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Role of Cardiac Catecholamines in Embryos and Adults Under Stress
Title
Role of Cardiac Catecholamines in Embryos and Adults Under Stress.
Creator
Baker, Candice, Ebert, Steven, Bossy-Wetzel, Ella, Siddiqi, Shadab, Lambert, Stephen, University of Central Florida
Abstract / Description
Cardiovascular disease is responsible for the loss of one life every 38 seconds and accounts for 26.6 percent of all infants that die of congenital birth defects. Adrenergic hormones are critically important regulators of cardiovascular physiology in embryos and adults. They are key mediators of stress responses and have profound stimulatory effects on cardiovascular function, and dysregulation of adrenergic function has been associated with many adverse cardiac conditions, including...
Show moreCardiovascular disease is responsible for the loss of one life every 38 seconds and accounts for 26.6 percent of all infants that die of congenital birth defects. Adrenergic hormones are critically important regulators of cardiovascular physiology in embryos and adults. They are key mediators of stress responses and have profound stimulatory effects on cardiovascular function, and dysregulation of adrenergic function has been associated with many adverse cardiac conditions, including congenital malformations, arrhythmias, ischemic heart disease, heart failure, and sudden cardiac death. Despite intensive study, the specific roles these hormones play in the developing heart is not well-understood. Further, there is little information available regarding how these important hormones mediate stress responses in adult females (before and after menopause) in comparison to males. My thesis thus has two major foci: (1) What role(s) do catecholamines play in the embryonic heart?, and (2) Do catecholamines differentially influence cardiac function in aging male and female hearts? Initially, we sought to uncover the roles of adrenergic hormones in the embryonic heart by utilizing an adrenergic-deficient (Dbh-/-) mouse model. We found that adrenergic hormones influence heart development by stimulating expression of the gap junction protein, connexin 43, facilitating atrioventricular conduction, and helping to maintain cardiac rhythm. As development progresses, cardiac energy demands increase substantially, and oxidative phosphorylation becomes vital. Adrenergic hormones regulate metabolism in adults, thus we hypothesized they may stimulate energy metabolism during the embryonic/fetal transition period. We examined ATP, ADP, oxygen consumption rate, and extracellular acidification rates and found these metabolic indices were significantly decreased in Dbh-/- hearts compared to Dbh+/+ controls. We employed transmission electron microscopy of embryonic cardiomyocytes and found the mitochondria were significantly larger in Dbh-/- hearts compared to controls, and had more branch points. Taken together, these results suggest adrenergic hormones play a major role mediating the shift from predominantly anaerobic to aerobic metabolism during the embryonic/fetal transition period.Since there are known differential cardiac responses due to sex, age, and menopause to stress, we used echocardiography to measure left ventricular (LV) function in adult (9, 18 and 21 month) male and female mice (pre and postmenopausal) in response to epinephrine, and immobilization stress to investigate the roles of these factors. My results show 9-month premenopausal female mice display significantly decreased LV responsiveness to epinephrine compared to males, and an increased response to epinephrine due to age, especially in the premenopausal females. Similar LV function was also observed between postmenopausal females and males, and this pattern persisted after immobilization stress. I also investigated anatomical differences in the distribution of adrenergic cells within the heart comparing age, sex, and menopausal status. Notably, the density of cells derived from an adrenergic lineage in the heart was significantly increased in postmenopausal mice compared to age-matched males and cycling females. The selective re-appearance of adrenergic cells in the heart following menopause may provide an explanation for the differential stress responses observed in our system, and could have important clinical ramifications for stress-induced cardiomyopathies.
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Date Issued
2014
Identifier
CFE0005458, ucf:50373
Format
Document (PDF)
PURL
http://purl.flvc.org/ucf/fd/CFE0005458
ROLE OF ADRENERGIC NEURONS IN MOTOR CONTROL: EXAMINATION OF CEREBELLAR PURKINJE NEURONS IN MICE FOLLOWING SELECTIVE ADRENERGIC CELL ABLATION IN VIVO
Title
ROLE OF ADRENERGIC NEURONS IN MOTOR CONTROL: EXAMINATION OF CEREBELLAR PURKINJE NEURONS IN MICE FOLLOWING SELECTIVE ADRENERGIC CELL ABLATION IN VIVO.
Creator
Mansour, Monica, Ebert, Steven, University of Central Florida
Abstract / Description
Phenylethanolamine-N-methyltransferase (Pnmt) is the enzyme that catalyzes the conversion of noradrenaline to adrenaline. These catecholamines are synthesized in the medulla of the adrenal gland and by some neurons of the central nervous system. The precise location of Pnmt action in the brain and its physiological significance are unknown. Prior studies led by Aaron Owji, a graduate student in Dr. Ebert�s laboratory, showed that mice with selectively ablated Pnmt cells show signs of...
