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Tobias Moser - One of the best experts on this subject based on the ideXlab platform.
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Exocytosis at the hair cell ribbon synapse apparently operates without neuronal SNARE proteins
Nature Neuroscience, 2011Co-Authors: Régis Nouvian, Anna V. Bulankina, Ellen Reisinger, Tina Pangršič, Stefan Sikorra, Jakob Neef, Thomas Binz, Nils Brose, Thomas Frank, Tobias MoserAbstract:In addition to the morphological difference, inner hair cell (IHC) synapses do not have the full complement of neuronal SNARE proteins found in other types of synapses. Here, Nouvian et al . provide a series of empirical evidence that shows that exocytosis in IHCs occurs independently of neuronal SNARE proteins. SNARE proteins mediate membrane fusion. Neurosecretion depends on neuronal soluble NSF attachment protein receptors (SNAREs; SNAP-25, syntaxin-1, and synaptobrevin-1 or synaptobrevin-2) and is blocked by neurotoxin-mediated cleavage or Genetic Ablation. We found that exocytosis in mouse inner hair cells (IHCs) was insensitive to neurotoxins and Genetic Ablation of neuronal SNAREs. mRNA, but no synaptically localized protein, of neuronal SNAREs was present in IHCs. Thus, IHC exocytosis is unconventional and may operate independently of neuronal SNAREs.
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Exocytosis at the hair cell ribbon synapse apparently operates without neuronal SNARE proteins
Nature Neuroscience, 2011Co-Authors: Régis Nouvian, Anna V. Bulankina, Ellen Reisinger, Tina Pangršič, Stefan Sikorra, Jakob Neef, Thomas Binz, Nils Brose, Thomas Frank, Tobias MoserAbstract:SNARE proteins mediate membrane fusion. Neurosecretion depends on neuronal soluble NSF attachment protein receptors (SNAREs; SNAP-25, syntaxin-1, and synaptobrevin-1 or synaptobrevin-2) and is blocked by neurotoxin-mediated cleavage or Genetic Ablation. We found that exocytosis in mouse inner hair cells (IHCs) was insensitive to neurotoxins and Genetic Ablation of neuronal SNAREs. mRNA, but no synaptically localized protein, of neuronal SNAREs was present in IHCs. Thus, IHC exocytosis is unconventional and may operate independently of neuronal SNAREs.
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Exocytosis at the hair cell ribbon synapse apparently operates without neuronal SNARE proteins
Nature Neuroscience, 2011Co-Authors: Régis Nouvian, Anna V. Bulankina, Ellen Reisinger, Tina Pangršič, Stefan Sikorra, Jakob Neef, Thomas Binz, Nils Brose, Thomas Frank, Tobias MoserAbstract:SNARE proteins mediate membrane fusion. Neurosecretion depends on neuronal SNAREs (SNAP-25, syntaxin-1, and synaptobrevin-1 or 2) and is blocked by neurotoxin-mediated cleavage or Genetic Ablation. We report that exocytosis in mouse inner hair cells (IHCs) is insensitive to neurotoxins and Genetic Ablation of neuronal SNAREs. We found mRNA but no synaptically localized protein of neuronal SNAREs in IHCs. Thus, IHC exocytosis is unconventional and may operate independently of neuronal SNAREs.
Régis Nouvian - One of the best experts on this subject based on the ideXlab platform.
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Exocytosis at the hair cell ribbon synapse apparently operates without neuronal SNARE proteins
Nature Neuroscience, 2011Co-Authors: Régis Nouvian, Anna V. Bulankina, Ellen Reisinger, Tina Pangršič, Stefan Sikorra, Jakob Neef, Thomas Binz, Nils Brose, Thomas Frank, Tobias MoserAbstract:In addition to the morphological difference, inner hair cell (IHC) synapses do not have the full complement of neuronal SNARE proteins found in other types of synapses. Here, Nouvian et al . provide a series of empirical evidence that shows that exocytosis in IHCs occurs independently of neuronal SNARE proteins. SNARE proteins mediate membrane fusion. Neurosecretion depends on neuronal soluble NSF attachment protein receptors (SNAREs; SNAP-25, syntaxin-1, and synaptobrevin-1 or synaptobrevin-2) and is blocked by neurotoxin-mediated cleavage or Genetic Ablation. We found that exocytosis in mouse inner hair cells (IHCs) was insensitive to neurotoxins and Genetic Ablation of neuronal SNAREs. mRNA, but no synaptically localized protein, of neuronal SNAREs was present in IHCs. Thus, IHC exocytosis is unconventional and may operate independently of neuronal SNAREs.
