Overexpression of a Neuronal Type Adenylyl Cyclase (Type 8) in Sinoatrial Node Markedly Impacts Heart Rate and Rhythm
Heart rate (HR) and HR variability (HRV), predictors of over-all organism health, are widely believed to be driven by autonomic input to the sinoatrial node (SAN), with sympathetic input increasing HR and reducing HRV. However, variability in spontaneous beating intervals in isolated SAN tissue and...
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| Format: | Article |
| Language: | English |
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Frontiers Media S.A.
2019-06-01
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| Series: | Frontiers in Neuroscience |
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| Online Access: | https://www.frontiersin.org/article/10.3389/fnins.2019.00615/full |
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| author | Jack M. Moen Jack M. Moen Michael G. Matt Michael G. Matt Christopher Ramirez Kirill V. Tarasov Khalid Chakir Yelena S. Tarasova Yevgeniya Lukyanenko Kenta Tsutsui Oliver Monfredi Oliver Monfredi Christopher H. Morrell Christopher H. Morrell Syevda Tagirova Yael Yaniv Thanh Huynh Karel Pacak Ismayil Ahmet Edward G. Lakatta |
| author_facet | Jack M. Moen Jack M. Moen Michael G. Matt Michael G. Matt Christopher Ramirez Kirill V. Tarasov Khalid Chakir Yelena S. Tarasova Yevgeniya Lukyanenko Kenta Tsutsui Oliver Monfredi Oliver Monfredi Christopher H. Morrell Christopher H. Morrell Syevda Tagirova Yael Yaniv Thanh Huynh Karel Pacak Ismayil Ahmet Edward G. Lakatta |
| author_sort | Jack M. Moen |
| collection | DOAJ |
| description | Heart rate (HR) and HR variability (HRV), predictors of over-all organism health, are widely believed to be driven by autonomic input to the sinoatrial node (SAN), with sympathetic input increasing HR and reducing HRV. However, variability in spontaneous beating intervals in isolated SAN tissue and single SAN cells, devoid of autonomic neural input, suggests that clocks intrinsic to SAN cells may also contribute to HR and HRV in vivo. We assessed contributions of both intrinsic and autonomic neuronal input mechanisms of SAN cell function on HR and HRV via in vivo, telemetric EKG recordings. This was done in both wild type (WT) mice, and those in which adenylyl cyclase type 8 (ADCY8), a main driver of intrinsic cAMP-PKA-Ca2+ mediated pacemaker function, was overexpressed exclusively in the heart (TGAC8). We hypothesized that TGAC8 mice would: (1) manifest a more coherent pattern of HRV in vivo, i.e., a reduced HRV driven by mechanisms intrinsic to SAN cells, and less so to modulation by autonomic input and (2) utilize unique adaptations to limit sympathetic input to a heart with high levels of intrinsic cAMP-Ca2+ signaling. Increased adenylyl cyclase (AC) activity in TGAC8 SAN tissue was accompanied by a marked increase in HR and a concurrent marked reduction in HRV, both in the absence or presence of dual autonomic blockade. The marked increase in intrinsic HR and coherence of HRV in TGAC8 mice occurred in the context of: (1) reduced HR and HRV responses to β-adrenergic receptor (β-AR) stimulation; (2) increased transcription of genes and expression of proteins [β-Arrestin, G Protein-Coupled Receptor Kinase 5 (GRK5) and Clathrin Adaptor Protein (Dab2)] that desensitize β-AR signaling within SAN tissue, (3) reduced transcripts or protein levels of enzymes [dopamine beta-hydorxylase (DBH) and phenylethanolamine N-methyltransferase (PNMT)] required for catecholamine production in intrinsic cardiac adrenergic cells, and (4) substantially reduced plasma catecholamine levels. Thus, mechanisms driven by cAMP-PKA-Ca2+ signaling intrinsic to SAN cells underlie the marked coherence of TGAC8 mice HRV. Adaptations to limit additional activation of AC signaling, via decreased neuronal sympathetic input, are utilized to ensure the hearts survival and prevent Ca2+ overload. |