Show morePhenylethanolamine-N-methyltransferase (Pnmt) is the enzyme that catalyzes the conversion of noradrenaline to adrenaline. These catecholamines are synthesized in the medulla of the adrenal gland and by some neurons of the central nervous system. The precise location of Pnmt action in the brain and its physiological significance are unknown. Prior studies led by Aaron Owji, a graduate student in Dr. Ebert�s laboratory, showed that mice with selectively ablated Pnmt cells show signs of neurological defects such as abnormal gait, weakened grip strength, lack of balance, reduced movement, and defective reflexes during tail suspension tests. The cerebellum is a small section of the brain that is responsible for fine-tuning motor commands. Since the Purkinje cells of the cerebellum act as the sole source of output from the cerebellar cortex, impairment of these cells could possibly account for the motor deficits seen in the mice models. The purpose of this project is to determine if there is indeed a change in Purkinje cells between wild type mice and Pnmt-ablated mice. The first aim is to identify quantitative differences in cell count between both genotypes. The second aim is to determine any morphological changes in the Purkinje cells. The main technique used in this project is immunohistochemistry in which cerebellum tissue from mice models are stained with Calbindin (a cellular marker for Purkinje neurons) and imaged with a confocal microscope. Results showed a slight reduction in the Purkinje cells of the ablated mice compared to the control genotype, accompanied with observable differences in cell structure. Understanding catecholamine pathway mechanisms in the nervous system is imperative for elucidating and targeting key players in neurodegenerative disorders.
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Date Issued
2016
Identifier
CFH2000053, ucf:45511
Format
Document (PDF)
PURL
http://purl.flvc.org/ucf/fd/CFH2000053
GENETIC AND PHYSIOLOGICAL CONTRIBUTION OF ADRENERGIC CELLS IN HEART DEVELOPMENT
Title
GENETIC AND PHYSIOLOGICAL CONTRIBUTION OF ADRENERGIC CELLS IN HEART DEVELOPMENT.
Creator
Osuala, Kingsley, Ebert, Steven, University of Central Florida
Abstract / Description
The adrenergic hormones norepinephrine (NE) and epinephrine (EPI) are essential for cardiovascular development as embryos lacking NE/EPI begin to die abruptly between embryonic days 10.5 and 11.5 due to apparent cardiac failure. The objective of this research aimed to elucidate the mechanism of embryonic fatality observed in the NE/EPI deficient mouse model. We utilized the dopamine [two]-hydroxylase knockout (Dbh-/-) mouse model, which lacks the gene and subsequent enzyme necessary for...
Show moreThe adrenergic hormones norepinephrine (NE) and epinephrine (EPI) are essential for cardiovascular development as embryos lacking NE/EPI begin to die abruptly between embryonic days 10.5 and 11.5 due to apparent cardiac failure. The objective of this research aimed to elucidate the mechanism of embryonic fatality observed in the NE/EPI deficient mouse model. We utilized the dopamine [two]-hydroxylase knockout (Dbh-/-) mouse model, which lacks the gene and subsequent enzyme necessary for conversion of dopamine to NE. We utilized embryonic mouse hearts at E10.5 from Dbh+/+ (control) and Dbh-/- (experimental model) mice for mRNA transcript expression profiling. Gene expression data suggests a novel connection between the ability of the heart to synthesize adrenergic hormones and the gene expression of enzymes involved in the production of retinoic acid. We found a statistically significant change in transcriptional expression of the retinol binding protein-1 (Rbp-1) [+ 1.4 fold], retinol dehydrogenase 12 (Rdh-12) [+ 2.1 fold], and the beta carotene monooxygenase-1(Bcmo1) [- 2.7 fold] genes in the hearts of E10.5 Dbh-/- embryos. These genes encode enzymes responsible for the transport and enzymatic conversion of retinoic acid precursor molecules. Since alterations in retinoic acid concentration have been shown to cause mid-gestational embryonic teratogenesis and lethality, we chose to quantify retinoic acid present in the Dbh-/-embryo at E10.5. Our results showed a significantly higher concentration of retinoic acid in E10.5 Dbh-/- embryos as compared to wild-type controls. This finding indicates that altered expression of genes involved in retinoic acid synthesis lead to a physiological change in retinoic acid concentration which may contribute to the mid-gestational lethality of the Dbh-/- embryos. Previous studies have shown that adrenergic hormones are produced within the heart itself beginning early in embryonic development, but little is known about the fate and disposition of adrenergic cells within the heart at later stages and into adulthood. To investigate this, we utilized a genetic mouse model that expresses [two]-galactosidase ([two]-Gal) in cells capable of synthesizing EPI in order to identify the spatial and temporal distribution of adrenergic-derived