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Exocytosis at the hair cell ribbon synapse apparently operates without neuronal SNARE proteins
Nature Neuroscience, 2011Co-Authors: Régis Nouvian, Anna V. Bulankina, Ellen Reisinger, Tina Pangršič, Stefan Sikorra, Jakob Neef, Thomas Binz, Nils Brose, Thomas Frank, Tobias MoserAbstract:SNARE proteins mediate membrane fusion. Neurosecretion depends on neuronal soluble NSF attachment protein receptors (SNAREs; SNAP-25, syntaxin-1, and synaptobrevin-1 or synaptobrevin-2) and is blocked by neurotoxin-mediated cleavage or Genetic Ablation. We found that exocytosis in mouse inner hair cells (IHCs) was insensitive to neurotoxins and Genetic Ablation of neuronal SNAREs. mRNA, but no synaptically localized protein, of neuronal SNAREs was present in IHCs. Thus, IHC exocytosis is unconventional and may operate independently of neuronal SNAREs.
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Exocytosis at the hair cell ribbon synapse apparently operates without neuronal SNARE proteins
Nature Neuroscience, 2011Co-Authors: Régis Nouvian, Anna V. Bulankina, Ellen Reisinger, Tina Pangršič, Stefan Sikorra, Jakob Neef, Thomas Binz, Nils Brose, Thomas Frank, Tobias MoserAbstract:SNARE proteins mediate membrane fusion. Neurosecretion depends on neuronal SNAREs (SNAP-25, syntaxin-1, and synaptobrevin-1 or 2) and is blocked by neurotoxin-mediated cleavage or Genetic Ablation. We report that exocytosis in mouse inner hair cells (IHCs) is insensitive to neurotoxins and Genetic Ablation of neuronal SNAREs. We found mRNA but no synaptically localized protein of neuronal SNAREs in IHCs. Thus, IHC exocytosis is unconventional and may operate independently of neuronal SNAREs.
Julien Roussel - One of the best experts on this subject based on the ideXlab platform.
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Genetic Ablation of G Protein-Gated Inwardly Rectifying K + Channels Prevents Training-Induced Sinus Bradycardia
Frontiers in physiology, 2021Co-Authors: Isabelle Bidaud, Eleonora Torre, Alicia D'souza, Gabriella Forte, Denis Greuet, Steeve Thirard, Cali Anderson, Antony Chung You Chong, Angelo G. Torrente, Julien RousselAbstract:Background: Endurance athletes are prone to bradyarrhythmias, which in the long-term may underscore the increased incidence of pacemaker implantation reported in this population. Our previous work in rodent models has shown training-induced sinus bradycardia to be due to microRNA (miR)-mediated transcriptional remodeling of the HCN4 channel, leading to a reduction of the "funny" (I f) current in the sinoatrial node (SAN). Objective: To test if Genetic Ablation of G-protein-gated inwardly rectifying potassium channel, also known as I KACh channels prevents sinus bradycardia induced by intensive exercise training in mice. Methods: Control wild-type (WT) and mice lacking GIRK4 (Girk4 -/-), an integral subunit of I KACh were assigned to trained or sedentary groups. Mice in the trained group underwent 1-h exercise swimming twice a day for 28 days, 7 days per week. We performed electrocardiogram recordings and echocardiography in both groups at baseline, during and after the training period. At training cessation, mice were euthanized and SAN tissues were isolated for patch clamp recordings in isolated SAN cells and molecular profiling by quantitative PCR (qPCR) and western blotting. Results: At swimming cessation trained WT mice presented with a significantly lower resting HR that was reversible by acute I KACh block whereas Girk4 -/- mice failed to develop a training-induced sinus bradycardia. In line with HR reduction, action potential rate, density of I f, as well as of T- and L-type Ca2+ currents (I CaT and I CaL ) were significantly reduced only in SAN cells obtained from WT-trained mice. I f reduction in WT mice was concomitant with downregulation of HCN4 transcript and protein, attributable to increased expression of corresponding repressor microRNAs (miRs) whereas reduced I CaL in WT mice was associated with reduced Cav1.3 protein levels. Strikingly, I KACh Ablation suppressed all training-induced molecular remodeling observed in WT mice. Conclusion: Genetic Ablation of cardiac I KACh in mice prevents exercise-induced sinus bradycardia by suppressing training induced remodeling of inward currents I f, I CaT and I CaL due in part to the prevention of miR-mediated transcriptional remodeling of HCN4 and likely post transcriptional remodeling of Cav1.3. Strategies targeting cardiac I KACh may therefore represent an alternative to pacemaker implantation for bradyarrhythmias seen in some veteran athletes.
