major hallmarks of diabetes mellitus and diabetes-related cardiovascular complications. Conversely, there is a growing body of data demonstrating that the acute activation of O-GlcNAc levels is an endogenous stress response designed to enhance cell survival. Reports on the effect of altered O-GlcNAc levels on the heart and cardiovascular system have been growing rapidly over the past few years and have implicated a role for O-GlcNAc in contributing to the adverse effects of diabetes on cardiovascular function as well as mediating the response to ischemic injury. Here, we summarize our present understanding of protein O-GlcNAcylation and its effect on the regulation of cardiovascular function. We examine the pathways regulating protein O-GlcNAcylation and discuss, in more detail, our understanding of the role of O-GlcNAc in both mediating the adverse effects of diabetes as well as its role in mediating cellular protective mechanisms in the cardiovascular system. In addition, we also explore the parallels between O-GlcNAc signaling and redox signaling, as an alternative paradigm for understanding the role of O-GlcNAcylation in regulating cell function.
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Affiliation(s)
- Boglarka Laczy
- Division of Cardiovascular Disease, Department of Medicine, University of Alabama at Birmingham, Birmingham, Alabama 35294-0007, USA
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Lebeche D, Davidoff AJ, Hajjar RJ. Interplay between impaired calcium regulation and insulin signaling abnormalities in diabetic cardiomyopathy. ACTA ACUST UNITED AC 2008; 5:715-24. [PMID: 18813212 DOI: 10.1038/ncpcardio1347] [Citation(s) in RCA: 90] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/30/2008] [Accepted: 07/30/2008] [Indexed: 02/06/2023]
Abstract
According to the International Diabetes Federation the number of people between the ages of 20 and 79 years diagnosed with diabetes mellitus is projected to reach 380 million worldwide by 2025. Cardiovascular disease, including heart failure, is the major cause of death in patients with diabetes. A contributing factor to heart failure in such patients is the development of diabetic cardiomyopathy--a clinical myocardial condition distinguished by ventricular dysfunction that can present independently of other risk factors such as hypertension or coronary artery disease. This disorder has been associated with both type 1 and type 2 diabetes, and is characterized by early-onset diastolic dysfunction and late-onset systolic dysfunction. The development of diabetic cardiomyopathy and the cellular and molecular perturbations associated with the pathology are complex and multifactorial. Hallmark mechanisms include abnormalities in regulation of calcium homeostasis, and associated abnormal ventricular excitation-contraction coupling, metabolic disturbances, and alterations in insulin signaling. An emerging concept is that disruptions in calcium homeostasis might be linked to diminished insulin responsiveness. An understanding of the cellular effect of these abnormalities on cardiomyocytes should be useful in predicting the maladaptive cardiac structural and functional consequences of diabetes.
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Affiliation(s)
- Djamel Lebeche
- Cardiovascular Research Center, Mount Sinai School of Medicine, New York, NY 10029, USA.
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28
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Trichosanthin suppresses HeLa cell proliferation through inhibition of the PKC/MAPK signaling pathway. Cell Biol Toxicol 2008; 25:479-88. [PMID: 18751959 DOI: 10.1007/s10565-008-9102-x] [Citation(s) in RCA: 30] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/12/2008] [Accepted: 08/01/2008] [Indexed: 10/21/2022]
Abstract
Trichosanthin (TCS) possesses a broad spectrum of biological and pharmacological activities, including anti-tumor activities. Our previous studies have shown that TCS inhibits HeLa cell proliferation by activating the apoptotic pathway. In particular, the transcriptional factor cAMP response element binding (CREB) protein plays a pivotal role in apoptotic HeLa cells. However, no information, to date, is available about the signaling pathways involved in the inhibition of cell proliferation induced by TCS. The present study showed that PKA and PKC activities were significantly inhibited by TCS treatment. However, specific inhibitor of PKA activity failed to affect the inhibition of HeLa cell proliferation induced by TCS, even in the presence of cAMP agonists. In contrast, PKC activator/inhibitor significantly attenuated/enhanced the inhibitory effect of TCS on cell proliferation. In particular, the reversed effect of cAMP agonist on cell proliferation was partly prevented by PKC, ERK1/2, and p38 MAPK blockade. Consistent with these results, the reversed effect of cAMP agonists on CREB phosphorylation was significantly decreased by inhibitors of these kinases, but not PKA inhibitor. Therefore, our results suggested that HeLa cell proliferation was inhibited by TCS via suppression of PKC/MAPK signaling pathway.