| first_indexed | 2024-12-21T16:13:07Z |
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| institution | Directory Open Access Journal |
| issn | 1662-453X |
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| last_indexed | 2024-12-21T16:13:07Z |
| publishDate | 2019-06-01 |
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| series | Frontiers in Neuroscience |
| spelling | doaj.art-7fc3b43c9f2d41fab516cf4172be9ad02022-12-21T18:57:46ZengFrontiers Media S.A.Frontiers in Neuroscience1662-453X2019-06-011310.3389/fnins.2019.00615455929Overexpression of a Neuronal Type Adenylyl Cyclase (Type 8) in Sinoatrial Node Markedly Impacts Heart Rate and RhythmJack M. Moen0Jack M. Moen1Michael G. Matt2Michael G. Matt3Christopher Ramirez4Kirill V. Tarasov5Khalid Chakir6Yelena S. Tarasova7Yevgeniya Lukyanenko8Kenta Tsutsui9Oliver Monfredi10Oliver Monfredi11Christopher H. Morrell12Christopher H. Morrell13Syevda Tagirova14Yael Yaniv15Thanh Huynh16Karel Pacak17Ismayil Ahmet18Edward G. Lakatta19Intramural Research Program, Laboratory of Cardiovascular Science, National Institute on Aging, National Institutes of Health, Baltimore, MD, United StatesCellular and Molecular Physiology, Yale University, New Haven, CT, United StatesIntramural Research Program, Laboratory of Cardiovascular Science, National Institute on Aging, National Institutes of Health, Baltimore, MD, United StatesSchool of Medicine, University of Pittsburgh, Pittsburgh, PA, United StatesIntramural Research Program, Laboratory of Cardiovascular Science, National Institute on Aging, National Institutes of Health, Baltimore, MD, United StatesIntramural Research Program, Laboratory of Cardiovascular Science, National Institute on Aging, National Institutes of Health, Baltimore, MD, United StatesIntramural Research Program, Laboratory of Cardiovascular Science, National Institute on Aging, National Institutes of Health, Baltimore, MD, United StatesIntramural Research Program, Laboratory of Cardiovascular Science, National Institute on Aging, National Institutes of Health, Baltimore, MD, United StatesIntramural Research Program, Laboratory of Cardiovascular Science, National Institute on Aging, National Institutes of Health, Baltimore, MD, United StatesIntramural Research Program, Laboratory of Cardiovascular Science, National Institute on Aging, National Institutes of Health, Baltimore, MD, United StatesIntramural Research Program, Laboratory of Cardiovascular Science, National Institute on Aging, National Institutes of Health, Baltimore, MD, United StatesDepartment of Cardiovascular and Electrophysiology, The Johns Hopkins Hospital, Baltimore, MD, United StatesIntramural Research Program, Laboratory of Cardiovascular Science, National Institute on Aging, National Institutes of Health, Baltimore, MD, United StatesDepartment of Mathematics, Loyola University Maryland, Baltimore, MD, United StatesIntramural Research Program, Laboratory of Cardiovascular Science, National Institute on Aging, National Institutes of Health, Baltimore, MD, United StatesFaculty of Biomedical Engineering, Technion Israel Institute of Technology, Haifa, IsraelSection on Medical Neuroendocrinology, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD, United StatesSection on Medical Neuroendocrinology, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD, United StatesIntramural Research Program, Laboratory of Cardiovascular Science, National Institute on Aging, National Institutes of Health, Baltimore, MD, United StatesIntramural Research Program, Laboratory of Cardiovascular Science, National Institute on Aging, National Institutes of Health, Baltimore, MD, United StatesHeart rate (HR) and HR variability (HRV), predictors of over-all organism health, are widely believed to be driven by autonomic input to the sinoatrial node (SAN), with sympathetic input increasing HR and reducing HRV. However, variability