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Rivera-Torres F, Maciel-Cerda A, González-Gómez GH, Falcón-Neri A, Gómez-Lizárraga K, Esquivel-Posadas HT, Vera-Graziano R. In Vitro Modulation of Spontaneous Activity in Embryonic Cardiomyocytes Cultured on Poly(vinyl alcohol)/Bioglass Type 58S Electrospun Scaffolds. NANOMATERIALS (BASEL, SWITZERLAND) 2024; 14:372. [PMID: 38392745 PMCID: PMC10892114 DOI: 10.3390/nano14040372] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 01/11/2024] [Revised: 02/12/2024] [Accepted: 02/13/2024] [Indexed: 02/24/2024]
Abstract
Because of the physiological and cardiac changes associated with cardiovascular disease, tissue engineering can potentially restore the biological functions of cardiac tissue through the fabrication of scaffolds. In the present study, hybrid nanofiber scaffolds of poly (vinyl alcohol) (PVA) and bioglass type 58S (58SiO2-33CaO-9P2O5, Bg) were fabricated, and their effect on the spontaneous activity of chick embryonic cardiomyocytes in vitro was determined. PVA/Bg nanofibers were produced by electrospinning and stabilized by chemical crosslinking with glutaraldehyde. The electrospun scaffolds were analyzed to determine their chemical structure, morphology, and thermal transitions. The crosslinked scaffolds were more stable to degradation in water. A Bg concentration of 25% in the hybrid scaffolds improved thermal stability and decreased degradation in water after PVA crosslinking. Cardiomyocytes showed increased adhesion and contractility in cells seeded on hybrid scaffolds with higher Bg concentrations. In addition, the effect of Ca2+ ions released from the bioglass on the contraction patterns of cultured cardiomyocytes was investigated. The results suggest that the scaffolds with 25% Bg led to a uniform beating frequency that resulted in synchronous contraction patterns.
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Affiliation(s)
- Filiberto Rivera-Torres
- Facultad de Química, Universidad Nacional Autónoma de México, Circuito Escolar de Ciudad Universitaria, Coyoacán, Ciudad de México 04510, Mexico; (F.R.-T.); (H.T.E.-P.)
| | - Alfredo Maciel-Cerda
- Instituto de Investigaciones en Materiales, Universidad Nacional Autónoma de México, Circuito Escolar de Ciudad Universitaria, Coyoacán, Ciudad de México 04510, Mexico;
| | - Gertrudis Hortensia González-Gómez
- Facultad de Ciencias, Universidad Nacional Autónoma de México, Circuito Escolar de Ciudad Universitaria, Coyoacán, Ciudad de México 04510, Mexico; (G.H.G.-G.); (A.F.-N.)
| | - Alicia Falcón-Neri
- Facultad de Ciencias, Universidad Nacional Autónoma de México, Circuito Escolar de Ciudad Universitaria, Coyoacán, Ciudad de México 04510, Mexico; (G.H.G.-G.); (A.F.-N.)
| | - Karla Gómez-Lizárraga
- Cátedra CONAHCyT/Instituto de Investigaciones en Materiales, Universidad Nacional Autónoma de México, Circuito Escolar de Ciudad Universitaria, Coyoacán, Ciudad de México 04510, Mexico;
| | - Héctor Tomás Esquivel-Posadas
- Facultad de Química, Universidad Nacional Autónoma de México, Circuito Escolar de Ciudad Universitaria, Coyoacán, Ciudad de México 04510, Mexico; (F.R.-T.); (H.T.E.-P.)
| | - Ricardo Vera-Graziano
- Instituto de Investigaciones en Materiales, Universidad Nacional Autónoma de México, Circuito Escolar de Ciudad Universitaria, Coyoacán, Ciudad de México 04510, Mexico;
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Li MR, Luo XJ, Peng J. Role of sonic hedgehog signaling pathway in the regulation of ion channels: focus on its association with cardio-cerebrovascular diseases. J Physiol Biochem 2023; 79:719-730. [PMID: 37676576 DOI: 10.1007/s13105-023-00982-0] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/19/2023] [Accepted: 08/25/2023] [Indexed: 09/08/2023]
Abstract
Sonic hedgehog (SHH) signaling is vital for cell differentiation and proliferation during embryonic development, yet its role in cardiac, cerebral, and vascular pathophysiology is under debate. Recent studies have demonstrated that several compounds of SHH signaling regulate ion channels, which in turn affect the behavior of target cells. Some of these ion channels are involved in the cardio-cerebrovascular system. Here, we first reviewed the SHH signaling cascades, then its interaction with ion channels, and their impact on cardio-cerebrovascular diseases. Considering the complex cross talk of SHH signaling with other pathways that also affect ion channels and their potential impact on the cardio-cerebrovascular system, we highlight the necessity of thoroughly studying the effect of SHH signaling on ion homeostasis, which could serve as a novel mechanism for cardio-cerebrovascular diseases. Activation of SHH signaling influence ion channels activity, which in turn influence ion homeostasis, membrane potential, and electrophysiology, could serve as a novel strategy for cardio-cerebrovascular diseases.
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Affiliation(s)
- Ming-Rui Li
- Department of Pharmacology, Xiangya School of Pharmaceutical Sciences, Central South University, Changsha, 410078, China
- Hunan Provincial Key Laboratory of Cardiovascular Research, Xiangya School of Pharmaceutical Sciences, Central South University, Changsha, 410078, China
| | - Xiu-Ju Luo
- Department of Laboratory Medicine, The Third Xiangya Hospital of Central South University, Changsha, 410013, China.
| | - Jun Peng
- Department of Pharmacology, Xiangya School of Pharmaceutical Sciences, Central South University, Changsha, 410078, China.
- Hunan Provincial Key Laboratory of Cardiovascular Research, Xiangya School of Pharmaceutical Sciences, Central South University, Changsha, 410078, China.
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3
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Shemarova I. The Dysfunction of Ca 2+ Channels in Hereditary and Chronic Human Heart Diseases and Experimental Animal Models. Int J Mol Sci 2023; 24:15682. [PMID: 37958665 PMCID: PMC10650855 DOI: 10.3390/ijms242115682] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/11/2023] [Revised: 10/20/2023] [Accepted: 10/23/2023] [Indexed: 11/15/2023] Open
Abstract
Chronic heart diseases, such as coronary heart disease, heart failure, secondary arterial hypertension, and dilated and hypertrophic cardiomyopathies, are widespread and have a fairly high incidence of mortality and disability. Most of these diseases are characterized by cardiac arrhythmias, conduction, and contractility disorders. Additionally, interruption of the electrical activity of the heart, the appearance of extensive ectopic foci, and heart failure are all symptoms of a number of severe hereditary diseases. The molecular mechanisms leading to the development of heart diseases are associated with impaired permeability and excitability of cell membranes and are mainly caused by the dysfunction of cardiac Ca2+ channels. Over the past 50 years, more than 100 varieties of ion channels have been found in the cardiovascular cells. The relationship between the activity of these channels and cardiac pathology, as well as the general cellular biological function, has been intensively studied on several cell types and experimental animal models in vivo and in situ. In this review, I discuss the origin of genetic Ca2+ channelopathies of L- and T-type voltage-gated calcium channels in humans and the role of the non-genetic dysfunctions of Ca2+ channels of various types: L-, R-, and T-type voltage-gated calcium channels, RyR2, including Ca2+ permeable nonselective cation hyperpolarization-activated cyclic nucleotide-gated (HCN), and transient receptor potential (TRP) channels, in the development of cardiac pathology in humans, as well as various aspects of promising experimental studies of the dysfunctions of these channels performed on animal models or in vitro.
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Affiliation(s)
- Irina Shemarova
- I.M. Sechenov Institute of Evolutionary Physiology and Biochemistry of the Russian Academy of Sciences, 194223 Saint-Petersburg, Russia
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4
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Kuznetsov SV, Kuznetsova NN. Effects of Ni2+ on Heart and Respiratory Rhythms in Newborn Rats. J EVOL BIOCHEM PHYS+ 2022. [DOI: 10.1134/s0022093022050088] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/07/2022]
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5
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T-Type Calcium Channels: A Mixed Blessing. Int J Mol Sci 2022; 23:ijms23179894. [PMID: 36077291 PMCID: PMC9456242 DOI: 10.3390/ijms23179894] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/03/2022] [Revised: 08/26/2022] [Accepted: 08/29/2022] [Indexed: 11/17/2022] Open
Abstract
The role of T-type calcium channels is well established in excitable cells, where they preside over action potential generation, automaticity, and firing. They also contribute to intracellular calcium signaling, cell cycle progression, and cell fate; and, in this sense, they emerge as key regulators also in non-excitable cells. In particular, their expression may be considered a prognostic factor in cancer. Almost all cancer cells express T-type calcium channels to the point that it has been considered a pharmacological target; but, as the drugs used to reduce their expression are not completely selective, several complications develop, especially within the heart. T-type calcium channels are also involved in a specific side effect of several anticancer agents, that act on microtubule transport, increase the expression of the channel, and, thus, the excitability of sensory neurons, and make the patient more sensitive to pain. This review puts into context the relevance of T-type calcium channels in cancer and in chemotherapy side effects, considering also the cardiotoxicity induced by new classes of antineoplastic molecules.
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Abramochkin DV, Filatova TS, Pustovit KB, Voronina YA, Kuzmin VS, Vornanen M. Ionic currents underlying different patterns of electrical activity in working cardiac myocytes of mammals and non-mammalian vertebrates. Comp Biochem Physiol A Mol Integr Physiol 2022; 268:111204. [PMID: 35346823 DOI: 10.1016/j.cbpa.2022.111204] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/26/2022] [Revised: 03/21/2022] [Accepted: 03/22/2022] [Indexed: 12/19/2022]
Abstract
The orderly contraction of the vertebrate heart is determined by generation and propagation of cardiac action potentials (APs). APs are generated by the integrated activity of time- and voltage-dependent ionic channels which carry inward Na+ and Ca2+ currents, and outward K+ currents. This review compares atrial and ventricular APs and underlying ion currents between different taxa of vertebrates. We have collected literature data and attempted to find common electrophysiological features for two or more vertebrate groups, show differences between taxa and cardiac chambers, and indicate gaps in the existing data. Although electrical excitability of the heart in all vertebrates is based on the same superfamily of channels, there is a vast variability of AP waveforms between atrial and ventricular myocytes, between different species of the same vertebrate class and between endothermic and ectothermic animals. The wide variability of AP shapes is related to species-specific differences in animal size, heart rate, stage of ontogenetic development, excitation-contraction coupling, temperature and oxygen availability. Some of the differences between taxa are related to evolutionary development of genomes, which appear e.g. in the expression of different Na+ and K+ channel orthologues in cardiomyocytes of vertebrates. There is a wonderful variability of AP shapes and underlying ion currents with which electrical excitability of vertebrate heart can be generated depending on the intrinsic and extrinsic conditions of animal body. This multitude of ionic mechanisms provides excellent material for studying how the function of the vertebrate heart can adapt or acclimate to prevailing physiological and environmental conditions.
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Affiliation(s)
- Denis V Abramochkin
- Department of Human and Animal Physiology, Lomonosov Moscow State University, Leninskiye gory, 1, 12, Moscow 119234, Russia.
| | - Tatiana S Filatova
- Department of Human and Animal Physiology, Lomonosov Moscow State University, Leninskiye gory, 1, 12, Moscow 119234, Russia
| | - Ksenia B Pustovit
- Department of Human and Animal Physiology, Lomonosov Moscow State University, Leninskiye gory, 1, 12, Moscow 119234, Russia
| | - Yana A Voronina
- Department of Human and Animal Physiology, Lomonosov Moscow State University, Leninskiye gory, 1, 12, Moscow 119234, Russia; Laboratory of Cardiac Electrophysiology, National Medical Research Center for Cardiology, 3(rd) Cherepkovskaya str., 15A, Moscow, Russia
| | - Vladislav S Kuzmin
- Department of Human and Animal Physiology, Lomonosov Moscow State University, Leninskiye gory, 1, 12, Moscow 119234, Russia; Department of Physiology, Pirogov Russian National Research Medical University, Ostrovityanova str., 1, Moscow, Russia
| | - Matti Vornanen
- Department of Environmental and Biological Sciences, University of Eastern Finland, Joensuu, Finland
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Marksteiner J, Ebner J, Salzer I, Lilliu E, Hackl B, Todt H, Kubista H, Hallström S, Koenig X, Hilber K. Evidence for a Physiological Role of T-Type Ca Channels in Ventricular Cardiomyocytes of Adult Mice. MEMBRANES 2022; 12:566. [PMID: 35736273 PMCID: PMC9230067 DOI: 10.3390/membranes12060566] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 03/30/2022] [Revised: 05/20/2022] [Accepted: 05/23/2022] [Indexed: 11/17/2022]
Abstract
T-type Ca channels are strongly expressed and important in the developing heart. In the adult heart, these channels play a significant role in pacemaker tissues, but there is uncertainty about their presence and physiological relevance in the working myocardium. Here, we show that the T-type Ca channel isoforms Cav3.1 and Cav3.2 are expressed at a protein level in ventricular cardiomyocytes from healthy adult C57/BL6 mice. Myocytes isolated from adult wild-type and Cav3.2 KO mice showed considerable whole cell T-type Ca currents under beta-adrenergic stimulation with isoprenaline. We further show that the detectability of basal T-type Ca currents in murine wild-type cardiomyocytes depends on the applied experimental conditions. Together, these findings reveal the presence of functional T-type Ca channels in the membrane of ventricular myocytes. In addition, electrically evoked Ca release from the sarcoplasmic reticulum was significantly impaired in Cav3.2 KO compared to wild-type cardiomyocytes. Our work implies a physiological role of T-type Ca channels in the healthy adult murine ventricular working myocardium.