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Fülöp N, Mason MM, Dutta K, Wang P, Davidoff AJ, Marchase RB, Chatham JC. Impact of Type 2 diabetes and aging on cardiomyocyte function and O-linked N-acetylglucosamine levels in the heart. Am J Physiol Cell Physiol 2006; 292:C1370-8. [PMID: 17135297 DOI: 10.1152/ajpcell.00422.2006] [Citation(s) in RCA: 108] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/22/2022]
Abstract
Increased levels of O-linked attachment of N-acetylglucosamine (O-GlcNAc) on nucleocytoplasmic proteins are implicated in the development of diabetic cardiomyopathy and are regulated by O-GlcNAc transferase (OGT) expression and its substrate UDP-GlcNAc. Therefore, the goal of this study was to determine whether the development of diabetes in the Zucker diabetic fatty (ZDF) rat, a model of Type 2 diabetes, results in defects in cardiomyocyte mechanical function and, if so, whether this is associated with increased levels of O-GlcNAc and increased OGT expression. Six-week-old ZDF rats were hyperinsulinemic but normoglycemic, and there were no differences in cardiomyocyte mechanical function, UDP-GlcNAc, O-GlcNAc, or OGT compared with age-matched lean control rats. Cardiomyocytes isolated from 22-wk-old hyperglycemic ZDF rats exhibited significantly impaired relaxation, compared with both age-matched lean control and 6-wk-old ZDF groups. There was also a significant increase in O-GlcNAc levels in high-molecular-mass proteins in the 22-wk-old ZDF group compared with age-matched lean control and 6-wk-old ZDF groups; this was associated with increased UDP-GlcNAc levels but not increased OGT expression. Surprisingly, there was a significant decrease in overall O-GlcNAc levels between 6 and 22 wk of age in lean, ZDF, and Sprague-Dawley rats that was associated with decreased OGT expression. These results support the notion that an increase in O-GlcNAc on specific proteins may contribute to impaired cardiomyocyte function in diabetes. However, this study also indicates that in the heart the level of O-GlcNAc on proteins appears to be differentially regulated by age and diabetes.
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Affiliation(s)
- Norbert Fülöp
- Division of Cardiovascular Disease, Department of Medicine, University of Alabama at Birmingham, Birmingham, Alabama 35294, USA
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30
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Vasanji Z, Cantor EJF, Juric D, Moyen M, Netticadan T. Alterations in cardiac contractile performance and sarcoplasmic reticulum function in sucrose-fed rats is associated with insulin resistance. Am J Physiol Cell Physiol 2006; 291:C772-80. [PMID: 16973823 DOI: 10.1152/ajpcell.00086.2005] [Citation(s) in RCA: 56] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/01/2023]
Abstract
Diabetes mellitus (DM) causes the development of a specific cardiomyopathy that results from the metabolic derangements present in DM and manifests as cardiac contractile dysfunction. Although myocardial dysfunction in Type 1 DM has been associated with defects in the function and regulation of the sarcoplasmic reticulum (SR), very little is known about SR function in Type 2 DM. Accordingly, this study examined whether abnormalities in cardiac contractile performance and SR function occur in the prestage of Type 2 DM (i.e., during insulin resistance). Sucrose feeding was used to induce whole body insulin resistance, whereas cardiac contractile performance was assessed by echocardiography and SR function was measured by SR calcium (Ca2+) uptake. Sucrose-fed rats exhibited hyperinsulinemia, hyperglycemia, and hyperlipidemia relative to control rats. Serial echocardiographic assessments in the sucrose-fed rats revealed early abnormalities in diastolic function followed by late systolic dysfunction and concurrent alterations in myocardial structure. The hearts of the 10-wk sucrose-fed rats showed depressed SR function demonstrated by a significant reduction in SR Ca2+uptake. The decline in SR Ca2+uptake was associated with a significant decrease in the cAMP-dependent protein kinase and Ca2+/calmodulin-dependent protein kinase II-mediated phosphorylation of phospholamban. The results show that abnormalities in cardiac contractile performance and SR function occur at an insulin-resistant stage before the manifestation of overt Type 2 DM.