in spontaneous beating intervals in isolated SAN tissue and single SAN cells, devoid of autonomic neural input, suggests that clocks intrinsic to SAN cells may also contribute to HR and HRV in vivo. We assessed contributions of both intrinsic and autonomic neuronal input mechanisms of SAN cell function on HR and HRV via in vivo, telemetric EKG recordings. This was done in both wild type (WT) mice, and those in which adenylyl cyclase type 8 (ADCY8), a main driver of intrinsic cAMP-PKA-Ca2+ mediated pacemaker function, was overexpressed exclusively in the heart (TGAC8). We hypothesized that TGAC8 mice would: (1) manifest a more coherent pattern of HRV in vivo, i.e., a reduced HRV driven by mechanisms intrinsic to SAN cells, and less so to modulation by autonomic input and (2) utilize unique adaptations to limit sympathetic input to a heart with high levels of intrinsic cAMP-Ca2+ signaling. Increased adenylyl cyclase (AC) activity in TGAC8 SAN tissue was accompanied by a marked increase in HR and a concurrent marked reduction in HRV, both in the absence or presence of dual autonomic blockade. The marked increase in intrinsic HR and coherence of HRV in TGAC8 mice occurred in the context of: (1) reduced HR and HRV responses to β-adrenergic receptor (β-AR) stimulation; (2) increased transcription of genes and expression of proteins [β-Arrestin, G Protein-Coupled Receptor Kinase 5 (GRK5) and Clathrin Adaptor Protein (Dab2)] that desensitize β-AR signaling within SAN tissue, (3) reduced transcripts or protein levels of enzymes [dopamine beta-hydorxylase (DBH) and phenylethanolamine N-methyltransferase (PNMT)] required for catecholamine production in intrinsic cardiac adrenergic cells, and (4) substantially reduced plasma catecholamine levels. Thus, mechanisms driven by cAMP-PKA-Ca2+ signaling intrinsic to SAN cells underlie the marked coherence of TGAC8 mice HRV. Adaptations to limit additional activation of AC signaling, via decreased neuronal sympathetic input, are utilized to ensure the hearts survival and prevent Ca2+ overload.https://www.frontiersin.org/article/10.3389/fnins.2019.00615/fullsinoatrial nodeadenylyl cyclaseheart rateheart rate variabilityadenylyl cyclase type 8parasympathetic activity |
| spellingShingle | Jack M. Moen Jack M. Moen Michael G. Matt Michael G. Matt Christopher Ramirez Kirill V. Tarasov Khalid Chakir Yelena S. Tarasova Yevgeniya Lukyanenko Kenta Tsutsui Oliver Monfredi Oliver Monfredi Christopher H. Morrell Christopher H. Morrell Syevda Tagirova Yael Yaniv Thanh Huynh Karel Pacak Ismayil Ahmet Edward G. Lakatta Overexpression of a Neuronal Type Adenylyl Cyclase (Type 8) in Sinoatrial Node Markedly Impacts Heart Rate and Rhythm Frontiers in Neuroscience sinoatrial node adenylyl cyclase heart rate heart rate variability adenylyl cyclase type 8 parasympathetic activity |
| title | Overexpression of a Neuronal Type Adenylyl Cyclase (Type 8) in Sinoatrial Node Markedly Impacts Heart Rate and Rhythm |
| title_full | Overexpression of a Neuronal Type Adenylyl Cyclase (Type 8) in Sinoatrial Node Markedly Impacts Heart Rate and Rhythm |
| title_fullStr | Overexpression of a Neuronal Type Adenylyl Cyclase (Type 8) in Sinoatrial Node Markedly Impacts Heart Rate and Rhythm |
| title_full_unstemmed | Overexpression of a Neuronal Type Adenylyl Cyclase (Type 8) in Sinoatrial Node Markedly Impacts Heart Rate and Rhythm |
| title_short | Overexpression of a Neuronal Type Adenylyl Cyclase (Type 8) in Sinoatrial Node Markedly Impacts Heart Rate and Rhythm |
| title_sort | overexpression of a neuronal type adenylyl cyclase type 8 in sinoatrial node markedly impacts heart rate and rhythm |
| topic | sinoatrial node adenylyl cyclase heart rate heart rate variability adenylyl cyclase type 8 parasympathetic activity |
| url | https://www.frontiersin.org/article/10.3389/fnins.2019.00615/full |
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