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Genetic Ablation of g protein gated inwardly rectifying k channels prevents training induced sinus bradycardia
Frontiers in Physiology, 2021Co-Authors: Isabelle Bidaud, Eleonora Torre, Gabriella Forte, Denis Greuet, Steeve Thirard, Cali Anderson, Antony Chung You Chong, Angelo G. Torrente, Alicia Dsouza, Julien RousselAbstract:Background: Endurance athletes are prone to bradyarrhythmias, which in the long-term may underscore the increased incidence of pacemaker implantation reported in this population. Our previous work in rodent models has shown training-induced sinus bradycardia to be due to microRNA (miR)-mediated transcriptional remodeling of the HCN4 channel, leading to a reduction of the "funny" (I f) current in the sinoatrial node (SAN). Objective: To test if Genetic Ablation of G-protein-gated inwardly rectifying potassium channel, also known as I KACh channels prevents sinus bradycardia induced by intensive exercise training in mice. Methods: Control wild-type (WT) and mice lacking GIRK4 (Girk4 -/-), an integral subunit of I KACh were assigned to trained or sedentary groups. Mice in the trained group underwent 1-h exercise swimming twice a day for 28 days, 7 days per week. We performed electrocardiogram recordings and echocardiography in both groups at baseline, during and after the training period. At training cessation, mice were euthanized and SAN tissues were isolated for patch clamp recordings in isolated SAN cells and molecular profiling by quantitative PCR (qPCR) and western blotting. Results: At swimming cessation trained WT mice presented with a significantly lower resting HR that was reversible by acute I KACh block whereas Girk4 -/- mice failed to develop a training-induced sinus bradycardia. In line with HR reduction, action potential rate, density of I f, as well as of T- and L-type Ca2+ currents (I CaT and I CaL ) were significantly reduced only in SAN cells obtained from WT-trained mice. I f reduction in WT mice was concomitant with downregulation of HCN4 transcript and protein, attributable to increased expression of corresponding repressor microRNAs (miRs) whereas reduced I CaL in WT mice was associated with reduced Cav1.3 protein levels. Strikingly, I KACh Ablation suppressed all training-induced molecular remodeling observed in WT mice. Conclusion: Genetic Ablation of cardiac I KACh in mice prevents exercise-induced sinus bradycardia by suppressing training induced remodeling of inward currents I f, I CaT and I CaL due in part to the prevention of miR-mediated transcriptional remodeling of HCN4 and likely post transcriptional remodeling of Cav1.3. Strategies targeting cardiac I KACh may therefore represent an alternative to pacemaker implantation for bradyarrhythmias seen in some veteran athletes.