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Affiliation(s)
- Zainisha Vasanji
- Institute of Cardiovascular Sciences, St. Boniface General Hospital Research Centre, Winnipeg, Manitoba, Canada
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31
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Fülöp N, Marchase RB, Chatham JC. Role of protein O-linked N-acetyl-glucosamine in mediating cell function and survival in the cardiovascular system. Cardiovasc Res 2006; 73:288-97. [PMID: 16970929 PMCID: PMC2848961 DOI: 10.1016/j.cardiores.2006.07.018] [Citation(s) in RCA: 128] [Impact Index Per Article: 6.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/27/2006] [Revised: 07/14/2006] [Accepted: 07/18/2006] [Indexed: 10/24/2022] Open
Abstract
There is growing recognition that the O-linked attachment of N-acetyl-glucosamine (O-GlcNAc) on serine and threonine residues of nuclear and cytoplasmic proteins is a highly dynamic post-translational modification that plays a key role in signal transduction pathways. Numerous proteins have been identified as targets of O-GlcNAc modifications including kinases, phosphatases, transcription factors, metabolic enzymes, chaperons, and cytoskeletal proteins. Modulation of O-GlcNAc levels has been shown to modify DNA binding, enzyme activity, protein-protein interactions, the half-life of proteins, and subcellular localization. The level of O-GlcNAc is regulated in part by the metabolism of glucose via the hexosamine biosynthesis pathway (HBP), and the metabolic abnormalities associated with insulin resistance and diabetes, such as hyperglycemia, hyperlipidemia, and hyperinsulinemia, are all associated with increased flux through the HBP and elevated O-GlcNAc levels. Increased HBP flux and O-GlcNAc levels have been implicated in the impaired relaxation of isolated cardiomyocytes, blunted response to angiotensin II and phenylephrine, hyperglycemia-induced cardiomyocyte apoptosis, and endothelial and vascular cell dysfunction. In contrast to these adverse effects, recent studies have also shown that O-GlcNAc levels increase in response to acute stress and that this is associated with increased cell survival. Thus, while the relationship between O-GlcNAc levels and cellular function is complex and not well-understood, it is clear that these pathways play a critical role in the regulation of cell function and survival in the cardiovascular system and may be implicated in the adverse effects of metabolic disease on the heart.
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Affiliation(s)
- Norbert Fülöp
- Department of Medicine, Division of Cardiovascular Disease, University of Alabama at Birmingham, Birmingham, Alabama
| | - Richard B. Marchase
- Department of Cell Biology, University of Alabama at Birmingham, Birmingham, Alabama
- Corresponding Author: John C. Chatham, University of Alabama at Birmingham, Department of Medicine, 1530 3 Avenue South, MCLM 684, Birmingham, AL 35294-0005. Telephone: (205) 934-0240;Fax: (205) 934-0950;
| | - John C. Chatham
- Department of Medicine, Division of Cardiovascular Disease, University of Alabama at Birmingham, Birmingham, Alabama
- Department of Cell Biology, University of Alabama at Birmingham, Birmingham, Alabama
- Corresponding Author: John C. Chatham, University of Alabama at Birmingham, Department of Medicine, 1530 3 Avenue South, MCLM 684, Birmingham, AL 35294-0005. Telephone: (205) 934-0240;Fax: (205) 934-0950;
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Schwanke ML, Dutta K, Podolin DA, Davidoff AJ. Cardiomyocyte dysfunction in insulin-resistant rats: a female advantage. Diabetologia 2006; 49:1097-105. [PMID: 16541279 DOI: 10.1007/s00125-006-0184-9] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/23/2005] [Accepted: 12/21/2005] [Indexed: 10/24/2022]
Abstract
AIMS/HYPOTHESIS The goal of this investigation was to determine whether there are sex-related differences in the development of cardiomyocyte dysfunction in prediabetic, insulin-resistant animals. MATERIALS AND METHODS Male and female rats were maintained on a high-sucrose diet for 5-11 weeks, and mechanical properties of isolated ventricular myocytes were measured by high-speed video edge detection. Several in vitro interventions were used to manipulate intracellular Ca(2+) in order to determine whether altered Ca(2+) availability contributes to the cardiomyocyte dysfunction. RESULTS Myocyte shortening and relengthening were significantly slower in sucrose-fed (insulin-resistant) males than in starch-fed (normal) male rats, whereas only relengthening was slower in sucrose-fed females when compared with normal females. Areas under the contraction and relaxation phases for sucrose-fed males were also significantly larger than in diet-matched females, and the slowed cardiomyocyte mechanics appeared earlier in males (7 vs 10 weeks). Prolonged relaxation was ameliorated in myocytes from sucrose-fed female rats by all interventions (i.e. 10(-8) mol/l isoprenaline, elevated extracellular Ca(2+), and higher rates of stimulation). Twice as much extracellular Ca(2+) (4 mmol/l) was required to restore normal time courses of contraction and relaxation in sucrose-fed males than in females, and mechanical responses to higher frequency stimulation remained impaired (slower) in some myocytes from sucrose-fed male rats. CONCLUSIONS/INTERPRETATION These data suggest that in myocytes from insulin-resistant rats altered Ca(2+) handling occurs, contributing to abnormal excitation-contraction coupling; female rats seem to have some cardioprotection during early stages in the progression towards type 2 diabetes. Females show delayed onset and milder abnormalities in metabolic status and cardiomyocyte function, but with a much tighter temporal coupling of these dysfunctions.
