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Overexpression of human Cu/Zn Superoxide Dismutase in Mice: A Model to Study the Effect of Increased Superoxide Scavenging on the Autonomic Control of the Heart.

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Date Issued:
2015
Abstract/Description:
Dysregulation of the autonomic cardiovascular control is a complication of diseases including diabetes, hypertension, sleep apnea, and aging. A common factor in these conditions is an increase in reactive oxygen species (ROS) in neural, cardiac, and endothelial tissues. Cu/Zn superoxide dismutase (SOD1) is an intracellular anti-oxidant enzyme that catalyzes dismutation of the superoxide anion (O2.-) to hydrogen peroxide (H2O2). Expression and function of this enzyme are diminished in pathologies that impair cardiovascular autonomic control. This study employed mice overexpressing a transgene for human SOD1 (hSOD1) to determine if its overexpression would alter autonomic regulation of BP, HR, and BRS in healthy animals, and if this animal line (C57B6SJL-Tg (SOD1)2 Gur/J) could be used in future studies to determine if hSOD1 overexpression can preserve cardiac autonomic function in disease models. To accomplish this aim, using anesthetized SOD1 and C57 (control) mice, we recorded HR, and aortic depressor nerve (ADN) activity changes in response to pharmacologically-induced BP changes in order to measure baroreflex and baroreceptor sensitivity, respectively. In order to identify any alterations in central, efferent, and cardiac components of the baroreflex arc, we electrically stimulated the left ADN and left cervical vagus and compared the reductions in BP and HR between the C57 and SOD1 mice. Time- and frequency-domain analysis of heart rate variability (HRV) was performed using pulse pressure recordings prior to pharmacologic or surgical procedures. We found that hSOD1 overexpression in the SOD1 mouse line, in comparison to C57 controls did not significantly affect resting HR (C57: 558 (&)#177; 8 vs. SOD1:553 (&)#177; 13 beats-per-minute) or blood pressure (C57: 88.8 (&)#177; 2.9 vs.SOD1: 85.8 (&)#177; 2.1 mmHg). hSOD1 overexpression did not affect the decrease in average mean arterial pressure (MAP) following injection of sodium nitroprusside (SNP) (C57: 38.7 (&)#177; 1.4 vs. SOD1: 39.5 (&)#177; 1.3 mmHg) or increase in average MAP (C57: 135.8 (&)#177; 3.1 vs. SOD1: 136.6 (&)#177; 3.5 mmHg) following injection of phenylephrine (PE). BRS, as measured by the averaged regression lines for ?HR/?MAP for the SNP-induced tachycardic baroreflex (C57: 0.57 (&)#177; 0.06 bpm/mmHg, SOD1: 0.61 (&)#177; 0.08 bpm/mmHg)) and the PE-induced bradycardic baroreflex (C57: -2.9 (&)#177; 0.57 bmp/mmHg, SOD1: -4.3 (&)#177; 0.84 bpm/mmHg) are not significantly different between C57 and SOD1. Baroreceptor activation showed a significant increase in gain (C57: 5.4 (&)#177; 0.3 vs. SOD1: 7.4 (&)#177; 0.5 %/mmHg, P (<) 0.01) in the SOD1 transgenic mice. Heart rate depression in response to electrical stimulation of the left ADN and cervical vagus was comparable between C57 and SOD1, though MAP reduction in response to ADN stimulation is slightly, but significantly increased at 50 Hz in SOD1 animals. Time- domain analysis of HRV did not reveal any significant difference in beat-to-beat variability between SOD1 and C57 (SDNN: C57: 2.78 (&)#177; 0.20, SOD1: 2.89 (&)#177; 0.27), although frequency-domain analysis uncovered a significant reduction in the low-frequency power component of the HRV power spectral distribution (C57: 1.19 (&)#177; 0.11, SOD1: 0.35 (&)#177; 0.06, P (<) 0.001). This study shows that although hSOD1 overexpression does not affect overall baroreflex function, it does potentiate baroreceptor sensitivity and brain stem control of arterial pressure, and reduces low-frequency beat-to-beat variations in HR, without affecting total HRV.
Title: Overexpression of human Cu/Zn Superoxide Dismutase in Mice: A Model to Study the Effect of Increased Superoxide Scavenging on the Autonomic Control of the Heart.