cells in the developing heart. The model was designed so that cells capable of expressing the gene phenylethanolamine N-methyltransferase (Pnmt), which is responsible for the synthesis of epinephrine, also produce the enzyme [two]-Gal as a reporter. Evaluation of the location of these cells in the embryonic heart showed a preferential distribution at the sinoatrial node and atrioventricular sulcus at E10.5, and later at E18.5 a more widely distributed ventricular pattern was observed. In the adult heart, the right myocardium showed two small cclusters of XGAL positive cells, one near the apex and another region of the sinoatrial node. However the left heart myocardium showed XGAL positive cells throughout the left atrium and scattered through the LV where the staining appeared localized to myocytes. Interestingly, the left-sided distribution in the LV appeared to be non-random and non-uniform, since specific regions near the base, mid-section, and apex were consistently XGAL-positive. These findings suggest that adrenergic cells differentiate into cardiac muscle tissue that is predominantly found on the left side of the heart by adult stages of development. Taken collectively, this study has shown a novel connection between adrenergic hormones and RA synthesis, two crucial developmental signaling pathways in the embryonic heart. Remarkably, adrenergic derived cells were also found to persist in the adult heart where they constitute relatively large sections of the left ventricle and atrium. These findings provide important new insights into the mechanism of adrenergic actions in the developing heart and a previously unanticipated structural role for cells descending from an adrenergic lineage in the formation of left myocardial tissue.
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Date Issued
2011
Identifier
CFE0003987, ucf:48653
Format
Document (PDF)
PURL
http://purl.flvc.org/ucf/fd/CFE0003987
CROSS-TALK OF RETINOIC ACID AND ADRENERGIC HORMONE SIGNALING MAY INFLUENCE DEVELOPMENT OF CARDIAC CONDUCTION AND RHYTHMICITY IN UTERO
Title
CROSS-TALK OF RETINOIC ACID AND ADRENERGIC HORMONE SIGNALING MAY INFLUENCE DEVELOPMENT OF CARDIAC CONDUCTION AND RHYTHMICITY IN UTERO.
Creator
Alam, Sabikha, Ebert, Steven, University of Central Florida
Abstract / Description
Stress hormones, adrenaline and noradrenaline, have been shown to be critical for heart development. Mice lacking dopamine beta-hydroxylase (Dbh), an enzyme responsible for synthesis of these adrenergic hormones, die during mid-gestation due to cardiac failure. Prior research showed that adrenergic cells are found within the electrical conduction system of the heart, and adrenergic deficiency leads to slowed cardiac conduction during embryogenesis. Microarray analysis of wild-type (Dbh+/+)...
Show moreStress hormones, adrenaline and noradrenaline, have been shown to be critical for heart development. Mice lacking dopamine beta-hydroxylase (Dbh), an enzyme responsible for synthesis of these adrenergic hormones, die during mid-gestation due to cardiac failure. Prior research showed that adrenergic cells are found within the electrical conduction system of the heart, and adrenergic deficiency leads to slowed cardiac conduction during embryogenesis. Microarray analysis of wild-type (Dbh+/+) and knockout (Dbh-/-) mouse hearts revealed significant differences in expression of retinoic acid (RA) signaling genes. RA signaling has also been shown to be critical for heart development. These data suggest that heart failure due to adrenergic deficiency may be dependent upon RA signaling. This led to the hypothesis that adrenergic hormones promote the development of the electrical conduction system through modulation of RA signaling. To test this, embryonic mouse hearts were cultured with LE 135, a RA receptor blocker. Heart rate, arrhythmic index (AI) and conduction time were measured. Under these conditions there was a marked increase in arrhythmias. Hearts treated with LE 135 showed a mean AI of 0.232+/-0.057 after 24 hours of treatment while when untreated had an AI of 0.083+/-0.028 (p<0.05;n=15). In contrast, there was no significant change in heart rate or conduction speed after 24 hours with or without the retinoic acid receptor blocker. To determine if adrenergic stimulus influences retinoic acid response, an established RA-sensitive reporter cell line was employed. These F9-RARE-LacZ cells were treated with forskolin (cAMP regulator) and isoproterenol (beta-agonist) to measure changes in RA signaling. Evaluation of RA signaling showed an increase in retinoic acid responsiveness when treated with an adrenergic signaling agonist. These results suggest that proper retinoic acid signaling is essential for maintaining cardiac rhythmicity during embryonic development and adrenergic stimulation can influence this response.
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Date Issued
2011
Identifier
CFH0003831, ucf:44726
Format
Document (PDF)
PURL
http://purl.flvc.org/ucf/fd/CFH0003831