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Affiliation(s)
- M L Schwanke
- College of Arts and Sciences, University of Maine at Farmington, Farmington, ME, USA
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33
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Davidoff AJ. CONVERGENCE OF GLUCOSE- AND FATTY ACID-INDUCED ABNORMAL MYOCARDIAL EXCITATION-CONTRACTION COUPLING AND INSULIN SIGNALLING. Clin Exp Pharmacol Physiol 2006; 33:152-8. [PMID: 16445715 DOI: 10.1111/j.1440-1681.2006.04343.x] [Citation(s) in RCA: 16] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/30/2022]
Abstract
1. Myocardial insulin resistance and abnormal Ca(2+) regulation are hallmarks of hypertrophic and diabetic hearts, but deprivation of energetic substrates does not tell the whole story. Is there a link between the aetiology of these dysfunctions? 2. Diabetic cardiomyopathy is defined as phenotypic changes in the heart muscle cell independent of associated coronary vascular disease. The cellular consequences of diabetes on excitation-contraction (E-C) coupling and insulin signalling are presented in various models of diabetes in order to set the stage for exploring the pathogenesis of heart disease. 3. Excess glucose or fatty acids can lead to augmented flux through the hexosamine biosynthesis pathway (HBP). The formation of uridine 5 cent-diphosphate-hexosamines has been shown to be involved in abnormal E-C coupling and myocardial insulin resistance. 4. There is growing evidence that O-linked glycosylation (downstream of HBP) may regulate the function of cytosolic and nuclear proteins in a dynamic manner, similar to phosphorylation and perhaps involving reciprocal or synergistic modification of serine/threonine sites. 5. This review focuses on the question of whether there is a role for HBP and dynamic O-linked glycosylation in the development of myocardial insulin resistance and abnormal E-C coupling. The emerging concept that O-linked glycosylation is a regulatory, post-translational modification of cytosolic/nuclear proteins that interacts with phosphorylation in the heart is explored.
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Affiliation(s)
- Amy J Davidoff
- Department of Pharmacology, College of Osteopathic Medicine, University of New England, Biddeford, ME, USA.
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Ouwens DM, Boer C, Fodor M, de Galan P, Heine RJ, Maassen JA, Diamant M. Cardiac dysfunction induced by high-fat diet is associated with altered myocardial insulin signalling in rats. Diabetologia 2005; 48:1229-37. [PMID: 15864533 DOI: 10.1007/s00125-005-1755-x] [Citation(s) in RCA: 172] [Impact Index Per Article: 8.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/27/2004] [Accepted: 02/03/2005] [Indexed: 10/25/2022]
Abstract
AIMS/HYPOTHESIS Diabetic cardiomyopathy (DCM) is common in type 2 diabetes. In DCM, insulin resistance may alter cardiac substrate supply and utilisation leading to changes in myocardial metabolism and cardiac function. In rats, exposure to excessive alimentary fat, inducing a type 2 diabetic phenotype, may result in myocardial insulin resistance and cardiac functional changes resembling DCM. MATERIALS AND METHODS Rats received high-fat (HFD) or low-fat (LFD) diets for 7 weeks. Prior to killing, insulin or saline was injected i.p. Contractile function and insulin signalling were assessed in papillary muscles and ventricular lysates, respectively. RESULTS Fasting and post-load blood glucose levels were increased in HFD- vs LFD-rats (all p < 0.02). Mean heart weight, but not body weight, was increased in HFD-rats (p < 0.01). HFD-hearts showed structural changes and triglyceride accumulation. HFD-muscles developed higher baseline and maximum forces, but showed impaired recovery from higher workloads. Insulin-associated modulation of Ca2+-induced force augmentation was abolished in HFD-muscles. HFD reduced insulin-stimulated IRS1-associated phosphatidylinositol 3'-kinase activity and phosphorylation of protein kinase B, glycogen synthase kinase-3beta, endothelial nitric oxide synthase, and forkhead transcription factors by 40-60% (all p < 0.05). Insulin-mediated phosphorylation of phospholamban, a critical regulator of myocardial contractility, was decreased in HFD-hearts (p < 0.05). CONCLUSIONS/INTERPRETATION HFD induced a hypertrophy-like cardiac phenotype, characterised by a higher basal contractile force, an impaired recovery from increased workloads and decreased insulin-mediated protection against Ca2+ overload. Cardiac dysfunction was associated with myocardial insulin resistance and phospholamban hypophosphorylation. Our data suggest that myocardial insulin resistance, resulting from exposure to excessive alimentary fat, may contribute to the pathogenesis of diabetes-related heart disease.