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Affiliation(s)
- Jessica Marksteiner
- Department of Neurophysiology and Pharmacology, Center for Physiology and Pharmacology, Medical University of Vienna, 1090 Vienna, Austria; (J.M.); (J.E.); (I.S.); (E.L.); (B.H.); (H.T.); (H.K.)
| | - Janine Ebner
- Department of Neurophysiology and Pharmacology, Center for Physiology and Pharmacology, Medical University of Vienna, 1090 Vienna, Austria; (J.M.); (J.E.); (I.S.); (E.L.); (B.H.); (H.T.); (H.K.)
| | - Isabella Salzer
- Department of Neurophysiology and Pharmacology, Center for Physiology and Pharmacology, Medical University of Vienna, 1090 Vienna, Austria; (J.M.); (J.E.); (I.S.); (E.L.); (B.H.); (H.T.); (H.K.)
| | - Elena Lilliu
- Department of Neurophysiology and Pharmacology, Center for Physiology and Pharmacology, Medical University of Vienna, 1090 Vienna, Austria; (J.M.); (J.E.); (I.S.); (E.L.); (B.H.); (H.T.); (H.K.)
| | - Benjamin Hackl
- Department of Neurophysiology and Pharmacology, Center for Physiology and Pharmacology, Medical University of Vienna, 1090 Vienna, Austria; (J.M.); (J.E.); (I.S.); (E.L.); (B.H.); (H.T.); (H.K.)
| | - Hannes Todt
- Department of Neurophysiology and Pharmacology, Center for Physiology and Pharmacology, Medical University of Vienna, 1090 Vienna, Austria; (J.M.); (J.E.); (I.S.); (E.L.); (B.H.); (H.T.); (H.K.)
| | - Helmut Kubista
- Department of Neurophysiology and Pharmacology, Center for Physiology and Pharmacology, Medical University of Vienna, 1090 Vienna, Austria; (J.M.); (J.E.); (I.S.); (E.L.); (B.H.); (H.T.); (H.K.)
| | - Seth Hallström
- Division of Physiological Chemistry, Otto Loewi Research Center, Medical University of Graz, 8036 Graz, Austria;
- Ludwig Boltzmann Institute for Cardiovascular Research at the Center for Biomedical Research, Medical University of Vienna, 1090 Vienna, Austria
| | - Xaver Koenig
- Department of Neurophysiology and Pharmacology, Center for Physiology and Pharmacology, Medical University of Vienna, 1090 Vienna, Austria; (J.M.); (J.E.); (I.S.); (E.L.); (B.H.); (H.T.); (H.K.)
| | - Karlheinz Hilber
- Department of Neurophysiology and Pharmacology, Center for Physiology and Pharmacology, Medical University of Vienna, 1090 Vienna, Austria; (J.M.); (J.E.); (I.S.); (E.L.); (B.H.); (H.T.); (H.K.)
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Liang X, Holy TE, Taghert PH. Circadian pacemaker neurons display cophasic rhythms in basal calcium level and in fast calcium fluctuations. Proc Natl Acad Sci U S A 2022; 119:e2109969119. [PMID: 35446620 PMCID: PMC9173584 DOI: 10.1073/pnas.2109969119] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/28/2021] [Accepted: 03/17/2022] [Indexed: 12/02/2022] Open
Abstract
Circadian pacemaker neurons in the Drosophila brain display daily rhythms in the levels of intracellular calcium. These calcium rhythms are driven by molecular clocks and are required for normal circadian behavior. To study their biological basis, we employed genetic manipulations in conjunction with improved methods of in vivo light-sheet microscopy to measure calcium dynamics in individual pacemaker neurons over complete 24-h durations at sampling frequencies as high as 5 Hz. This technological advance unexpectedly revealed cophasic daily rhythms in basal calcium levels and in high-frequency calcium fluctuations. Further, we found that the rhythms of basal calcium levels and of fast calcium fluctuations reflect the activities of two proteins that mediate distinct forms of calcium fluxes. One is the inositol trisphosphate receptor (ITPR), a channel that mediates calcium fluxes from internal endoplasmic reticulum calcium stores, and the other is a T-type voltage-gated calcium channel, which mediates extracellular calcium influx. These results suggest that Drosophila molecular clocks regulate ITPR and T-type channels to generate two distinct but coupled rhythms in basal calcium and in fast calcium fluctuations. We propose that both internal and external calcium fluxes are essential for circadian pacemaker neurons to provide rhythmic outputs and thereby, regulate the activities of downstream brain centers.
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Affiliation(s)
- Xitong Liang
- Department of Neuroscience, Washington University in St. Louis, St. Louis, MO 63110
| | - Timothy E. Holy
- Department of Neuroscience, Washington University in St. Louis, St. Louis, MO 63110
| | - Paul H. Taghert
- Department of Neuroscience, Washington University in St. Louis, St. Louis, MO 63110
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9
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Zhang Z, Qu Z. Mechanisms of phase-3 early afterdepolarizations and triggered activities in ventricular myocyte models. Physiol Rep 2021; 9:e14883. [PMID: 34110715 PMCID: PMC8191176 DOI: 10.14814/phy2.14883] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/14/2021] [Revised: 04/29/2021] [Accepted: 05/02/2021] [Indexed: 12/03/2022] Open
Abstract
Early afterdepolarizations (EADs) are abnormal depolarizations during the repolarizing phase of the action potential, which are associated with cardiac arrhythmogenesis. EADs are classified into phase-2 and phase-3 EADs. Phase-2 EADs occur during phase 2 of the action potential, with takeoff potentials typically above -40 mV. Phase-3 EADs occur during phase 3 of the action potential, with takeoff potential between -70 and -50 mV. Since the amplitude of phase-3 EADs can be as large as that of a regular action potential, they are also called triggered activities (TAs). This also makes phase-3 EADs and TAs much more arrhythmogenic than phase-2 EADs since they can propagate easily in tissue. Although phase-2 EADs have been widely observed, phase-3 EADs and TAs have been rarely demonstrated in isolated ventricular myocytes. Here we carry out computer simulations of three widely used ventricular action potential models to investigate the mechanisms of phase-3 EADs and TAs. We show that when the T-type Ca2+ current (ICa,T ) is absent (e.g., in normal ventricular myocytes), besides the requirement of increasing inward currents and reducing outward currents as for phase-2 EADs, the occurrence of phase-3 EADs and TAs requires a substantially large increase of the L-type Ca2+ current and the slow component of the delayed rectifier K+ current. The presence of ICa,T (e.g., in neonatal and failing ventricular myocytes) can greatly reduce the thresholds of these two currents for phase-3 EADs and TAs. This implies that ICa,T may play an important role in arrhythmogenesis in cardiac diseases.
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Affiliation(s)
- Zhaoyang Zhang
- Department of MedicineDavid Geffen School of MedicineUniversity of CaliforniaLos AngelesCAUSA
| | - Zhilin Qu
- Department of MedicineDavid Geffen School of MedicineUniversity of CaliforniaLos AngelesCAUSA
- Department of Computational MedicineDavid Geffen School of MedicineUniversity of CaliforniaLos AngelesCAUSA
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10
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Echeazarra L, Hortigón-Vinagre MP, Casis O, Gallego M. Adult and Developing Zebrafish as Suitable Models for Cardiac Electrophysiology and Pathology in Research and Industry. Front Physiol 2021; 11:607860. [PMID: 33519514 PMCID: PMC7838705 DOI: 10.3389/fphys.2020.607860] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/18/2020] [Accepted: 11/30/2020] [Indexed: 12/21/2022] Open
Abstract
The electrophysiological behavior of the zebrafish heart is very similar to that of the human heart. In fact, most of the genes that codify the channels and regulatory proteins required for human cardiac function have their orthologs in the zebrafish. The high fecundity, small size, and easy handling make the zebrafish embryos/larvae an interesting candidate to perform whole animal experiments within a plate, offering a reliable and low-cost alternative to replace rodents and larger mammals for the study of cardiac physiology and pathology. The employment of zebrafish embryos/larvae has widened from basic science to industry, being of particular interest for pharmacology studies, since the zebrafish embryo/larva is able to recapitulate a complete and integrated view of cardiac physiology, missed in cell culture. As in the human heart, IKr is the dominant repolarizing current and it is functional as early as 48 h post fertilization. Finally, genome editing techniques such as CRISPR/Cas9 facilitate the humanization of zebrafish embryos/larvae. These techniques allow one to replace zebrafish genes by their human orthologs, making humanized zebrafish embryos/larvae the most promising in vitro model, since it allows the recreation of human-organ-like environment, which is especially necessary in cardiac studies due to the implication of dynamic factors, electrical communication, and the paracrine signals in cardiac function.
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Affiliation(s)
- Leyre Echeazarra
- Departamento de Fisiología, Facultad de Farmacia, Universidad del País Vasco UPV/EHU, Vitoria-Gasteiz, Spain
| | - Maria Pura Hortigón-Vinagre
- Departamento de Bioquímica y Biología Molecular y Genética>, Facultad de Ciencias, Universidad de Extremadura, Badajoz, Spain
| | - Oscar Casis
- Departamento de Fisiología, Facultad de Farmacia, Universidad del País Vasco UPV/EHU, Vitoria-Gasteiz, Spain
| | - Mónica Gallego
- Departamento de Fisiología, Facultad de Farmacia, Universidad del País Vasco UPV/EHU, Vitoria-Gasteiz, Spain
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11
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Harraz OF, Jensen LJ. Aging, calcium channel signaling and vascular tone. Mech Ageing Dev 2020; 191:111336. [PMID: 32918949 PMCID: PMC8511598 DOI: 10.1016/j.mad.2020.111336] [Citation(s) in RCA: 29] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/17/2020] [Revised: 08/13/2020] [Accepted: 08/21/2020] [Indexed: 02/08/2023]
Abstract
Calcium signaling in vascular smooth muscle is crucial for arterial tone regulation and vascular function. Several proteins, including Ca2+ channels, function in an orchestrated fashion so that blood vessels can sense and respond to physiological stimuli such as changes in intravascular pressure. Activation of the voltage-dependent Ca2+ channel, Cav1.2, leads to Ca2+ influx and consequently arterial tone development and vasoconstriction. Unique among Ca2+ channels, the vascular Cav3.2 T-type channel mediates feedback inhibition of arterial tone-and therefore causes vasodilation-of resistance arteries by virtue of functional association with hyperpolarizing ion channels. During aging, several signaling modalities are altered along with vascular remodeling. There is a growing appreciation of how calcium channel signaling alters with aging and how this may affect vascular function. Here, we discuss key determinants of arterial tone development and the crucial involvement of Ca2+ channels. We next provide an updated view of key changes in Ca2+ channel expression and function during aging and how these affect vascular function. Further, this article synthesizes new questions in light of recent developments. We hope that these questions will outline a roadmap for new research, which, undoubtedly, will unravel a more comprehensive picture of arterial tone dysfunction during aging.
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Affiliation(s)
- Osama F. Harraz
- Dept. of Pharmacology, Larner College of Medicine, University of Vermont, Burlington, VT, 05405 USA,Corresponding author. (O.F. Harraz)
| | - Lars Jørn Jensen
- Pathobiological Sciences, Dept. of Veterinary and Animal Sciences, Faculty of Health and Medical Sciences, University of Copenhagen, DK-1870 Frederiksberg C, Denmark
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12
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Zhang X, Li Y, Zhang X, Piacentino V, Harris DM, Berretta R, Margulies KB, Houser SR, Chen X. A low voltage activated Ca 2+ current found in a subset of human ventricular myocytes. Channels (Austin) 2020; 14:231-245. [PMID: 32684070 PMCID: PMC7515576 DOI: 10.1080/19336950.2020.1794420] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/26/2022] Open
Abstract
Low voltage activated (ICa-LVA) calcium currents including Cav1.3 and T-type calcium current (ICa-T) have not been reported in adult human left ventricular myocytes (HLVMs). We tried to examine their existence and possible correlation with etiology and patient characteristics in a big number of human LVMs isolated from explanted terminally failing (F) hearts, failing hearts with left ventricular assist device (F-LVAD) and nonfailing (NF) human hearts. LVA (ICa-LVA) was determined by subtracting L-type Ca2+ current (ICa-L) recorded with the holding potential of −50 mV from total Ca2+ current recorded with the holding potential of −90 mV or −70 mV. ICa- LVA was further tested with its sensitivity to 100 µM CdCl2 and tetrodotoxin. Three HLVMs (3 of 137 FHLVMs) from 2 (N = 30 hearts) failing human hearts, of which one was idiopathic and the other was due to primary pulmonary hypertension, were found with ICa-LVA. ICa-LVA in one FHLVM was not sensitive to 100 µM CdCl2 while ICa-LVA in another two FHLVMs was not sensitive to tetrodotoxin. It peaked at the voltage of −40~-20 mV and had a time-dependent decay faster than ICa-L but slower than sodium current (INa). ICa-LVA was not found in any HLVMs from NF (75 HLVMs from 17 hearts) or F-LVAD hearts (82 HLVMs from 18 hearts) but a statistically significant correlation could not be established. In conclusion, ICa-LVA was detected in some HLVMs of a small portion of human hearts that happened to be nonischemic failing hearts.