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Genetic Ablation of G protein-gated inwardly rectifying K+ (Girk)4 channels prevents heart rate reduction induced by intensive exercise training
Archives of Cardiovascular Diseases Supplements, 2020Co-Authors: Isabelle Bidaud, Alicia D'souza, Denis Greuet, Angelo G. Torrente, Julien Roussel, A. Chung You Chong, M. Boyett, Matteo E. Mangoni, Pietro MesircaAbstract:Background The incidence of brady-arrhythmias is known to be higher in athletes. In rodent models of exercise training, bradycardia results from downregulation of f-(HCN4) channels leading to a reduction of the If current in the sino-atrial node (SAN). Objectives To test if Genetic Ablation of G-protein-gated inwardly rectifying potassium 4 (Girk4) channel prevents sinus bradycardia induced by intensive exercise training in mice. Methods Control (WT) and homozygous Girk4 knock-out (Girk4-/-) mice were assigned to trained or sedentary groups. Mice in the trained group underwent 1-hour exercise swimming twice a day for 28 days, 7 days per week whereas sedentary mice underwent 5-min swimming daily in the same period. We performed telemetric electrocardiogram recordings in both groups at baseline and during the training period. At training cessation, mice were euthanized and SAN tissues were isolated for patch clamp recordings in isolated SAN cells and transcriptional profiling by quantitative PCR (qPCR). Results At day 17 of the swimming regimen, heart rate (HR) reduction in trained WT mice was significantly different vs. WT sedentary mice, whereas Girk4-/- mice failed to develop sinus bradycardia. Action potential recordings in isolated SAN cells from trained WT mice showed lower rates of pacemaking in comparison to cells from mice of the other groups. In line with HR reduction, the density of If was significantly reduced only in SAN cells obtained from WT-trained mice. Correspondingly, qPCR analysis showed mRNA expression of HCN4 was significantly lower in WT-trained SAN relative to WT sedentary animals, but unchanged in Girk4-/- animals. This finding could be attributed to a significant increase in the expression of miR-423-5p (a transcriptional repressor of HCN4) observed in trained WT, but not trained Girk4-/- animals. Conclusion Genetic Ablation of Girk4 channels prevents sinus bradycardia induced by down regulation of f-HCN4 channels in trained WT mice.
Isabelle Bidaud - One of the best experts on this subject based on the ideXlab platform.
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Genetic Ablation of g protein gated inwardly rectifying k channels prevents training induced sinus bradycardia
Frontiers in Physiology, 2021Co-Authors: Isabelle Bidaud, Eleonora Torre, Gabriella Forte, Denis Greuet, Steeve Thirard, Cali Anderson, Antony Chung You Chong, Angelo G. Torrente, Alicia Dsouza, Julien RousselAbstract:Background: Endurance athletes are prone to bradyarrhythmias, which in the long-term may underscore the increased incidence of pacemaker implantation reported in this population. Our previous work in rodent models has shown training-induced sinus bradycardia to be due to microRNA (miR)-mediated transcriptional remodeling of the HCN4 channel, leading to a reduction of the "funny" (I f) current in the sinoatrial node (SAN). Objective: To test if Genetic Ablation of G-protein-gated inwardly rectifying potassium channel, also known as I KACh channels prevents sinus bradycardia induced by intensive exercise training in mice. Methods: Control wild-type (WT) and mice lacking GIRK4 (Girk4 -/-), an integral subunit of I KACh were assigned to trained or sedentary groups. Mice in the trained group underwent 1-h exercise swimming twice a day for 28 days, 7 days per week. We performed electrocardiogram recordings and echocardiography in both groups at baseline, during and after the training period. At training cessation, mice were euthanized and SAN tissues were isolated for patch clamp recordings in isolated SAN cells and molecular profiling by quantitative PCR (qPCR) and western blotting. Results: At swimming cessation trained WT mice presented with a significantly lower resting HR that was reversible by acute I KACh block whereas Girk4 -/- mice failed to develop a training-induced sinus bradycardia. In line with HR reduction, action potential rate, density of I f, as well as of T- and L-type Ca2+ currents (I CaT and I CaL ) were significantly reduced only in SAN cells obtained from WT-trained mice. I f reduction in WT mice was concomitant with downregulation of HCN4 transcript and protein, attributable to increased expression of corresponding repressor microRNAs (miRs) whereas reduced I CaL in WT mice was associated with reduced Cav1.3 protein levels. Strikingly, I KACh Ablation suppressed all training-induced molecular remodeling observed in WT mice. Conclusion: Genetic Ablation of cardiac I KACh in mice prevents exercise-induced sinus bradycardia by suppressing training induced remodeling of inward currents I f, I CaT and I CaL due in part to the prevention of miR-mediated transcriptional remodeling of HCN4 and likely post transcriptional remodeling of Cav1.3. Strategies targeting cardiac I KACh may therefore represent an alternative to pacemaker implantation for bradyarrhythmias seen in some veteran athletes.