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Affiliation(s)
- D M Ouwens
- Department of Molecular Cell Biology, Leiden University Medical Centre, Wassenaarseweg 72, 2333 AL, Leiden, The Netherlands,
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35
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Broderick TL, Poirier P, Gillis M. Exercise training restores abnormal myocardial glucose utilization and cardiac function in diabetes. Diabetes Metab Res Rev 2005; 21:44-50. [PMID: 15386820 DOI: 10.1002/dmrr.479] [Citation(s) in RCA: 49] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/06/2022]
Abstract
BACKGROUND Clinical and experimental studies have shown that a reduction in myocardial glucose utilization is a factor contributing to diabetic cardiomyopathy. This study determined whether exercise training could prevent the depression in glucose utilization observed in the diabetic rat heart. METHODS Diabetes was induced in Sprague-Dawley rats by an intravenous injection of streptozotocin (60 mg/kg). After 10 weeks of treadmill running, exogenous myocardial glucose utilization and cardiac function were determined in isolated working hearts perfused under aerobic conditions and then subjected to a 60-min period of low-flow ischemia followed by reperfusion. RESULTS Compared to aerobically perfused sedentary control hearts, rates of myocardial glucose oxidation and glycolysis were lower in diabetic hearts. Diabetes was also characterized by a pronounced decrease in cardiac function. Following exercise training, rates of myocardial glucose oxidation and glycolysis were restored and cardiac performance was improved compared to sedentary diabetic hearts. During low-flow ischemia, the decrease in glycolysis observed in hearts of sedentary diabetic rats was attenuated following exercise training. Following ischemia, glucose oxidation and glycolysis returned to preischemic levels in all groups. However, hearts from trained diabetic animals had higher rates of glucose oxidation compared to their respective sedentary group. This was accompanied by an enhanced recovery of heart function following ischemia. CONCLUSIONS Our results indicate that exercise training is effective in preventing the depression in myocardial glucose metabolism observed in the diabetic rat. This may explain the benefits of exercise in preventing cardiac dysfunction in diabetes.
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Affiliation(s)
- Tom L Broderick
- Department of Physiology, Midwestern University, 19555 59th Avenue, Glendale, AZ 85308, USA.
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Pastukh V, Wu S, Ricci C, Mozaffari M, Schaffer S. Reversal of hyperglycemic preconditioning by angiotensin II: role of calcium transport. Am J Physiol Heart Circ Physiol 2004; 288:H1965-75. [PMID: 15604129 DOI: 10.1152/ajpheart.00855.2004] [Citation(s) in RCA: 12] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/21/2022]
Abstract
Myocardial cell death is an important contributor to the development of diabetic cardiomyopathy. It has been proposed that diabetes-mediated upregulation of the renin-angiotensin system leads to oxidative stress, the trigger for cardiomyocyte death and contractile dysfunction. However, the adverse effect of ANG II on the diabetic heart may extend beyond the development of the cardiomyopathy. ANG II also alters specific modulators of ischemic injury, such as PKC and calcium transport. Therefore, the present study examined the effect of ANG II on hyperglycemic preconditioning, a glucose-mediated condition associated with the elevation of PKC activity and alterations in calcium transport that render the cell resistant to hypoxia. Exposure of the glucose-treated cell to ANG II during the prehypoxic period blocked glucose-mediated cardioprotection. The reversal of hyperglycemic preconditioning was associated with enhanced accumulation of Ca(2+) during hypoxia, an effect prevented by inhibition of the Na(+)/ H(+) exchanger and the T-type Ca(2+) channel. The inhibitors of hypoxia-mediated Ca(2+) accumulation also blocked the reversal of hyperglycemic preconditioning by ANG II. Thus ANG II and glucose treatment exert opposite actions on the Na(+)/ H(+) exchanger and the T-type Ca(2+) channel. Because those transporters are involved in hypoxia-mediated apoptosis, they are logical candidates for the beneficial effects of high glucose and the adverse effects of ANG II on the hypoxic cardiomyocyte.