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Affiliation(s)
- Xin Zhang
- Department of Infection Diseases The First Affiliated Hospital of China Medical University , Shenyang China.,Department of Physiology and Cardiovascular Research Center, Temple University Lewis Katz School of Medicine , Philadelphia, PA, USA
| | - Yijia Li
- Department of Physiology and Cardiovascular Research Center, Temple University Lewis Katz School of Medicine , Philadelphia, PA, USA
| | - Xiaoying Zhang
- Department of Physiology and Cardiovascular Research Center, Temple University Lewis Katz School of Medicine , Philadelphia, PA, USA
| | - Valentino Piacentino
- Department of Physiology and Cardiovascular Research Center, Temple University Lewis Katz School of Medicine , Philadelphia, PA, USA.,Department Grand Strand Surgical Care, Grand Strand Regional Medical Center , Myrtle Beach, SC
| | - David M Harris
- Department of Physiology and Cardiovascular Research Center, Temple University Lewis Katz School of Medicine , Philadelphia, PA, USA.,College of Medicine, University of Central Florida , Orlando, Florida, USA
| | - Remus Berretta
- Department of Physiology and Cardiovascular Research Center, Temple University Lewis Katz School of Medicine , Philadelphia, PA, USA
| | - Kenneth B Margulies
- Department of Physiology and Cardiovascular Research Center, Temple University Lewis Katz School of Medicine , Philadelphia, PA, USA.,Department of Medicine, University of Pennsylvania , Philadelphia, PA, USA
| | - Steven R Houser
- Department of Physiology and Cardiovascular Research Center, Temple University Lewis Katz School of Medicine , Philadelphia, PA, USA
| | - Xiongwen Chen
- Department of Physiology and Cardiovascular Research Center, Temple University Lewis Katz School of Medicine , Philadelphia, PA, USA
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13
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Asfaw TN, Tyan L, Glukhov AV, Bondarenko VE. A compartmentalized mathematical model of mouse atrial myocytes. Am J Physiol Heart Circ Physiol 2020; 318:H485-H507. [PMID: 31951471 DOI: 10.1152/ajpheart.00460.2019] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/01/2023]
Abstract
Various experimental mouse models are extensively used to research human diseases, including atrial fibrillation, the most common cardiac rhythm disorder. Despite this, there are no comprehensive mathematical models that describe the complex behavior of the action potential and [Ca2+]i transients in mouse atrial myocytes. Here, we develop a novel compartmentalized mathematical model of mouse atrial myocytes that combines the action potential, [Ca2+]i dynamics, and β-adrenergic signaling cascade for a subpopulation of right atrial myocytes with developed transverse-axial tubule system. The model consists of three compartments related to β-adrenergic signaling (caveolae, extracaveolae, and cytosol) and employs local control of Ca2+ release. It also simulates ionic mechanisms of action potential generation and describes atrial-specific Ca2+ handling as well as frequency dependences of the action potential and [Ca2+]i transients. The model showed that the T-type Ca2+ current significantly affects the later stage of the action potential, with little effect on [Ca2+]i transients. The block of the small-conductance Ca2+-activated K+ current leads to a prolongation of the action potential at high intracellular Ca2+. Simulation results obtained from the atrial model cells were compared with those from ventricular myocytes. The developed model represents a useful tool to study complex electrical properties in the mouse atria and could be applied to enhance the understanding of atrial physiology and arrhythmogenesis.NEW & NOTEWORTHY A new compartmentalized mathematical model of mouse right atrial myocytes was developed. The model simulated action potential and Ca2+ dynamics at baseline and after stimulation of the β-adrenergic signaling system. Simulations showed that the T-type Ca2+ current markedly prolonged the later stage of atrial action potential repolarization, with a minor effect on [Ca2+]i transients. The small-conductance Ca2+-activated K+ current block resulted in prolongation of the action potential only at the relatively high intracellular Ca2+.
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Affiliation(s)
- Tesfaye Negash Asfaw
- Department of Mathematics and Statistics, Georgia State University, Atlanta, Georgia
| | - Leonid Tyan
- Department of Medicine, School of Medicine and Public Health, University of Wisconsin-Madison, Madison, Wisconsin
| | - Alexey V Glukhov
- Department of Medicine, School of Medicine and Public Health, University of Wisconsin-Madison, Madison, Wisconsin
| | - Vladimir E Bondarenko
- Department of Mathematics and Statistics, Georgia State University, Atlanta, Georgia.,Neuroscience Institute, Georgia State University, Atlanta, Georgia
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14
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Kernik DC, Morotti S, Wu H, Garg P, Duff HJ, Kurokawa J, Jalife J, Wu JC, Grandi E, Clancy CE. A computational model of induced pluripotent stem-cell derived cardiomyocytes incorporating experimental variability from multiple data sources. J Physiol 2019; 597:4533-4564. [PMID: 31278749 PMCID: PMC6767694 DOI: 10.1113/jp277724] [Citation(s) in RCA: 87] [Impact Index Per Article: 14.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/18/2019] [Accepted: 07/05/2019] [Indexed: 12/22/2022] Open
Abstract
Key points
Induced pluripotent stem cell‐derived cardiomyocytes (iPSC‐CMs) capture patient‐specific genotype–phenotype relationships, as well as cell‐to‐cell variability of cardiac electrical activity Computational modelling and simulation provide a high throughput approach to reconcile multiple datasets describing physiological variability, and also identify vulnerable parameter regimes We have developed a whole‐cell model of iPSC‐CMs, composed of single exponential voltage‐dependent gating variable rate constants, parameterized to fit experimental iPSC‐CM outputs We have utilized experimental data across multiple laboratories to model experimental variability and investigate subcellular phenotypic mechanisms in iPSC‐CMs This framework links molecular mechanisms to cellular‐level outputs by revealing unique subsets of model parameters linked to known iPSC‐CM phenotypes Abstract There is a profound need to develop a strategy for predicting patient‐to‐patient vulnerability in the emergence of cardiac arrhythmia. A promising in vitro method to address patient‐specific proclivity to cardiac disease utilizes induced pluripotent stem cell‐derived cardiomyocytes (iPSC‐CMs). A major strength of this approach is that iPSC‐CMs contain donor genetic information and therefore capture patient‐specific genotype–phenotype relationships. A cited detriment of iPSC‐CMs is the cell‐to‐cell variability observed in electrical activity. We postulated, however, that cell‐to‐cell variability may constitute a strength when appropriately utilized in a computational framework to build cell populations that can be employed to identify phenotypic mechanisms and pinpoint key sensitive parameters. Thus, we have exploited variation in experimental data across multiple laboratories to develop a computational framework for investigating subcellular phenotypic mechanisms. We have developed a whole‐cell model of iPSC‐CMs composed of simple model components comprising ion channel models with single exponential voltage‐dependent gating variable rate constants, parameterized to fit experimental iPSC‐CM data for all major ionic currents. By optimizing ionic current model parameters to multiple experimental datasets, we incorporate experimentally‐observed variability in the ionic currents. The resulting population of cellular models predicts robust inter‐subject variability in iPSC‐CMs. This approach links molecular mechanisms to known cellular‐level iPSC‐CM phenotypes, as shown by comparing immature and mature subpopulations of models to analyse the contributing factors underlying each phenotype. In the future, the presented models can be readily expanded to include genetic mutations and pharmacological interventions for studying the mechanisms of rare events, such as arrhythmia triggers.
Induced pluripotent stem cell‐derived cardiomyocytes (iPSC‐CMs) capture patient‐specific genotype–phenotype relationships, as well as cell‐to‐cell variability of cardiac electrical activity Computational modelling and simulation provide a high throughput approach to reconcile multiple datasets describing physiological variability, and also identify vulnerable parameter regimes We have developed a whole‐cell model of iPSC‐CMs, composed of single exponential voltage‐dependent gating variable rate constants, parameterized to fit experimental iPSC‐CM outputs We have utilized experimental data across multiple laboratories to model experimental variability and investigate subcellular phenotypic mechanisms in iPSC‐CMs This framework links molecular mechanisms to cellular‐level outputs by revealing unique subsets of model parameters linked to known iPSC‐CM phenotypes
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Affiliation(s)
- Divya C Kernik
- Department of Physiology and Membrane Biology, Department of Pharmacology, School of Medicine, University of California, Davis, Davis, CA, USA
| | - Stefano Morotti
- Department of Pharmacology, School of Medicine, University of California, Davis, CA, USA
| | - HaoDi Wu
- Stanford Cardiovascular Institute, Department of Medicine, Division of Cardiovascular Medicine, Stanford University School of Medicine, Stanford, CA, USA
| | - Priyanka Garg
- Stanford Cardiovascular Institute, Department of Medicine, Division of Cardiovascular Medicine, Stanford University School of Medicine, Stanford, CA, USA
| | - Henry J Duff
- Libin Cardiovascular Institute of Alberta, Faculty of Medicine, University of Calgary, Calgary, AB, Canada
| | - Junko Kurokawa
- Department of Bio-Informational Pharmacology, School of Pharmaceutical Sciences, University of Shizuoka, Shizuoka, Japan
| | - José Jalife
- Department of Internal Medicine, Center for Arrhythmia Research, Cardiovascular Research Center, University of Michigan, Ann Arbor, MI, USA.,Centro Nacional de Investigaciones Cardiovasculares (CNIC), and CIBERV, Madrid, Spain
| | - Joseph C Wu
- Stanford Cardiovascular Institute, Department of Medicine, Division of Cardiovascular Medicine, Stanford University School of Medicine, Stanford, CA, USA
| | - Eleonora Grandi
- Department of Pharmacology, School of Medicine, University of California, Davis, CA, USA
| | - Colleen E Clancy
- Department of Physiology and Membrane Biology, Department of Pharmacology, School of Medicine, University of California, Davis, Davis, CA, USA
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15
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Andrade A, Brennecke A, Mallat S, Brown J, Gomez-Rivadeneira J, Czepiel N, Londrigan L. Genetic Associations between Voltage-Gated Calcium Channels and Psychiatric Disorders. Int J Mol Sci 2019; 20:E3537. [PMID: 31331039 PMCID: PMC6679227 DOI: 10.3390/ijms20143537] [Citation(s) in RCA: 62] [Impact Index Per Article: 10.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/18/2019] [Revised: 07/12/2019] [Accepted: 07/13/2019] [Indexed: 12/23/2022] Open
Abstract
Psychiatric disorders are mental, behavioral or emotional disorders. These conditions are prevalent, one in four adults suffer from any type of psychiatric disorders world-wide. It has always been observed that psychiatric disorders have a genetic component, however, new methods to sequence full genomes of large cohorts have identified with high precision genetic risk loci for these conditions. Psychiatric disorders include, but are not limited to, bipolar disorder, schizophrenia, autism spectrum disorder, anxiety disorders, major depressive disorder, and attention-deficit and hyperactivity disorder. Several risk loci for psychiatric disorders fall within genes that encode for voltage-gated calcium channels (CaVs). Calcium entering through CaVs is crucial for multiple neuronal processes. In this review, we will summarize recent findings that link CaVs and their auxiliary subunits to psychiatric disorders. First, we will provide a general overview of CaVs structure, classification, function, expression and pharmacology. Next, we will summarize tools to study risk loci associated with psychiatric disorders. We will examine functional studies of risk variations in CaV genes when available. Finally, we will review pharmacological evidence of the use of CaV modulators to treat psychiatric disorders. Our review will be of interest for those studying pathophysiological aspects of CaVs.
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Affiliation(s)
- Arturo Andrade
- Department of Biological Sciences, University of New Hampshire, Durham, NH 03824, USA.
| | - Ashton Brennecke
- Department of Biological Sciences, University of New Hampshire, Durham, NH 03824, USA
| | - Shayna Mallat
- Department of Biological Sciences, University of New Hampshire, Durham, NH 03824, USA
| | - Julian Brown
- Department of Biological Sciences, University of New Hampshire, Durham, NH 03824, USA
| | | | - Natalie Czepiel
- Department of Biological Sciences, University of New Hampshire, Durham, NH 03824, USA
| | - Laura Londrigan
- Department of Biological Sciences, University of New Hampshire, Durham, NH 03824, USA
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16
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Zhang M, Zou B, Gunaratna MJ, Weerasekara S, Tong Z, Nguyen TDT, Koldas S, Cao WS, Pascual C, Xie XS, Hua DH. SYNTHESIS OF 1,3,4-OXADIAZOLES AS SELECTIVE T-TYPE CALCIUM CHANNEL INHIBITORS. HETEROCYCLES 2019; 101:145-164. [PMID: 32773946 PMCID: PMC7413294 DOI: 10.3987/com-19-s(f)5] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/19/2022]
Abstract
Neuropathic pain, epilepsy, insomnia, and tremor disorder may arrive from an increase of intracellular Ca2+ concentration through a dysfunction of T-type Ca2+ channels. Thus, T-type calcium channels could be a target in drug discovery for the treatments of neuropathic pain and epilepsy. From rational drug design approach, a group of 2,5-disubstituted 1,3,4-oxadiazole molecules was synthesized and their selective T-type channel inhibitions were evaluated. The synthetic strategy consists of a short sequence of three reactions: (i) condensation of thiosemicarbazide with acid chlorides; (ii) ring closing by 1,3-dibromo-5,5- dimethylhydantoin; and (iii) coupling with various acid chlorides. 5-Chloro-N-(5- phenyl-1,3,4-oxadiazol-2-yl)thiophene-2-carboxamide (11) was found to selectively inhibit T-type Ca2+ channel over Na+ and K+ channels in mouse dorsal root ganglion neurons and/or human embryonic kidney (HEK)-293 cells and to suppress seizure-induced death in mouse model. Consequently, compound 11 is a useful probe for investigation of physiologic and pathophysiologic roles of the T-channel, and provides a basis to develop a novel therapeutic to treat chronic neuropathic and inflammatory pains.