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Genetic Ablation of G Protein-Gated Inwardly Rectifying K + Channels Prevents Training-Induced Sinus Bradycardia
Frontiers in physiology, 2021Co-Authors: Isabelle Bidaud, Eleonora Torre, Alicia D'souza, Gabriella Forte, Denis Greuet, Steeve Thirard, Cali Anderson, Antony Chung You Chong, Angelo G. Torrente, Julien RousselAbstract:Background: Endurance athletes are prone to bradyarrhythmias, which in the long-term may underscore the increased incidence of pacemaker implantation reported in this population. Our previous work in rodent models has shown training-induced sinus bradycardia to be due to microRNA (miR)-mediated transcriptional remodeling of the HCN4 channel, leading to a reduction of the "funny" (I f) current in the sinoatrial node (SAN). Objective: To test if Genetic Ablation of G-protein-gated inwardly rectifying potassium channel, also known as I KACh channels prevents sinus bradycardia induced by intensive exercise training in mice. Methods: Control wild-type (WT) and mice lacking GIRK4 (Girk4 -/-), an integral subunit of I KACh were assigned to trained or sedentary groups. Mice in the trained group underwent 1-h exercise swimming twice a day for 28 days, 7 days per week. We performed electrocardiogram recordings and echocardiography in both groups at baseline, during and after the training period. At training cessation, mice were euthanized and SAN tissues were isolated for patch clamp recordings in isolated SAN cells and molecular profiling by quantitative PCR (qPCR) and western blotting. Results: At swimming cessation trained WT mice presented with a significantly lower resting HR that was reversible by acute I KACh block whereas Girk4 -/- mice failed to develop a training-induced sinus bradycardia. In line with HR reduction, action potential rate, density of I f, as well as of T- and L-type Ca2+ currents (I CaT and I CaL ) were significantly reduced only in SAN cells obtained from WT-trained mice. I f reduction in WT mice was concomitant with downregulation of HCN4 transcript and protein, attributable to increased expression of corresponding repressor microRNAs (miRs) whereas reduced I CaL in WT mice was associated with reduced Cav1.3 protein levels. Strikingly, I KACh Ablation suppressed all training-induced molecular remodeling observed in WT mice. Conclusion: Genetic Ablation of cardiac I KACh in mice prevents exercise-induced sinus bradycardia by suppressing training induced remodeling of inward currents I f, I CaT and I CaL due in part to the prevention of miR-mediated transcriptional remodeling of HCN4 and likely post transcriptional remodeling of Cav1.3. Strategies targeting cardiac I KACh may therefore represent an alternative to pacemaker implantation for bradyarrhythmias seen in some veteran athletes.
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Concomitant Genetic Ablation of L-type Ca_v1.3 (α_1D) and T-type Ca_v3.1 (α_1G) Ca^2+ channels disrupts heart automaticity
Scientific Reports, 2020Co-Authors: M Baudot, L Fossier, L Talssi, Isabelle Bidaud, Joel Nargeot, Eleonora Torre, Julien Louradour, Stéphanie Barrère-lemaire, Angelo G. Torrente, Pietro MesircaAbstract:Cardiac automaticity is set by pacemaker activity of the sinus node (SAN). In addition to the ubiquitously expressed cardiac voltage-gated L-type Ca_v1.2 Ca^2+ channel isoform, pacemaker cells within the SAN and the atrioventricular node co-express voltage-gated L-type Ca_v1.3 and T-type Ca_v3.1 Ca^2+ channels (SAN-VGCCs). The role of SAN-VGCCs in automaticity is incompletely understood. We used knockout mice carrying individual Genetic Ablation of Ca_v1.3 ( Ca _ v 1.3 ^ −/ −) or Ca_v3.1 ( Ca _ v 3.1 ^ −/ −) channels and double mutant Ca _ v 1.3 ^ −/ −/ Ca _ v 3.1 ^ −/ − mice expressing only Ca_v1.2 channels. We show that concomitant loss of SAN-VGCCs prevents physiological SAN automaticity, blocks impulse conduction and compromises ventricular rhythmicity. Coexpression of SAN-VGCCs is necessary for impulse formation in the central SAN. In mice lacking SAN-VGCCs, residual pacemaker activity is predominantly generated in peripheral nodal and extranodal sites by f-channels and TTX-sensitive Na^+ channels. In beating SAN cells, Ablation of SAN-VGCCs disrupted late diastolic local intracellular Ca^2+ release, which demonstrates an important role for these channels in supporting the sarcoplasmic reticulum based “ Ca ^ 2 + clock ” mechanism during normal pacemaking. These data implicate an underappreciated role for co-expression of SAN-VGCCs in heart automaticity and define an integral role for these channels in mechanisms that control the heartbeat.