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Affiliation(s)
- Viktor Pastukh
- Dept. of Pharmacology, University of South Alabama College of Medicine, Mobile, AL 36688, USA
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37
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Belke DD, Swanson EA, Dillmann WH. Decreased sarcoplasmic reticulum activity and contractility in diabetic db/db mouse heart. Diabetes 2004; 53:3201-8. [PMID: 15561951 DOI: 10.2337/diabetes.53.12.3201] [Citation(s) in RCA: 199] [Impact Index Per Article: 9.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/11/2023]
Abstract
Although it is known that insulin-dependent (type 1) diabetes results in depressed contractile performance associated with diminished sarcoendoplasmic reticular Ca2+-ATPase (SERCA2a) activity, findings in insulin-resistant (type 2) diabetes suggest a less clear association. The db/db insulin-resistant mouse model exhibits decreased cardiac performance both in situ and in isolated ex vivo working hearts. In this study, contractile performance and calcium transients were measured in Langendorff-perfused hearts and isolated cardiac myocytes. Diabetic (db/db) mouse hearts demonstrated decreased rates of contraction, relaxation, and pressure development. Calcium transients from isolated myocytes revealed significantly lower diastolic and systolic levels of calcium in diabetic hearts. Furthermore, the decay rate of the calcium transient was significantly reduced in diabetic myocytes, suggesting a diminished capacity for cytosolic calcium removal not associated with a change in sodium-calcium exchanger activity. Calcium leakage from the sarcoplasmic reticulum (SR) measured using tetracaine was significantly increased in diabetic myocytes. Western blot analysis indicated only a small decrease in SERCA2a expression in diabetic mice, but a large increase in phospholamban expression. Expression of the ryanodine receptor did not differ between groups. In conclusion, the decreased contractile function observed in the db/db diabetic mouse model appears to be related to decreased calcium handling by the SR.
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Affiliation(s)
- Darrell D Belke
- Department of Medicine, University of California, San Diego, CA 92092-0618, USA
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Abstract
The purpose of this study was to examine cardiac function in the diabetic-prone BB Wor rat. The study involved 2 groups: diabetic resistant control littermates of BB rats and diabetic-prone BB rats that had yet to demonstrate overt signs of diabetes. Hearts from these animals were isolated and cardiac function examined in response to incremental increases in left atrial filling pressure. Hearts were also perfused at an increased aortic afterload resistance with buffer consisting of glucose alone or glucose in the presence of palmitate. Hearts from diabetic-prone rats exhibited depressed contractility and ventricular relaxation at high filling pressures. Ventricular function, expressed as cardiac output, was also depressed in diabetic-prone rats perfused at increased afterload resistance, but only in the presence of palmitate. Our results indicate that hearts from diabetic-prone BB Wor rats demonstrate abnormalities in contractile performance and thus may be a useful model for the study of cardiac function in the prediabetic state.