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Affiliation(s)
- Man Zhang
- Department of Chemistry, Kansas State University, 1212 Mid Campus Drive, Manhattan, KS 66506, U. S. A
| | - Bende Zou
- AfaSci Research Laboratories, Redwood City, CA 94063, U. S. A
| | - Medha J Gunaratna
- Department of Chemistry, Kansas State University, 1212 Mid Campus Drive, Manhattan, KS 66506, U. S. A
| | - Sahani Weerasekara
- Department of Chemistry, Kansas State University, 1212 Mid Campus Drive, Manhattan, KS 66506, U. S. A
| | - Zongbo Tong
- Department of Chemistry, Kansas State University, 1212 Mid Campus Drive, Manhattan, KS 66506, U. S. A
| | - Thi D T Nguyen
- Department of Chemistry, Kansas State University, 1212 Mid Campus Drive, Manhattan, KS 66506, U. S. A
| | - Serkan Koldas
- Department of Chemistry, Kansas State University, 1212 Mid Campus Drive, Manhattan, KS 66506, U. S. A
| | - William S Cao
- AfaSci Research Laboratories, Redwood City, CA 94063, U. S. A
| | - Conrado Pascual
- AfaSci Research Laboratories, Redwood City, CA 94063, U. S. A
| | | | - Duy H Hua
- Department of Chemistry, Kansas State University, 1212 Mid Campus Drive, Manhattan, KS 66506, U. S. A
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17
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Paterek A, Mackiewicz U, Mączewski M. Iron and the heart: A paradigm shift from systemic to cardiomyocyte abnormalities. J Cell Physiol 2019; 234:21613-21629. [DOI: 10.1002/jcp.28820] [Citation(s) in RCA: 62] [Impact Index Per Article: 10.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/20/2018] [Revised: 04/16/2019] [Accepted: 04/17/2019] [Indexed: 12/13/2022]
Affiliation(s)
- Aleksandra Paterek
- Department of Clinical Physiology Centre of Postgraduate Medical Education Warsaw Poland
| | - Urszula Mackiewicz
- Department of Clinical Physiology Centre of Postgraduate Medical Education Warsaw Poland
| | - Michał Mączewski
- Department of Clinical Physiology Centre of Postgraduate Medical Education Warsaw Poland
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18
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Qu YS, Lazzerini PE, Capecchi PL, Laghi-Pasini F, El Sherif N, Boutjdir M. Autoimmune Calcium Channelopathies and Cardiac Electrical Abnormalities. Front Cardiovasc Med 2019; 6:54. [PMID: 31119135 PMCID: PMC6507622 DOI: 10.3389/fcvm.2019.00054] [Citation(s) in RCA: 15] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/07/2018] [Accepted: 04/16/2019] [Indexed: 12/24/2022] Open
Abstract
Patients with autoimmune diseases are at increased risk for developing cardiovascular diseases, and abnormal electrocardiographic findings are common. Voltage-gated calcium channels play a major role in the cardiovascular system and regulate cardiac excitability and contractility. Particularly, by virtue of their localization and expression in the heart, calcium channels modulate pace making at the sinus node, conduction at the atrioventricular node and cardiac repolarization in the working myocardium. Consequently, emerging evidence suggests that calcium channels are targets to autoantibodies in autoimmune diseases. Autoimmune-associated cardiac calcium channelopathies have been recognized in both sinus node dysfunction atrioventricular block in patients positive for anti-Ro/La antibodies, and ventricular arrhythmias in patients with dilated cardiomyopathy. In this review, we discuss mechanisms of autoimmune-associated calcium channelopathies and their relationship with the development of cardiac electrical abnormalities.
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Affiliation(s)
- Yongxia Sarah Qu
- Department of Cardiology, New York Presbyterian Brooklyn Methodist Hospital, Brooklyn, NY, United States.,VA New York Harbor Healthcare System and State University of New York Downstate Medical Center, Brooklyn, NY, United States
| | - Pietro Enea Lazzerini
- Department of Medical Sciences, Surgery and Neurosciences, University of Siena, Siena, Italy
| | - Pier Leopoldo Capecchi
- Department of Medical Sciences, Surgery and Neurosciences, University of Siena, Siena, Italy
| | - Franco Laghi-Pasini
- Department of Medical Sciences, Surgery and Neurosciences, University of Siena, Siena, Italy
| | - Nabil El Sherif
- VA New York Harbor Healthcare System and State University of New York Downstate Medical Center, Brooklyn, NY, United States
| | - Mohamed Boutjdir
- VA New York Harbor Healthcare System and State University of New York Downstate Medical Center, Brooklyn, NY, United States.,NYU School of Medicine, New York, NY, United States
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19
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Abstract
Iron overload cardiomyopathy (IOC) is a major cause of death in patients with diseases associated with chronic anemia such as thalassemia or sickle cell disease after chronic blood transfusions. Associated with iron overload conditions, there is excess free iron that enters cardiomyocytes through both L- and T-type calcium channels thereby resulting in increased reactive oxygen species being generated via Haber-Weiss and Fenton reactions. It is thought that an increase in reactive oxygen species contributes to high morbidity and mortality rates. Recent studies have, however, suggested that it is iron overload in mitochondria that contributes to cellular oxidative stress, mitochondrial damage, cardiac arrhythmias, as well as the development of cardiomyopathy. Iron chelators, antioxidants, and/or calcium channel blockers have been demonstrated to prevent and ameliorate cardiac dysfunction in animal models as well as in patients suffering from cardiac iron overload. Hence, either a mono-therapy or combination therapies with any of the aforementioned agents may serve as a novel treatment in iron-overload patients in the near future. In the present article, we review the mechanisms of cytosolic and/or mitochondrial iron load in the heart which may contribute synergistically or independently to the development of iron-associated cardiomyopathy. We also review available as well as potential future novel treatments.
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20
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Liu Y, Wang P, Ma F, Zheng M, Liu G, Kume S, Kurokawa T, Ono K. Asparagine-linked glycosylation modifies voltage-dependent gating properties of Ca V3.1-T-type Ca 2+ channel. J Physiol Sci 2019; 69:335-343. [PMID: 30600443 PMCID: PMC10717069 DOI: 10.1007/s12576-018-0650-4] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/16/2018] [Accepted: 12/05/2018] [Indexed: 01/11/2023]
Abstract
T-type channels are low-voltage-activated channels that play a role in the cardiovascular system particularly for pacemaker activity. Glycosylation is one of the most prevalent post-translational modifications in protein. Among various glycosylation types, the most common one is asparagine-linked (N-linked) glycosylation. The aim of this study was to elucidate the roles of N-linked glycosylation for the gating properties of the CaV3.1-T-type Ca2+ channel. N-linked glycosylation synthesis inhibitor tunicamycin causes a reduction of CaV3.1-T-type Ca2+ channel current (CaV3.1-ICa.T) when applied for 12 h or longer. Tunicamycin (24 h) significantly shifted the activation curve to the depolarization potentials, whereas the steady-state inactivation curve was unaffected. Use-dependent inactivation of CaV3.1-ICa.T was accelerated, and recovery from inactivation was prolonged by tunicamycin (24 h). CaV3.1-ICa.T was insensitive to a glycosidase PNGase F when the channels were expressed on the plasma membrane. These findings suggest that N-glycosylation contributes not only to the cell surface expression of the CaV3.1-T-type Ca2+ channel but to the regulation of the gating properties of the channel when the channel proteins were processed during the folding and trafficking steps in the cell.
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Affiliation(s)
- Yangong Liu
- Department of Cardiology, The First Hospital of Hebei Medical University, 89 Donggang Road, Shijiazhuang, Hebei Province, 050031, People's Republic of China
- Department of Pathophysiology, Oita University School of Medicine, Yufu, Oita, 879-5593, Japan
| | - Pu Wang
- Department of Cardiology, The First Hospital of Hebei Medical University, 89 Donggang Road, Shijiazhuang, Hebei Province, 050031, People's Republic of China
- Department of Pathophysiology, Oita University School of Medicine, Yufu, Oita, 879-5593, Japan
| | - Fangfang Ma
- Department of Cardiology, The First Hospital of Hebei Medical University, 89 Donggang Road, Shijiazhuang, Hebei Province, 050031, People's Republic of China
- Department of Pathophysiology, Oita University School of Medicine, Yufu, Oita, 879-5593, Japan
| | - Mingqi Zheng
- Department of Cardiology, The First Hospital of Hebei Medical University, 89 Donggang Road, Shijiazhuang, Hebei Province, 050031, People's Republic of China
| | - Gang Liu
- Department of Cardiology, The First Hospital of Hebei Medical University, 89 Donggang Road, Shijiazhuang, Hebei Province, 050031, People's Republic of China
| | - Shinichiro Kume
- Department of Pathophysiology, Oita University School of Medicine, Yufu, Oita, 879-5593, Japan
| | - Tatsuki Kurokawa
- Department of Pathophysiology, Oita University School of Medicine, Yufu, Oita, 879-5593, Japan
| | - Katsushige Ono
- Department of Pathophysiology, Oita University School of Medicine, Yufu, Oita, 879-5593, Japan.
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21
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Abstract
INTRODUCTION T-type calcium channels are attractive targets for potential treatment of epilepsy inflammatory or neuropathic pain, insomnia, Parkinson's disease, and cancer. Three isoforms having different biophysical functions are expressed in peripheral and central nerve. Since the withdrawal of mibefradil, the first compound marketed for selective T-type calcium channel blockade, extensive efforts have been made to identify more selective T-type calcium channel blockers. AREAS COVERED This review covers the 43 patents describing 'organic small molecules as T-type calcium channel blockers'-published since 2012. The most recent similar patent review was published in 2011. Information from a recent review article and relevant research papers has been included, as well as biological data and clinical trial results where available. EXPERT OPINION Triazinone derivatives, carbazole compounds, and aryl triazole/imidazole amide derivatives display potent blockade activity α1H, α1G, and pan T-type calcium channel subtypes, respectively, though the specificity of the letter is still unsatisfactory. Nonetheless, improvements seen in the efficacy of compounds targeting α1H T-type calcium channels indicate significant progress. Ongoing clinical trials are for the candidates Z944 (Phase II) and ACT-709478 (Phase II) appear promising. These studies may lead to a new generation of inhibitors with higher selectivity, improved physicochemical properties, and reduced side effects.
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Affiliation(s)
- Ghilsoo Nam
- a Center for Neuro-Medicine , Brain Science Institute, Korea Institutes of Science and Technology (KIST) , Seoul , Republic of Korea.,b Division of Bio-Medical Science, KIST School , Korea University of Science and Technology Seoul , Seoul , Republic of Korea
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22
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Voltage-Dependent Sarcolemmal Ion Channel Abnormalities in the Dystrophin-Deficient Heart. Int J Mol Sci 2018; 19:ijms19113296. [PMID: 30360568 PMCID: PMC6274787 DOI: 10.3390/ijms19113296] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/28/2018] [Revised: 10/18/2018] [Accepted: 10/19/2018] [Indexed: 12/28/2022] Open
Abstract
Mutations in the gene encoding for the intracellular protein dystrophin cause severe forms of muscular dystrophy. These so-called dystrophinopathies are characterized by skeletal muscle weakness and degeneration. Dystrophin deficiency also gives rise to considerable complications in the heart, including cardiomyopathy development and arrhythmias. The current understanding of the pathomechanisms in the dystrophic heart is limited, but there is growing evidence that dysfunctional voltage-dependent ion channels in dystrophin-deficient cardiomyocytes play a significant role. Herein, we summarize the current knowledge about abnormalities in voltage-dependent sarcolemmal ion channel properties in the dystrophic heart, and discuss the potentially underlying mechanisms, as well as their pathophysiological relevance.
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23
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Ravens U. Ionic basis of cardiac electrophysiology in zebrafish compared to human hearts. PROGRESS IN BIOPHYSICS AND MOLECULAR BIOLOGY 2018; 138:38-44. [DOI: 10.1016/j.pbiomolbio.2018.06.008] [Citation(s) in RCA: 24] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Received: 03/23/2018] [Revised: 05/23/2018] [Accepted: 06/15/2018] [Indexed: 12/14/2022]
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24
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Koyama R, Mannic T, Ito J, Amar L, Zennaro MC, Rossier MF, Maturana AD. MicroRNA-204 Is Necessary for Aldosterone-Stimulated T-Type Calcium Channel Expression in Cardiomyocytes. Int J Mol Sci 2018; 19:E2941. [PMID: 30262720 PMCID: PMC6212903 DOI: 10.3390/ijms19102941] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/14/2018] [Revised: 09/14/2018] [Accepted: 09/19/2018] [Indexed: 01/03/2023] Open
Abstract
Activation of the mineralocorticoid receptor (MR) in the heart is considered to be a cardiovascular risk factor. MR activation leads to heart hypertrophy and arrhythmia. In ventricular cardiomyocytes, aldosterone induces a profound remodeling of ion channel expression, in particular, an increase in the expression and activity of T-type voltage-gated calcium channels (T-channels). The molecular mechanisms immediately downstream from MR activation, which lead to the increased expression of T-channels and, consecutively, to an acceleration of spontaneous cell contractions in vitro, remain poorly investigated. Here, we investigated the putative role of a specific microRNA in linking MR activation to the regulation of T-channel expression and cardiomyocyte beating frequency. A screening assay identified microRNA 204 (miR-204) as one of the major upregulated microRNAs after aldosterone stimulation of isolated neonatal rat cardiomyocytes. Aldosterone significantly increased the level of miR-204, an effect blocked by the MR antagonist spironolactone. When miR-204 was overexpressed in isolated cardiomyocytes, their spontaneous beating frequency was significantly increased after 24 h, like upon aldosterone stimulation, and messenger RNAs coding T-channels (CaV3.1 and CaV3.2) were increased. Concomitantly, T-type calcium currents were significantly increased upon miR-204 overexpression. Specifically repressing the expression of miR-204 abolished the aldosterone-induced increase of CaV3.1 and CaV3.2 mRNAs, as well as T-type calcium currents. Finally, aldosterone and miR-204 overexpression were found to reduce REST-NRSF, a known transcriptional repressor of CaV3.2 T-type calcium channels. Our study thus strongly suggests that miR-204 expression stimulated by aldosterone promotes the expression of T-channels in isolated rat ventricular cardiomyocytes, and therefore, increases the frequency of the cell spontaneous contractions, presumably through the inhibition of REST-NRSF protein.
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Affiliation(s)
- Riko Koyama
- Graduate School of Bioagricultural Sciences, Nagoya University, Nagoya 464-8601, Japan.
| | - Tiphaine Mannic
- Department of Human Protein Science, University of Geneva, CH-1211 Geneva, Switzerland.
| | - Jumpei Ito
- Graduate School of Bioagricultural Sciences, Nagoya University, Nagoya 464-8601, Japan.
| | - Laurence Amar
- Inserm, UMRS_970, Paris Cardiovascular Research Center, 75015 Paris, France.
- Université Paris Descartes, Sorbonne Paris Cité, 75015 Paris, France.
- Assistance Publique-Hôpitaux de Paris, Hôpital Européen Georges Pompidou, Unité Hypertension artérielle, 75015 Paris, France.
| | - Maria-Christina Zennaro
- Inserm, UMRS_970, Paris Cardiovascular Research Center, 75015 Paris, France.
- Université Paris Descartes, Sorbonne Paris Cité, 75015 Paris, France.
- Assistance Publique-Hôpitaux de Paris, Hôpital Européen Georges Pompidou, Service de Génétique, 75015 Paris, France.
| | - Michel Florian Rossier
- Department of Human Protein Science, University of Geneva, CH-1211 Geneva, Switzerland.
- Central Institute of Hospitals, Hospital of Valais, CH-1951 Sion, Switzerland.