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Concomitant Genetic Ablation of L-type Cav1.3 (α1D) and T-type Cav3.1 (α1G) Ca2+ channels disrupts heart automaticity
Scientific Reports, 2020Co-Authors: M Baudot, L Fossier, L Talssi, Isabelle Bidaud, Joel Nargeot, Eleonora Torre, Julien Louradour, Angelo Torrente, Stéphanie Barrère-lemaire, Pietro MesircaAbstract:Cardiac automaticity is set by pacemaker activity of the sinus node (SAN). In addition to the ubiquitously expressed cardiac voltage-gated L-type Cav1.2 Ca2+ channel isoform, pacemaker cells within the SAN and the atrioventricular node co-express voltage-gated L-type Cav1.3 and T-type Cav3.1 Ca2+ channels (SAN-VGCCs). The role of SAN-VGCCs in automaticity is incompletely understood. We used knockout mice carrying individual Genetic Ablation of Cav1.3 (Cav1.3-/-) or Cav3.1 (Cav3.1-/-) channels and double mutant Cav1.3-/-/Cav3.1-/- mice expressing only Cav1.2 channels. We show that concomitant loss of SAN-VGCCs prevents physiological SAN automaticity, blocks impulse conduction and compromises ventricular rhythmicity. Coexpression of SAN-VGCCs is necessary for impulse formation in the central SAN. In mice lacking SAN-VGCCs, residual pacemaker activity is predominantly generated in peripheral nodal and extranodal sites by f-channels and TTX-sensitive Na+ channels. In beating SAN cells, Ablation of SAN-VGCCs disrupted late diastolic local intracellular Ca2+ release, which demonstrates an important role for these channels in supporting the sarcoplasmic reticulum based "Ca2+ clock" mechanism during normal pacemaking. These data implicate an underappreciated role for co-expression of SAN-VGCCs in heart automaticity and define an integral role for these channels in mechanisms that control the heartbeat.
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Genetic Ablation of G protein-gated inwardly rectifying K+ (Girk)4 channels prevents heart rate reduction induced by intensive exercise training
Archives of Cardiovascular Diseases Supplements, 2020Co-Authors: Isabelle Bidaud, Alicia D'souza, Denis Greuet, Angelo G. Torrente, Julien Roussel, A. Chung You Chong, M. Boyett, Matteo E. Mangoni, Pietro MesircaAbstract:Background The incidence of brady-arrhythmias is known to be higher in athletes. In rodent models of exercise training, bradycardia results from downregulation of f-(HCN4) channels leading to a reduction of the If current in the sino-atrial node (SAN). Objectives To test if Genetic Ablation of G-protein-gated inwardly rectifying potassium 4 (Girk4) channel prevents sinus bradycardia induced by intensive exercise training in mice. Methods Control (WT) and homozygous Girk4 knock-out (Girk4-/-) mice were assigned to trained or sedentary groups. Mice in the trained group underwent 1-hour exercise swimming twice a day for 28 days, 7 days per week whereas sedentary mice underwent 5-min swimming daily in the same period. We performed telemetric electrocardiogram recordings in both groups at baseline and during the training period. At training cessation, mice were euthanized and SAN tissues were isolated for patch clamp recordings in isolated SAN cells and transcriptional profiling by quantitative PCR (qPCR). Results At day 17 of the swimming regimen, heart rate (HR) reduction in trained WT mice was significantly different vs. WT sedentary mice, whereas Girk4-/- mice failed to develop sinus bradycardia. Action potential recordings in isolated SAN cells from trained WT mice showed lower rates of pacemaking in comparison to cells from mice of the other groups. In line with HR reduction, the density of If was significantly reduced only in SAN cells obtained from WT-trained mice. Correspondingly, qPCR analysis showed mRNA expression of HCN4 was significantly lower in WT-trained SAN relative to WT sedentary animals, but unchanged in Girk4-/- animals. This finding could be attributed to a significant increase in the expression of miR-423-5p (a transcriptional repressor of HCN4) observed in trained WT, but not trained Girk4-/- animals. Conclusion Genetic Ablation of Girk4 channels prevents sinus bradycardia induced by down regulation of f-HCN4 channels in trained WT mice.