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Affiliation(s)
- Tom L Broderick
- Department of Physiology, Midwestern University, Glendale, AZ 85308, USA
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Matsumoto T, Wakabayashi K, Kobayashi T, Kamata K. Diabetes-related changes in cAMP-dependent protein kinase activity and decrease in relaxation response in rat mesenteric artery. Am J Physiol Heart Circ Physiol 2004; 287:H1064-71. [PMID: 15130892 DOI: 10.1152/ajpheart.00069.2004] [Citation(s) in RCA: 45] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/22/2022]
Abstract
Using superior mesenteric artery rings isolated from age-matched controls and streptozotocin (STZ)-induced diabetic rats, we recently demonstrated that EDHF-type relaxation is impaired in STZ-induced diabetic rats, possibly due to a reduced action of cAMP via increased phosphodiesterase (PDE) activity (Matsumoto T, Kobayashi T, and Kamata K. Am J Physiol Heart Circ Physiol 285: H283-H291, 2003). Here, we investigated the activity and expression of cAMP-dependent protein kinase (PKA), an enzyme that is produced by a pleiotropic and plays key roles in the transduction of many external signals through the cAMP second messenger pathway and in cAMP-mediated vasorelaxation. The relaxation induced by cilostamide, a selective PDE3 inhibitor, was significantly weaker in superior mesenteric artery rings from STZ-induced diabetic rats than in those from age-matched controls. The relaxation responses to 8-bromo-cAMP (8Br-cAMP) and N6,O2-dibutyryl-adenosine-cAMP (db-cAMP), a cell-permeant cAMP analog, were also impaired in the STZ diabetic group. PKA activity in the db-cAMP-treated mesenteric artery was significantly lower in the STZ diabetic group. The expression levels of the mRNA and protein for PKA catalytic subunit Cat-alpha were significantly decreased in the STZ diabetic group, but those for PKA regulatory subunit isoform RII-beta were increased. We conclude that the abnormal vascular relaxation responsiveness seen in STZ-induced diabetic rats may be attributable not only to increased PDE activity but also to decreased PKA activity. Possibly, the decreased PKA activity may result from an imbalance between PKA catalytic and regulatory subunit expressions.
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Affiliation(s)
- Takayuki Matsumoto
- Department of Physiology and Morphology, Institute of Medicinal Chemistry, Hoshi University, Shinagawa-ku, Tokyo 142-8501, Japan
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Davidoff AJ, Mason MM, Davidson MB, Carmody MW, Hintz KK, Wold LE, Podolin DA, Ren J. Sucrose-induced cardiomyocyte dysfunction is both preventable and reversible with clinically relevant treatments. Am J Physiol Endocrinol Metab 2004; 286:E718-24. [PMID: 15102617 DOI: 10.1152/ajpendo.00358.2003] [Citation(s) in RCA: 45] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/22/2022]
Abstract
We recently identified cardiomyocyte dysfunction in the early stage of type 2 diabetes (i.e., diet-induced insulin resistance). The present investigation was designed to determine whether a variety of clinically relevant interventions are sufficient to prevent and reverse cardiomyocyte dysfunction in sucrose (SU)-fed insulin-resistant rats. Subsets of animals were allowed to exercise (free access to wheel attached to cage) or were treated with bezafibrate in drinking water to determine whether these interventions would prevent the adverse effects of SU feeding on cardiomyocyte function. After 6-8 wk on diet and treatment, animals were surgically prepared to assess whole body insulin sensitivity (intravenous glucose tolerance test), and isolated ventricular myocyte mechanics were evaluated (video edge recording). SU feeding produced hyperinsulinemia and hypertriglyceridemia, with euglycemia, and induced characteristic whole body insulin resistance. Both exercise and bezafibrate treatment prevented these metabolic abnormalities. Ventricular myocyte shortening and relengthening were slower in SU-fed rats (42-63%) compared with starch (ST)-fed controls, and exercise or bezafibrate completely prevented cardiomyocyte dysfunction in SU-fed rats. In separate cohorts of animals, after 5 wk of SU feeding, animals were either switched back to an ST diet or given menhaden oil for an additional 7-9 wk to determine whether the cardiomyocyte dysfunction was reversible. Both interventions have previously been shown to have favorable metabolic effects, and both improved myocyte mechanics, but only the ST diet reversed all indications of cardiomyocyte dysfunction induced by SU feeding. Thus phenotypic changes in cardiomyocyte mechanics associated with early stages of type 2 diabetes were found to be both preventable and reversible with clinically relevant treatments, suggesting that the cellular processes contributing to this dysfunction are modifiable.
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Affiliation(s)
- Amy J Davidoff
- Univ. of New England, College of Osteopathic Medicine, 11 Hills Beach Rd., Biddeford, ME 04005, USA.
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Jain M, Liao R, Miller TA, LeBrasseur NK, Sawyer DB. Mechanisms in the pathogenesis of diabetic cardiomyopathy. ACTA ACUST UNITED AC 2003. [DOI: 10.1097/00060793-200308000-00004] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/25/2022]
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