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25
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Okada M, Imoto K, Sugiyama A, Yasuda J, Yamawaki H. New Insights into the Role of Basement Membrane-Derived Matricryptins in the Heart. Biol Pharm Bull 2018; 40:2050-2060. [PMID: 29199230 DOI: 10.1248/bpb.b17-00308] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/22/2022]
Abstract
The extracellular matrix (ECM), which contributes to structural homeostasis as well as to the regulation of cellular function, is enzymatically cleaved by proteases, such as matrix metalloproteinases and cathepsins, in the normal and diseased heart. During the past two decades, matricryptins have been defined as fragments of ECM with a biologically active cryptic site, namely the 'matricryptic site,' and their biological activities have been initially identified and clarified, including anti-angiogenic and anti-tumor effects. Thus, matricryptins are expected to be novel anti-tumor drugs, and thus widely investigated. Although there are a smaller number of studies on the expression and function of matricryptins in fields other than cancer research, some matricryptins have been recently clarified to have biological functions beyond an anti-angiogenic effect in heart. This review particularly focuses on the expression and function of basement membrane-derived matricryptins, including arresten, canstatin, tumstatin, endostatin and endorepellin, during cardiac diseases leading to heart failure such as cardiac hypertrophy and myocardial infarction.
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Affiliation(s)
- Muneyoshi Okada
- Laboratory of Veterinary Pharmacology, School of Veterinary Medicine, Kitasato University
| | - Keisuke Imoto
- Laboratory of Veterinary Pharmacology, School of Veterinary Medicine, Kitasato University
| | - Akira Sugiyama
- Laboratory of Veterinary Pharmacology, School of Veterinary Medicine, Kitasato University
| | - Jumpei Yasuda
- Laboratory of Veterinary Pharmacology, School of Veterinary Medicine, Kitasato University
| | - Hideyuki Yamawaki
- Laboratory of Veterinary Pharmacology, School of Veterinary Medicine, Kitasato University
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Haverinen J, Hassinen M, Dash SN, Vornanen M. Expression of calcium channel transcripts in the zebrafish heart: dominance of T-type channels. ACTA ACUST UNITED AC 2018; 221:jeb.179226. [PMID: 29739832 DOI: 10.1242/jeb.179226] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/12/2018] [Accepted: 04/06/2018] [Indexed: 12/13/2022]
Abstract
Calcium channels are necessary for cardiac excitation-contraction (E-C) coupling, but Ca2+ channel composition of fish hearts is still largely unknown. To this end, we determined transcript expression of Ca2+ channels in the heart of zebrafish (Danio rerio), a popular model species. Altogether, 18 Ca2+ channel α-subunit genes were expressed in both atrium and ventricle. Transcripts for 7 L-type (Cav1.1a, Cav1.1b, Cav1.2, Cav1.3a, Cav1.3b, Cav1.4a, Cav1.4b), 5 T-type (Cav3.1, Cav3.2a, Cav3.2b, Cav3.3a, Cav3.3b) and 6 P/Q-, N- and R-type (Cav2.1a, Cav2.1b, Cav2.2a, Cav2.2b, Cav2.3a, Cav2.3b) Ca2+ channels were expressed. In the ventricle, T-type channels formed 54.9%, L-type channels 41.1% and P/Q-, N- and R-type channels 4.0% of the Ca2+ channel transcripts. In the atrium, the relative expression of T-type and L-type Ca2+ channel transcripts was 64.1% and 33.8%, respectively (others accounted for 2.1%). Thus, at the transcript level, T-type Ca2+ channels are prevalent in zebrafish atrium and ventricle. At the functional level, peak densities of ventricular T-type (ICaT) and L-type (ICaL) Ca2+ current were 6.3±0.8 and 7.7±0.8 pA pF-1, respectively. ICaT mediated a sizeable sarcolemmal Ca2+ influx into ventricular myocytes: the increment in total cellular Ca2+ content via ICaT was 41.2±7.3 µmol l-1, which was 31.7% of the combined Ca2+ influx (129 µmol l-1) via ICaT and ICaL (88.5±20.5 µmol l-1). The diversity of expressed Ca2+ channel genes in zebrafish heart is high, but dominated by the members of the T-type subfamily. The large ventricular ICaT is likely to play a significant role in E-C coupling.
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Affiliation(s)
- Jaakko Haverinen
- Department of Environmental and Biological Sciences, University of Eastern Finland, PO Box 111, 80101 Joensuu, Finland
| | - Minna Hassinen
- Department of Environmental and Biological Sciences, University of Eastern Finland, PO Box 111, 80101 Joensuu, Finland
| | - Surjya Narayan Dash
- Department of Environmental and Biological Sciences, University of Eastern Finland, PO Box 111, 80101 Joensuu, Finland.,Neuroscience Center and Department of Anatomy, Faculty of Medicine, University of Helsinki, PO Box 63, 00014 Helsinki, Finland
| | - Matti Vornanen
- Department of Environmental and Biological Sciences, University of Eastern Finland, PO Box 111, 80101 Joensuu, Finland
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Falcón D, González-Montelongo R, Sánchez de Rojas-de Pedro E, Ordóñez A, Ureña J, Castellano A. Dexamethasone-induced upregulation of Ca V3.2 T-type Ca 2+ channels in rat cardiac myocytes. J Steroid Biochem Mol Biol 2018; 178:193-202. [PMID: 29262379 DOI: 10.1016/j.jsbmb.2017.12.013] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/16/2017] [Revised: 11/21/2017] [Accepted: 12/14/2017] [Indexed: 12/27/2022]
Abstract
Glucocorticoids are widely used to treat acute and chronic diseases. Unfortunately, their therapeutic use is associated with severe side effects. Glucocorticoids are known to regulate several ion channels in cardiac myocytes, including voltage-dependent Ca2+ channels. Low-voltage-activated T-type Ca2+ channels are expressed in ventricular myocytes during the fetal and perinatal period, but are practically absent in the adult. However, these channels can be re-expressed in adult cardiomyocytes under some pathological conditions. We have investigated the glucocorticoid regulation of T-type Ca2+ channels in rat cardiomyocytes. Molecular studies revealed that dexamethasone induces the upregulation of CaV3.2 mRNA in neonatal rat ventricular myocytes, whereas CaV3.1 mRNA is only slightly affected. Patch-clamp recordings confirmed that T-type Ca2+ channel currents were upregulated in dexamethasone treated cardiomyocytes, and the addition of 50 μmol/L NiCl2 demonstrated that the CaV3.2 channel is responsible for this upregulation. The effect of dexamethasone on CaV3.2 is mediated by the activation and translocation to the cell nucleus of the glucocorticoid receptor (GR). We have isolated the upstream promoter of the Cacna1h gene and tested its activity in transfected ventricular myocytes. The initial in silico analysis of Cacna1h promoter revealed putative glucocorticoid response elements (GREs). Transcriptional activity assays combined with deletion analyses and chromatin immunoprecipitation assays demonstrated that GR binds to a region a GRE located in -1006/-985 bp of Cacna1h promoter. Importantly, upregulation of the CaV3.2 channel is also observed in vitro in adult rat ventricular myocytes, and in vivo in a rat model of excess of glucocorticoids.
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Affiliation(s)
- D Falcón
- Instituto de Biomedicina de Sevilla (IBiS), Hospital Universitario Virgen del Rocío/CSIC/ Universidad de Sevilla, Sevilla, Spain; Departamento de Fisiología Médica y Biofísica, Facultad de Medicina, Universidad de Sevilla, Sevilla, Spain
| | - R González-Montelongo
- Instituto de Biomedicina de Sevilla (IBiS), Hospital Universitario Virgen del Rocío/CSIC/ Universidad de Sevilla, Sevilla, Spain; Departamento de Fisiología Médica y Biofísica, Facultad de Medicina, Universidad de Sevilla, Sevilla, Spain
| | - E Sánchez de Rojas-de Pedro
- Instituto de Biomedicina de Sevilla (IBiS), Hospital Universitario Virgen del Rocío/CSIC/ Universidad de Sevilla, Sevilla, Spain
| | - A Ordóñez
- Instituto de Biomedicina de Sevilla (IBiS), Hospital Universitario Virgen del Rocío/CSIC/ Universidad de Sevilla, Sevilla, Spain; CIBERCV Instituto de Salud Carlos III, Madrid, Spain
| | - J Ureña
- Instituto de Biomedicina de Sevilla (IBiS), Hospital Universitario Virgen del Rocío/CSIC/ Universidad de Sevilla, Sevilla, Spain; Departamento de Fisiología Médica y Biofísica, Facultad de Medicina, Universidad de Sevilla, Sevilla, Spain
| | - A Castellano
- Instituto de Biomedicina de Sevilla (IBiS), Hospital Universitario Virgen del Rocío/CSIC/ Universidad de Sevilla, Sevilla, Spain; Departamento de Fisiología Médica y Biofísica, Facultad de Medicina, Universidad de Sevilla, Sevilla, Spain.
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Rubi L, Todt H, Kubista H, Koenig X, Hilber K. Calcium current properties in dystrophin-deficient ventricular cardiomyocytes from aged mdx mice. Physiol Rep 2018; 6:e13567. [PMID: 29333726 PMCID: PMC5789658 DOI: 10.14814/phy2.13567] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/07/2017] [Accepted: 12/11/2017] [Indexed: 11/24/2022] Open
Abstract
Duchenne muscular dystrophy (DMD), caused by mutations in the gene encoding for the cytoskeletal protein dystrophin, is linked with severe cardiac complications including cardiomyopathy development and cardiac arrhythmias. We and others recently reported that currents through L-type calcium (Ca) channels were significantly increased, and channel inactivation was reduced in dystrophin-deficient ventricular cardiomyocytes derived from the mdx mouse, the most commonly used animal model for human DMD. These gain-of-function Ca channel abnormalities may enhance the risk of Ca-dependent arrhythmias and cellular Ca overload in the dystrophic heart. All studies, which have so far investigated L-type Ca channel properties in dystrophic cardiomyocytes, have used hearts from either neonatal or young adult mdx mice as cell source. In consequence, the dimension of the Ca channel abnormalities present in the severely-diseased aged dystrophic heart has remained unknown. Here, we have studied potential abnormalities in Ca currents and intracellular Ca transients in ventricular cardiomyocytes derived from aged dystrophic mdx mice. We found that both the L-type and T-type Ca current properties of mdx cardiomyocytes were similar to those of myocytes derived from aged wild-type mice. Accordingly, Ca release from the sarcoplasmic reticulum was normal in cardiomyocytes from aged mdx mice. This suggests that, irrespective of the presence of a pronounced cardiomyopathy in aged mdx mice, Ca currents and Ca release in dystrophic cardiomyocytes are normal. Finally, our data imply that dystrophin- regulation of L-type Ca channel function in the heart is lost during aging.
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MESH Headings
- Action Potentials
- Aging/metabolism
- Animals
- Calcium/metabolism
- Calcium Channels, L-Type/genetics
- Calcium Channels, L-Type/metabolism
- Calcium Channels, T-Type/metabolism
- Calcium Signaling
- Cells, Cultured
- Heart Ventricles/cytology
- Heart Ventricles/growth & development
- Male
- Mice
- Mice, Inbred C57BL
- Mice, Inbred mdx
- Muscular Dystrophy, Duchenne/genetics
- Muscular Dystrophy, Duchenne/metabolism
- Myocytes, Cardiac/metabolism
- Myocytes, Cardiac/physiology
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Affiliation(s)
- Lena Rubi
- Center for Physiology and PharmacologyMedical University of ViennaViennaAustria
| | - Hannes Todt
- Center for Physiology and PharmacologyMedical University of ViennaViennaAustria
| | - Helmut Kubista
- Center for Physiology and PharmacologyMedical University of ViennaViennaAustria
| | - Xaver Koenig
- Center for Physiology and PharmacologyMedical University of ViennaViennaAustria
| | - Karlheinz Hilber
- Center for Physiology and PharmacologyMedical University of ViennaViennaAustria
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Kumari N, Gaur H, Bhargava A. Cardiac voltage gated calcium channels and their regulation by β-adrenergic signaling. Life Sci 2017; 194:139-149. [PMID: 29288765 DOI: 10.1016/j.lfs.2017.12.033] [Citation(s) in RCA: 22] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/23/2017] [Revised: 12/17/2017] [Accepted: 12/24/2017] [Indexed: 01/08/2023]
Abstract
Voltage-gated calcium channels (VGCCs) are the predominant source of calcium influx in the heart leading to calcium-induced calcium release and ultimately excitation-contraction coupling. In the heart, VGCCs are modulated by the β-adrenergic signaling. Signaling through β-adrenergic receptors (βARs) and modulation of VGCCs by β-adrenergic signaling in the heart are critical signaling and changes to these have been significantly implicated in heart failure. However, data related to calcium channel dysfunction in heart failure is divergent and contradictory ranging from reduced function to no change in the calcium current. Many recent studies have highlighted the importance of functional and spatial microdomains in the heart and that may be the key to answer several puzzling questions. In this review, we have briefly discussed the types of VGCCs found in heart tissues, their structure, and significance in the normal and pathological condition of the heart. More importantly, we have reviewed the modulation of VGCCs by βARs in normal and pathological conditions incorporating functional and structural aspects. There are different types of βARs, each having their own significance in the functioning of the heart. Finally, we emphasize the importance of location of proteins as it relates to their function and modulation by co-signaling molecules. Its implication on the studies of heart failure is speculated.
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Affiliation(s)
- Neema Kumari
- Ion Channel Biology Lab, Department of Biotechnology, Indian Institute of Technology Hyderabad, Telangana 502285, India
| | - Himanshu Gaur
- Ion Channel Biology Lab, Department of Biotechnology, Indian Institute of Technology Hyderabad, Telangana 502285, India
| | - Anamika Bhargava
- Ion Channel Biology Lab, Department of Biotechnology, Indian Institute of Technology Hyderabad, Telangana 502285, India.