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Name(s): Hatcher, Jeffrey, Author
Cheng, Zixi, Committee Chair
Bossy-Wetzel, Ella, Committee Member
Fernandez-Valle, Cristina, Committee Member
Belfield, Kevin, Committee Member
University of Central Florida, Degree Grantor
Type of Resource: text
Date Issued: 2015
Publisher: University of Central Florida
Language(s): English
Abstract/Description: Dysregulation of the autonomic cardiovascular control is a complication of diseases including diabetes, hypertension, sleep apnea, and aging. A common factor in these conditions is an increase in reactive oxygen species (ROS) in neural, cardiac, and endothelial tissues. Cu/Zn superoxide dismutase (SOD1) is an intracellular anti-oxidant enzyme that catalyzes dismutation of the superoxide anion (O2.-) to hydrogen peroxide (H2O2). Expression and function of this enzyme are diminished in pathologies that impair cardiovascular autonomic control. This study employed mice overexpressing a transgene for human SOD1 (hSOD1) to determine if its overexpression would alter autonomic regulation of BP, HR, and BRS in healthy animals, and if this animal line (C57B6SJL-Tg (SOD1)2 Gur/J) could be used in future studies to determine if hSOD1 overexpression can preserve cardiac autonomic function in disease models. To accomplish this aim, using anesthetized SOD1 and C57 (control) mice, we recorded HR, and aortic depressor nerve (ADN) activity changes in response to pharmacologically-induced BP changes in order to measure baroreflex and baroreceptor sensitivity, respectively. In order to identify any alterations in central, efferent, and cardiac components of the baroreflex arc, we electrically stimulated the left ADN and left cervical vagus and compared the reductions in BP and HR between the C57 and SOD1 mice. Time- and frequency-domain analysis of heart rate variability (HRV) was performed using pulse pressure recordings prior to pharmacologic or surgical procedures. We found that hSOD1 overexpression in the SOD1 mouse line, in comparison to C57 controls did not significantly affect resting HR (C57: 558 (&)#177; 8 vs. SOD1:553 (&)#177; 13 beats-per-minute) or blood pressure (C57: 88.8 (&)#177; 2.9 vs.SOD1: 85.8 (&)#177; 2.1 mmHg). hSOD1 overexpression did not affect the decrease in average mean arterial pressure (MAP) following injection of sodium nitroprusside (SNP) (C57: 38.7 (&)#177; 1.4 vs. SOD1: 39.5 (&)#177; 1.3 mmHg) or increase in average MAP (C57: 135.8 (&)#177; 3.1 vs. SOD1: 136.6 (&)#177; 3.5 mmHg) following injection of phenylephrine (PE). BRS, as measured by the averaged regression lines for ?HR/?MAP for the SNP-induced tachycardic baroreflex (C57: 0.57 (&)#177; 0.06 bpm/mmHg, SOD1: 0.61 (&)#177; 0.08 bpm/mmHg)) and the PE-induced bradycardic baroreflex (C57: -2.9 (&)#177; 0.57 bmp/mmHg, SOD1: -4.3 (&)#177; 0.84 bpm/mmHg) are not significantly different between C57 and SOD1. Baroreceptor activation showed a significant increase in gain (C57: 5.4 (&)#177; 0.3 vs. SOD1: 7.4 (&)#177; 0.5 %/mmHg, P (<) 0.01) in the SOD1 transgenic mice. Heart rate depression in response to electrical stimulation of the left ADN and cervical vagus was comparable between C57 and SOD1, though MAP reduction in response to ADN stimulation is slightly, but significantly increased at 50 Hz in SOD1 animals. Time- domain analysis of HRV did not reveal any significant difference in beat-to-beat variability between SOD1 and C57 (SDNN: C57: 2.78 (&)#177; 0.20, SOD1: 2.89 (&)#177; 0.27), although frequency-domain analysis uncovered a significant reduction in the low-frequency power component of the HRV power spectral distribution (C57: 1.19 (&)#177; 0.11, SOD1: 0.35 (&)#177; 0.06, P (<) 0.001). This study shows that although hSOD1 overexpression does not affect overall baroreflex function, it does potentiate baroreceptor sensitivity and brain stem control of arterial pressure, and reduces low-frequency beat-to-beat variations in HR, without affecting total HRV.
Identifier: CFE0005803 (IID), ucf:50025 (fedora)
Note(s): 2015-08-01
Ph.D.
Medicine, Burnett School of Biomedical Sciences
Doctoral
This record was generated from author submitted information.
Subject(s): Superoxide Dismutase -- SOD1 -- Heart Rate Variability -- HRV -- Baroreflex -- Autonomic Nervous System
Persistent Link to This Record: http://purl.flvc.org/ucf/fd/CFE0005803
Restrictions on Access: campus 2016-08-15
Host Institution: UCF

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