Irfan Rahman - One of the best experts on this subject based on the ideXlab platform.
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Genetic Ablation of histone deacetylase 2 leads to lung cellular senescence and lymphoid follicle formation in COPD/emphysema.
FASEB journal : official publication of the Federation of American Societies for Experimental Biology, 2018Co-Authors: Isaac K. Sundar, Kahkashan Rashid, Janice Gerloff, Javier Rangel-moreno, Irfan RahmanAbstract:Histone deacetylase 2 (HDAC2), a critical determinant of chromatin remodeling, is reduced as a consequence of oxidative stress-mediated DNA damage and impaired repair. Cigarette smoke (CS) exposure causes DNA damage and cellular senescence. However, no information is available on the role of HDAC2 in CS-induced DNA damage, stress-induced premature senescence (SIPS), and senescence-associated secretory phenotype (SASP) during the pathogenesis of chronic obstructive pulmonary disease (COPD)/emphysema. We hypothesized that CS causes persistent DNA damage and cellular senescence via HDAC2-dependent mechanisms. We used HDAC2 global knockout (KO) and HDAC2 lung epithelial cell-specific KO [Clara cell-specific HDAC2 deletion (HDAC2 CreCC10)] mice to determine whether HDAC2 is a major player in CS-induced oxidative stress, SIPS, and SASP. HDAC2 KO mice exposed to CS show exaggerated DNA damage, inflammatory response, and decline in lung function leading to airspace enlargement. Chronic CS exposure augments lung senescence-associated β-galactosidase activity in HDAC2 KO, but not in HDAC2 CreCC10 mice. HDAC2 lung epithelial cell-specific KO did not further augment CS-induced inflammatory response and airspace enlargement but instead caused an increase in lymphoid aggregate formation. Our study reveals that HDAC2 is a key player regulating CS-induced DNA damage, inflammatory response, and cellular senescence leading to COPD/emphysema.-Sundar, I. K., Rashid, K., Gerloff, J., Rangel-Moreno, J., Li, D., Rahman, I. Genetic Ablation of histone deacetylase 2 leads to lung cellular senescence and lymphoid follicle formation in COPD/emphysema.
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Genetic Ablation of histone deacetylase 2 leads to lung cellular senescence and lymphoid follicle formation in copd emphysema
The FASEB Journal, 2018Co-Authors: Isaac K. Sundar, Kahkashan Rashid, Janice Gerloff, Javier Rangelmoreno, Irfan RahmanAbstract:Histone deacetylase 2 (HDAC2), a critical determinant of chromatin remodeling, is reduced as a consequence of oxidative stress-mediated DNA damage and impaired repair. Cigarette smoke (CS) exposure causes DNA damage and cellular senescence. However, no information is available on the role of HDAC2 in CS-induced DNA damage, stress-induced premature senescence (SIPS), and senescence-associated secretory phenotype (SASP) during the pathogenesis of chronic obstructive pulmonary disease (COPD)/emphysema. We hypothesized that CS causes persistent DNA damage and cellular senescence via HDAC2-dependent mechanisms. We used HDAC2 global knockout (KO) and HDAC2 lung epithelial cell-specific KO [Clara cell-specific HDAC2 deletion (HDAC2 CreCC10)] mice to determine whether HDAC2 is a major player in CS-induced oxidative stress, SIPS, and SASP. HDAC2 KO mice exposed to CS show exaggerated DNA damage, inflammatory response, and decline in lung function leading to airspace enlargement. Chronic CS exposure augments lung senescence-associated β-galactosidase activity in HDAC2 KO, but not in HDAC2 CreCC10 mice. HDAC2 lung epithelial cell-specific KO did not further augment CS-induced inflammatory response and airspace enlargement but instead caused an increase in lymphoid aggregate formation. Our study reveals that HDAC2 is a key player regulating CS-induced DNA damage, inflammatory response, and cellular senescence leading to COPD/emphysema.-Sundar, I. K., Rashid, K., Gerloff, J., Rangel-Moreno, J., Li, D., Rahman, I. Genetic Ablation of histone deacetylase 2 leads to lung cellular senescence and lymphoid follicle formation in COPD/emphysema.