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T-type and L-type Calcium Channel Blockers for the Treatment of Cardiac Iron Overload: An Update. J Cardiovasc Pharmacol 2017; 70:277-283. [DOI: 10.1097/fjc.0000000000000525] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/26/2022]
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Bernal Sierra YA, Haseleu J, Kozlenkov A, Bégay V, Lewin GR. Genetic Tracing of Ca v3.2 T-Type Calcium Channel Expression in the Peripheral Nervous System. Front Mol Neurosci 2017; 10:70. [PMID: 28360836 PMCID: PMC5350092 DOI: 10.3389/fnmol.2017.00070] [Citation(s) in RCA: 21] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/01/2016] [Accepted: 03/01/2017] [Indexed: 02/01/2023] Open
Abstract
Characterizing the distinct functions of the T-type ion channel subunits Cav3.1, 3.2 or 3.3 has proven difficult due to their highly conserved amino-acid sequences and the lack of pharmacological blockers specific for each subunit. To precisely determine the expression pattern of the Cav3.2 channel in the nervous system we generated two knock-in mouse strains that express EGFP or Cre recombinase under the control of the Cav3.2 gene promoter. We show that in the brains of these animals, the Cav3.2 channel is predominantly expressed in the dentate gyrus of the hippocampus. In the peripheral nervous system, the activation of the promoter starts at E9.5 in neural crest cells that will give rise to dorsal root ganglia (DRG) neurons, but not sympathetic neurons. As development progresses the number of DRG cells expressing the Cav3.2 channel reaches around 7% of the DRG at E16.5, and remains constant until E18.5. Characterization of sensory neuron subpopulations at E18.5 showed that EGFP+ cells are a heterogeneous population consisting mainly of TrkB+ and TrkC+ cells, while only a small percentage of DRG cells were TrkA+. Genetic tracing of the sensory nerve end-organ innervation of the skin showed that the activity of the Cav3.2 channel promoter in sensory progenitors marks many mechanoreceptor and nociceptor endings, but spares slowly adapting mechanoreceptors with endings associated with Merkel cells. Our genetic analysis reveals for the first time that progenitors that express the Cav3.2 T-type calcium channel, defines a sensory specific lineage that populates a large proportion of the DRG. Using our Cav3.2-Cre mice together with AAV viruses containing a conditional fluorescent reporter (tdTomato) we could also show that Cre expression is largely restricted to two functionally distinct sensory neuron types in the adult ganglia. Cav3.2 positive neurons innervating the skin were found to only form lanceolate endings on hair follicles and are probably identical to D-hair receptors. A second population of nociceptive sensory neurons expressing the Cav3.2 gene was found to be positive for the calcitonin-gene related peptide but these neurons are deep tissue nociceptors that do not innervate the skin.
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Affiliation(s)
- Yinth A Bernal Sierra
- Department of Neuroscience, Max Delbrück Center for Molecular Medicine in the Helmholtz Association and Charité - Universitätsmedizin Berlin Berlin, Germany
| | - Julia Haseleu
- Department of Neuroscience, Max Delbrück Center for Molecular Medicine in the Helmholtz Association and Charité - Universitätsmedizin Berlin Berlin, Germany
| | - Alexey Kozlenkov
- Department of Neuroscience, Max Delbrück Center for Molecular Medicine in the Helmholtz Association and Charité - Universitätsmedizin Berlin Berlin, Germany
| | - Valérie Bégay
- Department of Neuroscience, Max Delbrück Center for Molecular Medicine in the Helmholtz Association and Charité - Universitätsmedizin Berlin Berlin, Germany
| | - Gary R Lewin
- Department of Neuroscience, Max Delbrück Center for Molecular Medicine in the Helmholtz Association and Charité - Universitätsmedizin Berlin Berlin, Germany
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Li Z, Li S, Hu L, Li F, Cheung AC, Shao W, Que Y, Leung GPH, Yang C. MECHANISMS UNDERLYING ACTION OF XINMAILONG INJECTION, A TRADITIONAL CHINESE MEDICINE IN CARDIAC FUNCTION IMPROVEMENT. AFRICAN JOURNAL OF TRADITIONAL, COMPLEMENTARY, AND ALTERNATIVE MEDICINES : AJTCAM 2017; 14:241-252. [PMID: 28573241 PMCID: PMC5446449 DOI: 10.21010/ajtcam.v14i2.26] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
Abstract
BACKGROUND As a bioactive composite extracted from American cockroach, Xinmailong injection (XML) is used for the treatment of congestive heart failure (CHF) in China. Clinical data has provided evidence that XML has positive inotropic properties. The objective of this study was to assess the mechanisms involved in the therapeutical effect of XML on CHF. MATERIALS AND METHODS The effects of XML on the cardiac function in isolated rat heart were measured. A Ca2+ imaging technology was used in rat cardiomyocytes (H9c2 cells) to reveal the role of XML on Ca2+ channels. Meanwhile, the effects of XML on the activities of Na+/K+ ATPase and sodium/calcium exchanger were measured. In addition, the level of reactive oxygen species and the protein expressions for the superoxide dismutase and hemeoxygenase were determined in the cardiomyocytes. RESULTS The results showed that XML increased the electrical impulse-induced [Ca2+]i in H9c2 cells, which was dependant on extracellular Ca2+ and was abolished by ML218-HCl (a T-type Ca2+channels antagonist) but not nimodipine (a L-type Ca2+channels antagonist). Ouabain, a Na+/K+-ATPase inhibitor, increased the electrical impulse-induced [Ca2+]i, which was significantly inhibited by XML. Moreover, XML markedly inhibited the Na+/K+ ATPase activity in H9c2 cells. In addition, XML notably reduced the production of reactive oxygen species and enhanced the protein expressions of antioxidant enzymes including superoxide dismutase 1, superoxide dismutase 2 and hemeoxygenase 1 in H9c2 cell. CONCLUSION Our findings pave the ways to the better understandings of the therapeutic effects of XML on cardiovascular system.
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Affiliation(s)
- Zhengtao Li
- Ethnic Drug Screening & Pharmacology Center, Key Laboratory of Chemistry in Ethnic Medicinal Resources, State Ethnic Affairs Commission & Ministry of Education, Yunnan Minzu University, Kunming 650500, P.R. China
| | - Sujuan Li
- Ethnic Drug Screening & Pharmacology Center, Key Laboratory of Chemistry in Ethnic Medicinal Resources, State Ethnic Affairs Commission & Ministry of Education, Yunnan Minzu University, Kunming 650500, P.R. China
| | - Lin Hu
- Ethnic Drug Screening & Pharmacology Center, Key Laboratory of Chemistry in Ethnic Medicinal Resources, State Ethnic Affairs Commission & Ministry of Education, Yunnan Minzu University, Kunming 650500, P.R. China
| | - Fang Li
- Ethnic Drug Screening & Pharmacology Center, Key Laboratory of Chemistry in Ethnic Medicinal Resources, State Ethnic Affairs Commission & Ministry of Education, Yunnan Minzu University, Kunming 650500, P.R. China
| | - Alex Chun Cheung
- Department of Pharmacology & Pharmacy, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong SAR, P.R. China
| | - Weizai Shao
- Tengyao Pharmaceutical Company Limited by Shares Yunnan, Tengchong 679100, P.R. China
| | - Yuling Que
- Tengyao Pharmaceutical Company Limited by Shares Yunnan, Tengchong 679100, P.R. China
| | - George Pek-heng Leung
- Department of Pharmacology & Pharmacy, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong SAR, P.R. China
| | - Cui Yang
- Ethnic Drug Screening & Pharmacology Center, Key Laboratory of Chemistry in Ethnic Medicinal Resources, State Ethnic Affairs Commission & Ministry of Education, Yunnan Minzu University, Kunming 650500, P.R. China
- Department of Pharmacology & Pharmacy, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong SAR, P.R. China
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Vornanen M. Electrical Excitability of the Fish Heart and Its Autonomic Regulation. FISH PHYSIOLOGY 2017. [DOI: 10.1016/bs.fp.2017.04.002] [Citation(s) in RCA: 18] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/19/2022]
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Tamargo J, Ruilope LM. Investigational calcium channel blockers for the treatment of hypertension. Expert Opin Investig Drugs 2016; 25:1295-1309. [DOI: 10.1080/13543784.2016.1241764] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/26/2023]
Affiliation(s)
- J Tamargo
- Department of Pharmacology, School of Medicine, Instituto de Investigación Sanitaria Gregorio Marañón, Universidad Complutense, Madrid, Spain. CIBER of Cardiovascular Diseases
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Limbu B, Shah K, Weinberg SH, Deo M. Role of Cytosolic Calcium Diffusion in Murine Cardiac Purkinje Cells. CLINICAL MEDICINE INSIGHTS-CARDIOLOGY 2016; 10:17-26. [PMID: 27478391 PMCID: PMC4955978 DOI: 10.4137/cmc.s39705] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/28/2016] [Revised: 06/12/2016] [Accepted: 06/25/2016] [Indexed: 11/24/2022]
Abstract
Cardiac Purkinje cells (PCs) are morphologically and electrophysiologically different from ventricular myocytes and, importantly, exhibit distinct calcium (Ca2+) homeostasis. Recent studies suggest that PCs are more susceptible to action potential (AP) abnormalities than ventricular myocytes; however, the exact mechanisms are poorly understood. In this study, we utilized a detailed biophysical mathematical model of a murine PC to systematically examine the role of cytosolic Ca2+ diffusion in shaping the AP in PCs. A biphasic spatiotemporal Ca2+ diffusion process, as recorded experimentally, was implemented in the model. In this study, we investigated the role of cytosolic Ca2+ dynamics on AP and ionic current properties by varying the effective Ca2+ diffusion rate. It was observed that AP morphology, specifically the plateau, was affected due to changes in the intracellular Ca2+ dynamics. Elevated Ca2+ concentration in the sarcolemmal region activated inward sodium–Ca2+ exchanger (NCX) current, resulting in a prolongation of the AP plateau at faster diffusion rates. Artificially clamping the NCX current to control values completely reversed the alterations in the AP plateau, thus confirming the role of NCX in modifying the AP morphology. Our results demonstrate that cytosolic Ca2+ diffusion waves play a significant role in shaping APs of PCs and could provide mechanistic insights in the increased arrhythmogeneity of PCs.
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Affiliation(s)
- Bijay Limbu
- Department of Engineering, Norfolk State University, Norfolk, VA, USA
| | - Kushal Shah
- Department of Engineering, Norfolk State University, Norfolk, VA, USA
| | - Seth H Weinberg
- Department of Biomedical Engineering, Virginia Commonwealth University, Richmond, VA, USA
| | - Makarand Deo
- Department of Engineering, Norfolk State University, Norfolk, VA, USA
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Santamaria-Herrera MA, Ríos-Pérez EB, de la Rosa JAM, García-Castañeda M, Osornio-Garduño DS, Ramos-Mondragón R, Mancilla-Percino T, Avila G. MDIMP, a novel cardiac Ca(2+) channel blocker with atrial selectivity. Eur J Pharmacol 2016; 781:218-28. [PMID: 27089820 DOI: 10.1016/j.ejphar.2016.04.027] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/17/2016] [Revised: 04/12/2016] [Accepted: 04/13/2016] [Indexed: 11/20/2022]
Abstract
In cardiac muscle cells both T-and L-type Ca(2+) channels (TTCCs and LTCCs, respectively) are expressed, and the latter are relevant to a process known as excitation-contraction coupling (ECC). Evidence obtained from docking studies suggests that isoindolines derived from α-amino acids bind to the LTCC CaV1.2. In the present study, we investigated whether methyl (S)-2-(1,3-dihydroisoindol-2-yl)-4-methylpentanoate (MDIMP), which is derived from L-leucine, modulates both Ca(2+) channels and ECC. To this end, mechanical properties, as well as Ca(2+) transients and currents, were all investigated in isolated cardiac myocytes. The effects of MDIMP on CaV1.2 (transiently expressed in 293T/17 cells) were also studied. In this system, evidence was found for an inhibitory action that develops and recovers in min, with an IC50 of 450µM. With respect to myocytes: atrial-TTCCs, atrial-LTCCs, and ventricular-LTCCs were also inhibited, in that order of potency. Accordingly, Ca(2+) transients, contractions, and window currents of LTCCs were all reduced more strongly in atrial cells. Interestingly, while the modulation of LTCCs was state-independent in these cells, it was state-dependent, and dual, on the ventricular ones. Furthermore, practically all of the ventricular LTCCs were closed at resting membrane potentials. This could explain their resistance to MDIMP, as they were affected in only open or inactivated states. All these features in turn explain the preferential down-regulation of the atrial ECC. Thus, our results support the view that isoindolines bind to Ca(2+) channels, improve our knowledge of the corresponding structure-function relationship, and may be relevant for conditions where decreased atrial activity is desired.
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Affiliation(s)
| | | | | | | | | | - Roberto Ramos-Mondragón
- Department of Biochemistry, Cinvestav-IPN, AP 14-740, México City, DF 07000, Mexico; Division of Cardiovascular Medicine, Department of Internal Medicine, University of Michigan, 2800 Plymouth Rd, 26-235N, Ann Arbor, MI 48109, USA
| | | | - Guillermo Avila
- Department of Biochemistry, Cinvestav-IPN, AP 14-740, México City, DF 07000, Mexico.
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Endostatin is protective against monocrotaline-induced right heart disease through the inhibition of T-type Ca(2+) channel. Pflugers Arch 2016; 468:1259-1270. [PMID: 27023352 DOI: 10.1007/s00424-016-1810-0] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/20/2015] [Revised: 03/03/2016] [Accepted: 03/15/2016] [Indexed: 12/27/2022]
Abstract
Endostatin (ES), a C-terminal fragment of collagen XVIIIα1, has a potent anti-angiogenic effect. ES prevents tumor proliferation through inhibiting T-type Ca(2+) channel. T-type Ca(2+) channel is re-expressed during heart diseases including monocrotaline (MCT)-induced right heart failure. The present study aimed to clarify the effects of ES on T-type Ca(2+) channel and pathogenesis of MCT-induced right ventricular disease. MCT or saline was injected intraperitoneally to rats. After cardiomyocytes were isolated from right ventricles (RVs), T-type Ca(2+) channel current (I CaT) was measured by a patch-clamp method. After ES small interfering RNA (siRNA) or control siRNA (20 μg) was administrated for 1 week via the right jugular vein 1 week after MCT injection, echocardiography and histological analysis were done. I CaT was significantly increased in RV from MCT-injected rats, and ES significantly inhibited it. The survival rate of ES siRNA-administrated MCT rats (MCT ES si group) was decreased. In echocardiography, although ES siRNA did not affect pulmonary arterial pressure, RV systolic function was impaired in MCT ES si group compared with control siRNA-administrated MCT rats (MCT cont si group). In the histological analysis of RV, ES expression was increased in MCT cont si group, and ES siRNA inhibited it. Furthermore, although MCT cont si group showed only cardiomyocyte hypertrophy, MCT ES si group showed notable enlargement of intercellular spaces. The present study for the first time revealed that ES inhibits T-type Ca(2+) channel activity in RV from MCT-injected rats. ES gene knockdown deteriorates MCT-induced right heart disease. ES is thus cardioprotective possibly through inhibiting T-type Ca(2+) channel activity.