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Genetic Ablation of CXCR2 Protects against Cigarette Smoke-Induced Lung Inflammation and Injury.
Frontiers in pharmacology, 2016Co-Authors: Chad A. Lerner, Wei Lei, Isaac K. Sundar, Irfan RahmanAbstract:Antagonism of CXCR2 receptors, predominately located on neutrophils and critical for their immunomodulatory activity, is an attractive pharmacological therapeutic approach aimed at reducing the potentially damaging effects of heightened neutrophil influx into the lung caused by environmental agents including tobacco smoke. The role CXCR2 in lung inflammation in response to cigarette smoke (CS) inhalation using the mutant mouse approach is not known. We hypothesized that Genetic Ablation of CXCR2 would protect mice against CS-induced inflammation and DNA damaging response. We used CXCR2 -/- deficient/mutant (knock-out, KO) mice, and assessed the changes in critical lung inflammatory NF-B-driven chemokines released from the parenchyma of CS-exposed mice, and indications of the extent of tissue damage assessed by the number of DNA damaging γH2AX positive cells. CXCR2 KO mice exhibited protection from heightened levels of neutrophils measured in BALF taken from mice exposed to CS. IL-8 (KC mouse) levels in the BALF from CS-exposed CXCR2 KO were elevated compared to WT. IL-6 levels in BALF were refractory to increase by CS in CXCR2 KO mice. There were no significant changes to MIP-2, MCP-1, or IL-1β. Total levels of NF-κB were maintained at lower levels in CS-exposed CXCR2 KO mice compared to WT mice exposed to CS. Finally CXCR2 KO mice were protected from increased number of lung cells positive for DNA damage response and senescence marker γH2AX, CXCR2 KO mice are protected from heightened inflammatory response mediated by increased neutrophil response as a result of acute 3 day CS exposure. This is also associated with changes in pro-inflammatory chemokines and reduced incursion of γH2AX indicating CXCR2 deficient mice are protected from lung injury. Thus CXCR2 may be a pharmacological target in setting of inflammation and DNA damage in the pathogenesis of COPD.
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Genetic Ablation of NADPH Oxidase Enhances Susceptibility to Cigarette Smoke-Induced Lung Inflammation and Emphysema in Mice
The American journal of pathology, 2008Co-Authors: Hongwei Yao, Indika Edirisinghe, Se-ran Yang, Saravanan Rajendrasozhan, Aruna Kode, Samuel Caito, David Adenuga, Irfan RahmanAbstract:Cigarette smoke (CS) induces recruitment of inflammatory cells in the lungs leading to the generation of reactive oxygen species (ROS), which are involved in lung inflammation and injury. Nicotinamide adenine dinucleotide phosphate (NADPH) oxidase is a multimeric system that is responsible for ROS production in mammalian cells. We hypothesized that NADPH oxidase-derived ROS play an important role in lung inflammation and injury and that targeted Ablation of components of NADPH oxidase (p47phox and gp91phox) would protect lungs against the detrimental effects of CS. To test this hypothesis, we exposed p47phox−/− and gp91phox−/− mice to CS and examined inflammatory response and injury in the lung. Surprisingly, although CS-induced ROS production was decreased in the lungs of p47phox−/− and gp91phox−/− mice compared with wild-type mice, the inflammatory response was significantly increased and was accompanied by development of distal airspace enlargement and alveolar destruction. This pathological abnormality was associated with enhanced activation of the TLR4-nuclear factor-κB pathway in response to CS exposure in p47phox−/− and gp91phox−/− mice. This phenomenon was confirmed by in vitro studies in which treatment of peritoneal macrophages with a nuclear factor-κB inhibitor reversed the CS-induced release of proinflammatory mediators. Thus, these data suggest that Genetic Ablation of components of NADPH oxidase enhances susceptibility to the proinflammatory effects of CS leading to airspace enlargement and alveolar damage.