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González-Rodríguez P, Falcón D, Castro MJ, Ureña J, López-Barneo J, Castellano A. Hypoxic induction of T-type Ca(2+) channels in rat cardiac myocytes: role of HIF-1α and RhoA/ROCK signalling. J Physiol 2015; 593:4729-45. [PMID: 26331302 DOI: 10.1113/jp271053] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/29/2015] [Accepted: 08/24/2015] [Indexed: 01/08/2023] Open
Abstract
T-type Ca(2+) channels are expressed in the ventricular myocytes of the fetal and perinatal heart, but are normally downregulated as development progresses. Interestingly, however, these channels are re-expressed in adult cardiomyocytes under pathological conditions. We investigated low voltage-activated T-type Ca(2+) channel regulation in hypoxia in rat cardiomyocytes. Molecular studies revealed that hypoxia induces the upregulation of Cav 3.2 mRNA, whereas Cav 3.1 mRNA is not significantly altered. The effect of hypoxia on Cav 3.2 mRNA was time- and dose-dependent, and required hypoxia inducible factor-1α (HIF-1α) stabilization. Patch-clamp recordings confirmed that T-type Ca(2+) channel currents were upregulated in hypoxic conditions, and the addition of 50 μm NiCl2 (a T-type channel blocker) demonstrated that the Cav 3.2 channel is responsible for this upregulation. This increase in current density was not accompanied by significant changes in the Cav 3.2 channel electrophysiological properties. The small monomeric G-protein RhoA and its effector Rho-associated kinase I (ROCKI), which are known to play important roles in cardiovascular physiology, were also upregulated in neonatal rat ventricular myocytes subjected to hypoxia. Pharmacological experiments indicated that both proteins were involved in the observed upregulation of the Cav 3.2 channel and the stabilization of HIF-1α that occurred in response to hypoxia. These results suggest a possible role for Cav 3.2 channels in the increased probability of developing arrhythmias observed in ischaemic situations, and in the pathogenesis of diseases associated with hypoxic Ca(2+) overload.
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Affiliation(s)
- P González-Rodríguez
- Instituto de Biomedicina de Sevilla (IBiS), Hospital Universitario Virgen del Rocío/CSIC/Universidad de Sevilla, Sevilla, Spain.,Departamento de Fisiología Médica y Biofísica, Facultad de Medicina, Universidad de Sevilla, Sevilla, Spain
| | - D Falcón
- Instituto de Biomedicina de Sevilla (IBiS), Hospital Universitario Virgen del Rocío/CSIC/Universidad de Sevilla, Sevilla, Spain.,Departamento de Fisiología Médica y Biofísica, Facultad de Medicina, Universidad de Sevilla, Sevilla, Spain
| | - M J Castro
- Instituto de Biomedicina de Sevilla (IBiS), Hospital Universitario Virgen del Rocío/CSIC/Universidad de Sevilla, Sevilla, Spain
| | - J Ureña
- Instituto de Biomedicina de Sevilla (IBiS), Hospital Universitario Virgen del Rocío/CSIC/Universidad de Sevilla, Sevilla, Spain.,Departamento de Fisiología Médica y Biofísica, Facultad de Medicina, Universidad de Sevilla, Sevilla, Spain
| | - J López-Barneo
- Instituto de Biomedicina de Sevilla (IBiS), Hospital Universitario Virgen del Rocío/CSIC/Universidad de Sevilla, Sevilla, Spain.,Departamento de Fisiología Médica y Biofísica, Facultad de Medicina, Universidad de Sevilla, Sevilla, Spain
| | - A Castellano
- Instituto de Biomedicina de Sevilla (IBiS), Hospital Universitario Virgen del Rocío/CSIC/Universidad de Sevilla, Sevilla, Spain.,Departamento de Fisiología Médica y Biofísica, Facultad de Medicina, Universidad de Sevilla, Sevilla, Spain
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40
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Pushparaj C, Das A, Purroy R, Nàger M, Herreros J, Pamplona R, Cantí C. Voltage-gated calcium channel blockers deregulate macroautophagy in cardiomyocytes. Int J Biochem Cell Biol 2015; 68:166-75. [PMID: 26429067 DOI: 10.1016/j.biocel.2015.09.010] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/27/2015] [Revised: 09/04/2015] [Accepted: 09/26/2015] [Indexed: 10/23/2022]
Abstract
Voltage-gated calcium channel blockers are widely used for the management of cardiovascular diseases, however little is known about their effects on cardiac cells in vitro. We challenged neonatal ventricular cardiomyocytes (CMs) with therapeutic L-type and T-type Ca(2+) channel blockers (nifedipine and mibefradil, respectively), and measured their effects on cell stress and survival, using fluorescent microscopy, Q-PCR and Western blot. Both nifedipine and mibefradil induced a low-level and partially transient up-regulation of three key mediators of the Unfolded Protein Response (UPR), indicative of endoplasmic (ER) reticulum stress. Furthermore, nifedipine triggered the activation of macroautophagy, as evidenced by increased lipidation of microtubule-associated protein 1 light chain 3 (LC3), decreased levels of polyubiquitin-binding protein p62/SQSTM1 and ubiquitinated protein aggregates, that was followed by cell death. In contrast, mibefradil inhibited CMs constitutive macroautophagy and did not promote cell death. The siRNA-mediated gene silencing approach confirmed the pharmacological findings for T-type channels. We conclude that L-type and T-type Ca(2+) channel blockers induce ER stress, which is divergently transduced into macroautophagy induction and inhibition, respectively, with relevance for cell viability. Our work identifies VGCCs as novel regulators of autophagy in the heart muscle and provides new insights into the effects of VGCC blockers on CMs homeostasis, that may underlie both noxious and cardioprotective effects.
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Affiliation(s)
- Charumathi Pushparaj
- Universitat de Lleida, Institut de Recerca Biomèdica de Lleida (IRBLleida), Spain
| | - Arindam Das
- Universitat de Lleida, Institut de Recerca Biomèdica de Lleida (IRBLleida), Spain
| | - Rosa Purroy
- Universitat de Lleida, Institut de Recerca Biomèdica de Lleida (IRBLleida), Spain
| | - Mireia Nàger
- Universitat de Lleida, Institut de Recerca Biomèdica de Lleida (IRBLleida), Spain
| | - Judit Herreros
- Universitat de Lleida, Institut de Recerca Biomèdica de Lleida (IRBLleida), Spain
| | - Reinald Pamplona
- Universitat de Lleida, Institut de Recerca Biomèdica de Lleida (IRBLleida), Spain
| | - Carles Cantí
- Universitat de Lleida, Institut de Recerca Biomèdica de Lleida (IRBLleida), Spain.
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41
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Marcu IC, Illaste A, Heuking P, Jaconi ME, Ullrich ND. Functional Characterization and Comparison of Intercellular Communication in Stem Cell-Derived Cardiomyocytes. Stem Cells 2015; 33:2208-18. [PMID: 25968594 DOI: 10.1002/stem.2009] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/24/2014] [Accepted: 03/08/2015] [Indexed: 02/05/2023]
Abstract
One novel treatment strategy for the diseased heart focuses on the use of pluripotent stem cell-derived cardiomyocytes (SC-CMs) to overcome the heart's innate deficiency for self-repair. However, targeted application of SC-CMs requires in-depth characterization of their true cardiogenic potential in terms of excitability and intercellular coupling at cellular level and in multicellular preparations. In this study, we elucidated the electrical characteristics of single SC-CMs and intercellular coupling quality of cell pairs, and concomitantly compared them with well-characterized murine native neonatal and immortalized HL-1 cardiomyocytes. Firstly, we investigated the electrical properties and Ca(2+) signaling mechanisms specific to cardiac contraction in single SC-CMs. Despite heterogeneity of the new cardiac cell population, their electrophysiological activity and Ca(2+) handling were similar to native cells. Secondly, we investigated the capability of paired SC-CMs to form an adequate subunit of a functional syncytium and analyzed gap junctions and signal transmission by dye transfer in cell pairs. We discovered significantly diminished coupling in SC-CMs compared with native cells, which could not be enhanced by a coculture approach combining SC-CMs and primary CMs. Moreover, quantitative and structural analysis of gap junctions presented significantly reduced connexin expression levels compared with native CMs. Strong dependence of intercellular coupling on gap junction density was further confirmed by computational simulations. These novel findings demonstrate that despite the cardiogenic electrophysiological profile, SC-CMs present significant limitations in intercellular communication. Inadequate coupling may severely impair functional integration and signal transmission, which needs to be carefully considered for the prospective use of SC-CMs in cardiac repair. Stem Cells 2015;33:2208-2218.
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Affiliation(s)
- Irene C Marcu
- Department of Physiology, University of Bern, Bern, Switzerland.,Department of Physiology and Pathophysiology, University of Heidelberg, Heidelberg, Germany
| | - Ardo Illaste
- Department of Physiology, University of Bern, Bern, Switzerland
| | - Pernilla Heuking
- Department of Pathology and Immunology, University of Geneva, Geneva, Switzerland
| | - Marisa E Jaconi
- Department of Pathology and Immunology, University of Geneva, Geneva, Switzerland
| | - Nina D Ullrich
- Department of Physiology, University of Bern, Bern, Switzerland.,Department of Physiology and Pathophysiology, University of Heidelberg, Heidelberg, Germany
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42
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The Cardioprotective Effects of Hydrogen Sulfide in Heart Diseases: From Molecular Mechanisms to Therapeutic Potential. OXIDATIVE MEDICINE AND CELLULAR LONGEVITY 2015; 2015:925167. [PMID: 26078822 PMCID: PMC4442295 DOI: 10.1155/2015/925167] [Citation(s) in RCA: 100] [Impact Index Per Article: 10.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 11/03/2014] [Accepted: 12/18/2014] [Indexed: 11/23/2022]
Abstract
Hydrogen sulfide (H2S) is now recognized as a third gaseous mediator along with nitric oxide (NO) and carbon monoxide (CO), though it was originally considered as a malodorous and toxic gas. H2S is produced endogenously from cysteine by three enzymes in mammalian tissues. An increasing body of evidence suggests the involvement of H2S in different physiological and pathological processes. Recent studies have shown that H2S has the potential to protect the heart against myocardial infarction, arrhythmia, hypertrophy, fibrosis, ischemia-reperfusion injury, and heart failure. Some mechanisms, such as antioxidative action, preservation of mitochondrial function, reduction of apoptosis, anti-inflammatory responses, angiogenic actions, regulation of ion channel, and interaction with NO, could be responsible for the cardioprotective effect of H2S. Although several mechanisms have been identified, there is a need for further research to identify the specific molecular mechanism of cardioprotection in different cardiac diseases. Therefore, insight into the molecular mechanisms underlying H2S action in the heart may promote the understanding of pathophysiology of cardiac diseases and lead to new therapeutic targets based on modulation of H2S production.
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Bladen C, McDaniel SW, Gadotti VM, Petrov RR, Berger ND, Diaz P, Zamponi GW. Characterization of novel cannabinoid based T-type calcium channel blockers with analgesic effects. ACS Chem Neurosci 2015; 6:277-87. [PMID: 25314588 PMCID: PMC4372069 DOI: 10.1021/cn500206a] [Citation(s) in RCA: 38] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/04/2022] Open
Abstract
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Low-voltage-activated
(T-type) calcium channels are important regulators
of the transmission of nociceptive information in the primary afferent
pathway and finding ligands that modulate these channels is a key
focus of the drug discovery field. Recently, we characterized a set
of novel compounds with mixed cannabinoid receptor/T-type channel
blocking activity and examined their analgesic effects in animal models
of pain. Here, we have built on these previous findings and synthesized
a new series of small organic compounds. We then screened them using
whole-cell voltage clamp techniques to identify the most potent T-type
calcium channel inhibitors. The two most potent blockers (compounds 9 and 10) were then characterized using radioligand
binding assays to determine their affinity for CB1 and CB2 receptors.
The structure–activity relationship and optimization studies
have led to the discovery of a new T-type calcium channel blocker,
compound 9. Compound 9 was efficacious in
mediating analgesia in mouse models of acute inflammatory pain and
in reducing tactile allodynia in the partial nerve ligation model.
This compound was shown to be ineffective in Cav3.2 T-type calcium
channel null mice at therapeutically relevant concentrations, and
it caused no significant motor deficits in open field tests. Taken
together, our data reveal a novel class of compounds whose physiological
and therapeutic actions are mediated through block of Cav3.2 calcium
channels.
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Affiliation(s)
- Chris Bladen
- Department of Physiology & Pharmacology, Hotchkiss Brain Institute, Cumming School of Medicine, University of Calgary, Calgary, AB T2N 1N4, Canada
| | - Steven W. McDaniel
- Core
Laboratory for Neuromolecular Production, The University of Montana, Missoula, Montana 59812, United States
| | - Vinicius M. Gadotti
- Department of Physiology & Pharmacology, Hotchkiss Brain Institute, Cumming School of Medicine, University of Calgary, Calgary, AB T2N 1N4, Canada
| | - Ravil R. Petrov
- Core
Laboratory for Neuromolecular Production, The University of Montana, Missoula, Montana 59812, United States
| | - N. Daniel Berger
- Department of Physiology & Pharmacology, Hotchkiss Brain Institute, Cumming School of Medicine, University of Calgary, Calgary, AB T2N 1N4, Canada
| | - Philippe Diaz
- Core
Laboratory for Neuromolecular Production, The University of Montana, Missoula, Montana 59812, United States
| | - Gerald W. Zamponi
- Department of Physiology & Pharmacology, Hotchkiss Brain Institute, Cumming School of Medicine, University of Calgary, Calgary, AB T2N 1N4, Canada
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44
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Alday A, Alonso H, Gallego M, Urrutia J, Letamendia A, Callol C, Casis O. Ionic channels underlying the ventricular action potential in zebrafish embryo. Pharmacol Res 2014; 84:26-31. [DOI: 10.1016/j.phrs.2014.03.011] [Citation(s) in RCA: 32] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/17/2014] [Revised: 03/28/2014] [Accepted: 03/31/2014] [Indexed: 01/31/2023]
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45
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Zhang Y, Wang H, Qian Z, Feng B, Zhao X, Jiang X, Tao J. Low-voltage-activated T-type Ca2+ channel inhibitors as new tools in the treatment of glioblastoma: the role of endostatin. Pflugers Arch 2014; 466:811-8. [PMID: 24407946 DOI: 10.1007/s00424-013-1427-5] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/27/2013] [Revised: 12/16/2013] [Accepted: 12/18/2013] [Indexed: 11/25/2022]
Abstract
Ca(2+) plays a key role in intracellular signaling and controls various cellular processes such as proliferation, differentiation, cell growth, death, and apoptosis. Aberrant changes in intracellular Ca(2+) levels can promote undesired cell proliferation and migration and are therefore associated with certain tumor types. Many research groups have suggested a potential role for voltage-gated Ca(2+) channels in the regulation of tumor growth and progression, particularly T-type channels due to their unique biophysical properties. T-type channels are expressed in normal tissues throughout the body and in different types of tumors such as breast carcinoma, retinoblastoma, neuroblastoma, and glioma. It has been demonstrated that increased functional expression of the α1 subunit of T-type channels plays a role in the abnormal proliferation of glioblastoma cells. As such, siRNA-mediated knockdown of the expression of the α1 subunit of T-type channels decreases the proliferation of these cells. Moreover, pharmacological blockade of T-type channels significantly decreases tumor growth. In this review, we focus on the use of T-type channel blockers for the potential treatment of cancers, particularly highly proliferative tumors such as glioblastoma. We conclude that T-type channel blockers such as endostatin can serve as a potential therapeutic tool for tumors whose proliferation depends on increased T-type channel expression.
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Affiliation(s)
- Yuan Zhang
- The Special Procurement Ward, Department of Geriatrics & Neurology, The Second Affiliated Hospital of Soochow University, Suzhou, 215004, China
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46
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Le Quang K, Benito B, Naud P, Qi XY, Shi YF, Tardif JC, Gillis MA, Dobrev D, Charpentier F, Nattel S. T-Type Calcium Current Contributes to Escape Automaticity and Governs the Occurrence of Lethal Arrhythmias After Atrioventricular Block in Mice. Circ Arrhythm Electrophysiol 2013; 6:799-808. [DOI: 10.1161/circep.113.000407] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/16/2022]
Affiliation(s)
- Khai Le Quang
- From the Department of Medicine and Research Centre, Montreal Heart Institute, Université de Montréal, Montreal, Quebec, Canada (K.L.Q., B.B., P.N., X.Y.Q., Y.F.S., J.-C.T., M.-A.G., S.N.); Department of Medicine, Laval University, Quebec, Canada (K.L.Q.); IMIM Parc de Salut Mar, Hospital del Mar, Barcelona, Spain (B.B.); Institute of Pharmacology, University of Duisburg-Essen, Essen, Germany (D.D.); Division of Experimental Cardiology, University of Heidelberg, Heidelberg, Germany (D.D.); and
| | - Begoña Benito
- From the Department of Medicine and Research Centre, Montreal Heart Institute, Université de Montréal, Montreal, Quebec, Canada (K.L.Q., B.B., P.N., X.Y.Q., Y.F.S., J.-C.T., M.-A.G., S.N.); Department of Medicine, Laval University, Quebec, Canada (K.L.Q.); IMIM Parc de Salut Mar, Hospital del Mar, Barcelona, Spain (B.B.); Institute of Pharmacology, University of Duisburg-Essen, Essen, Germany (D.D.); Division of Experimental Cardiology, University of Heidelberg, Heidelberg, Germany (D.D.); and
| | - Patrice Naud
- From the Department of Medicine and Research Centre, Montreal Heart Institute, Université de Montréal, Montreal, Quebec, Canada (K.L.Q., B.B., P.N., X.Y.Q., Y.F.S., J.-C.T., M.-A.G., S.N.); Department of Medicine, Laval University, Quebec, Canada (K.L.Q.); IMIM Parc de Salut Mar, Hospital del Mar, Barcelona, Spain (B.B.); Institute of Pharmacology, University of Duisburg-Essen, Essen, Germany (D.D.); Division of Experimental Cardiology, University of Heidelberg, Heidelberg, Germany (D.D.); and
| | - Xiao Yan Qi
- From the Department of Medicine and Research Centre, Montreal Heart Institute, Université de Montréal, Montreal, Quebec, Canada (K.L.Q., B.B., P.N., X.Y.Q., Y.F.S., J.-C.T., M.-A.G., S.N.); Department of Medicine, Laval University, Quebec, Canada (K.L.Q.); IMIM Parc de Salut Mar, Hospital del Mar, Barcelona, Spain (B.B.); Institute of Pharmacology, University of Duisburg-Essen, Essen, Germany (D.D.); Division of Experimental Cardiology, University of Heidelberg, Heidelberg, Germany (D.D.); and
| | - Yan Fen Shi
- From the Department of Medicine and Research Centre, Montreal Heart Institute, Université de Montréal, Montreal, Quebec, Canada (K.L.Q., B.B., P.N., X.Y.Q., Y.F.S., J.-C.T., M.-A.G., S.N.); Department of Medicine, Laval University, Quebec, Canada (K.L.Q.); IMIM Parc de Salut Mar, Hospital del Mar, Barcelona, Spain (B.B.); Institute of Pharmacology, University of Duisburg-Essen, Essen, Germany (D.D.); Division of Experimental Cardiology, University of Heidelberg, Heidelberg, Germany (D.D.); and
| | - Jean-Claude Tardif
- From the Department of Medicine and Research Centre, Montreal Heart Institute, Université de Montréal, Montreal, Quebec, Canada (K.L.Q., B.B., P.N., X.Y.Q., Y.F.S., J.-C.T., M.-A.G., S.N.); Department of Medicine, Laval University, Quebec, Canada (K.L.Q.); IMIM Parc de Salut Mar, Hospital del Mar, Barcelona, Spain (B.B.); Institute of Pharmacology, University of Duisburg-Essen, Essen, Germany (D.D.); Division of Experimental Cardiology, University of Heidelberg, Heidelberg, Germany (D.D.); and
| | - Marc-Antoine Gillis
- From the Department of Medicine and Research Centre, Montreal Heart Institute, Université de Montréal, Montreal, Quebec, Canada (K.L.Q., B.B., P.N., X.Y.Q., Y.F.S., J.-C.T., M.-A.G., S.N.); Department of Medicine, Laval University, Quebec, Canada (K.L.Q.); IMIM Parc de Salut Mar, Hospital del Mar, Barcelona, Spain (B.B.); Institute of Pharmacology, University of Duisburg-Essen, Essen, Germany (D.D.); Division of Experimental Cardiology, University of Heidelberg, Heidelberg, Germany (D.D.); and
| | - Dobromir Dobrev
- From the Department of Medicine and Research Centre, Montreal Heart Institute, Université de Montréal, Montreal, Quebec, Canada (K.L.Q., B.B., P.N., X.Y.Q., Y.F.S., J.-C.T., M.-A.G., S.N.); Department of Medicine, Laval University, Quebec, Canada (K.L.Q.); IMIM Parc de Salut Mar, Hospital del Mar, Barcelona, Spain (B.B.); Institute of Pharmacology, University of Duisburg-Essen, Essen, Germany (D.D.); Division of Experimental Cardiology, University of Heidelberg, Heidelberg, Germany (D.D.); and
| | - Flavien Charpentier
- From the Department of Medicine and Research Centre, Montreal Heart Institute, Université de Montréal, Montreal, Quebec, Canada (K.L.Q., B.B., P.N., X.Y.Q., Y.F.S., J.-C.T., M.-A.G., S.N.); Department of Medicine, Laval University, Quebec, Canada (K.L.Q.); IMIM Parc de Salut Mar, Hospital del Mar, Barcelona, Spain (B.B.); Institute of Pharmacology, University of Duisburg-Essen, Essen, Germany (D.D.); Division of Experimental Cardiology, University of Heidelberg, Heidelberg, Germany (D.D.); and
| | - Stanley Nattel
- From the Department of Medicine and Research Centre, Montreal Heart Institute, Université de Montréal, Montreal, Quebec, Canada (K.L.Q., B.B., P.N., X.Y.Q., Y.F.S., J.-C.T., M.-A.G., S.N.); Department of Medicine, Laval University, Quebec, Canada (K.L.Q.); IMIM Parc de Salut Mar, Hospital del Mar, Barcelona, Spain (B.B.); Institute of Pharmacology, University of Duisburg-Essen, Essen, Germany (D.D.); Division of Experimental Cardiology, University of Heidelberg, Heidelberg, Germany (D.D.); and
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47
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Michel PP, Toulorge D, Guerreiro S, Hirsch EC. Specific needs of dopamine neurons for stimulation in order to survive: implication for Parkinson disease. FASEB J 2013; 27:3414-23. [PMID: 23699175 DOI: 10.1096/fj.12-220418] [Citation(s) in RCA: 57] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/11/2023]
Abstract
Parkinson disease (PD) is a degenerative brain disorder characterized by motor symptoms that are unequivocally associated with the loss of dopaminergic (DA) neurons in the substantia nigra (SN). Although our knowledge of the mechanisms that contribute to DA cell death in both hereditary and sporadic forms of the disease has advanced significantly, the nature of the pathogenic process remains poorly understood. In this review, we present evidence that neurodegeneration occurs when the electrical activity and excitability of these neurons is reduced. In particular, we will focus on the specific need these neurons may have for stimulation in order to survive and on the molecular and cellular mechanisms that may be compromised when this need is no longer met in PD.
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Affiliation(s)
- Patrick P Michel
- Université Pierre et Marie Curie-Paris 6, Centre de Recherche de l'Institut du Cerveau et de la Moelle Epinière, Unité Mixte de Recherche (UMR) S975, Paris, France.
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48
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Adachi T, Shibata S, Okamoto Y, Sato S, Fujisawa S, Ohba T, Ono K. The mechanism of increased postnatal heart rate and sinoatrial node pacemaker activity in mice. J Physiol Sci 2013; 63:133-46. [PMID: 23288563 PMCID: PMC10717579 DOI: 10.1007/s12576-012-0248-1] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/24/2012] [Accepted: 12/09/2012] [Indexed: 01/26/2023]
Abstract
Heart rate (HR) of mammalian species changes postnatally, i.e., HR of large animals including humans decreases, while HR in small animals such as mice and rats increases. To clarify cellular mechanisms underlying the postnatal HR changes, we performed in vivo HR measurement and electrophysiological analysis on sinoatrial node (SAN) cells in mice. The in vivo HR was ~320 beats min(-1) (bpm) immediately after birth, and increased with age to ~690 bpm at postnatal day 14. Under blockage of autonomic nervous systems, HR remained constant until postnatal day 5 and then increased day by day. The spontaneous beating rate of SAN preparation showed a similar postnatal change. The density of the L-type Ca(2+) current (LCC) was smaller in neonatal SAN cells than in adult cells, accompanied by a positive shift of voltage-dependent activation. Thus, the postnatal increase in HR is caused by both the increased sympathetic influence and the intrinsic activity of SAN cells. The different conductance and kinetics of LCC may be involved in the postnatal increase in pacemaker activity.
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Affiliation(s)
- Takeshi Adachi
- Department of Cell Physiology, Akita University Graduate School of Medicine, 1-1-1 Hondo, Akita, 010-8543 Japan
| | - Shigehiro Shibata
- Department of Cell Physiology, Akita University Graduate School of Medicine, 1-1-1 Hondo, Akita, 010-8543 Japan
| | - Yosuke Okamoto
- Department of Cell Physiology, Akita University Graduate School of Medicine, 1-1-1 Hondo, Akita, 010-8543 Japan
| | - Shinichi Sato
- Department of Cell Physiology, Akita University Graduate School of Medicine, 1-1-1 Hondo, Akita, 010-8543 Japan
| | - Susumu Fujisawa
- Department of Cell Physiology, Akita University Graduate School of Medicine, 1-1-1 Hondo, Akita, 010-8543 Japan
| | - Takayoshi Ohba
- Department of Cell Physiology, Akita University Graduate School of Medicine, 1-1-1 Hondo, Akita, 010-8543 Japan
| | - Kyoichi Ono
- Department of Cell Physiology, Akita University Graduate School of Medicine, 1-1-1 Hondo, Akita, 010-8543 Japan
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49
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Giordanetto F, Wållberg A, Knerr L, Selmi N, Ullah V, Thorstensson F, Lindelöf Å, Karlsson S, Nikitidis G, Llinas A, Wang QD, Lindqvist A, Högberg Å, Lindhardt E, Åstrand A, Duker G. Discovery of N-[[1-[2-(tert-butylcarbamoylamino)ethyl]-4-(hydroxymethyl)-4-piperidyl]methyl]-3,5-dichloro-benzamide as a selective T-type calcium channel (Cav3.2) inhibitor. Bioorg Med Chem Lett 2013. [DOI: 10.1016/j.bmcl.2012.10.140] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/20/2022]
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50
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Kuwahara K. [Ca2+ channels as novel therapeutic targets in heart failure]. Nihon Yakurigaku Zasshi 2012; 140:255-258. [PMID: 23229630 DOI: 10.1254/fpj.140.255] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 06/01/2023]
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