Browsing by Author "Tucker, Selina"
Now showing 1 - 5 of 5
- Results Per Page
- Sort Options
Item Effect of Sigma-1 Receptor Activation on Renal Injury and Hypertension in Female Mice with Lupus(2023) Dinh, Viet; Chaudhari, Sarika; Young-Stubbs, Cassandra M.; Shimoura, Caroline; Tucker, Selina; Essajee, Salman; Warne, Cooper; Luedtke, Robert R.; Mathis, Keisa W.Systemic lupus erythematosus (SLE) is a female-dominant autoimmune disease with prominent renal injury and hypertension, contributing to its morbidity and mortality. Novel therapies to reduce these detrimental outcomes could be beneficial to SLE patients. The sigma-1 receptor (S1R) is a cytoprotective ligand-regulated chaperone protein that decreases protein aggregation, cellular stress, and cell death, thus preventing tissue injury. S1R activation with pharmacological ligands enhances cytoprotection in autoimmune diseases like multiple sclerosis and Huntington’s disease; however, the efficacy of S1R agonists in SLE is unknown. We hypothesize that S1R activation via the agonist LS-1-127 will reduce renal injury and halt the progression of hypertension in SLE mice. Female SLE (NZBWF1) and control (NZW) mice were weighed and urine collected via metabolic cages weekly starting at 30 weeks of age. Albuminuria was measured via dipsticks. At 33 weeks of age, SLE and control mice were treated with LS-1-127 (10 mg/kg IP) or equal volume of vehicle (10% DMSO; IP) three times a week for two weeks. At 35 weeks, mean arterial pressure (MAP) was measured in conscious mice using indwelling carotid catheters for two consecutive days and then mice were euthanized. Wire myography was used to assess potassium chloride (KCl)-induced contraction and acetylcholine (ACh)-induced relaxation in excised aorta. Markers of renal injury – urinary neutrophil gelatinase-associated lipocalin (NGAL), kidney injury molecule-1 (KIM-1), and creatinine – as well as plasma double-stranded (ds)DNA autoantibodies were measured by ELISA. Albuminuria was present in 44.4% (4 of 9) of SLE mice and no controls. LS-1-127 did not improve albuminuria in SLE mice (50%; 3 of 6). NGAL:creatinine ratio (ng/mg) was higher in SLE mice compared to controls (327.3 ± 119.8 vs 63.2 ± 4.3 ng/mg; n=9–12; P=0.0007). LS-1-127 did not significantly alter NGAL:creatinine ratio in SLE mice (484.3 ± 209.0; n=6) or controls (71.7 ± 5.2; n=10). KIM1:creatinine ratio (ng/mg) did not differ between groups. dsDNA autoantibodies were higher in SLE mice compared to controls (6.9e5 ± 1.1e5 vs. 1.4e5 ± 3.1e4 U/mL; n=9–10; P<0.0001). LS-1-127 did not significantly alter dsDNA autoantibodies in SLE mice (7.1e5 ± 1.2e5; n=6) or controls (1.5e5 ± 4.0e4; n=10). MAP was higher in SLE mice compared to controls (146 ± 4 vs. 123 ± 3 mmHg; n=9–10; P <0.0001). LS-1-127 did not significantly alter MAP in SLE mice (150 ± 8; n=6) or controls (124 ± 2; n=10). KCl-induced aortic contraction was similar in SLE and controls (21 ± 7 vs. 25 ± 4 mM, n=3–4). Sensitivity to KCl after LS-1-127 treatment was 11 ± 3 and 21 ± 2 mM in SLE and controls (n=2–4). ACh-induced aortic relaxation did not differ between groups. In conclusion, two weeks of S1R activation with LS-1-127 did not significantly alter markers of renal injury, autoimmunity, blood pressure, or vascular reactivity in female SLE mice with advanced disease. Further inquiry into the effect of LS-1-127 on the expression of renal proinflammatory cytokines will be conducted. S1R activation at different stages of SLE disease progression also warrants future investigation.Item The effects of esmolol on the control of coronary blood flow and myocardial oxygen supply-demand balance in sepsis(2024-03-21) Digilio, Michaela; Warne, Cooper; Heard, Michael; Tucker, Selina; Essajee, Sal; Bradford, Ni' Ja D.; Hodge, Lisa; Tune, Johnathan; Dick, GregoryPurpose: Sepsis is an acute organ dysfunction secondary to infection that results in tachycardia, tachypnea, fever, decreased blood pressure, and lactic acidosis. This results in an overall myocardial oxygen supply-demand imbalance leading to cardiac dysfunction and ultimately death. The current treatment for sepsis is antibiotic therapy, vasopressors, and fluid therapy. However, this regimen does not address the tachycardia that leads to cardiovascular decompensation. Beta-blocker therapy addresses this myocardial oxygen supply-demand imbalance and is expected to promote survival in sepsis. We hypothesize that treatment with beta-blocker therapy during acute sepsis will address the myocardial oxygen supply-demand imbalance to maintain coronary perfusion pressure, improve myocardial oxygen delivery, and promote survival. Methods: Female and male Yorkshire pigs were used as the animal model for this project. Pigs were anesthetized, intubated, and a rectal thermometer and oximeter were placed. Catheters placed in ear vein, great cardiac vein, femoral artery, and bilateral femoral veins. Pressure transducer placed in the femoral artery. A transonic flow transducer placed around the left anterior descending artery. After instrumentation, baseline values were collected. Then, infusion with Escherichia coli lipopolysaccharide (LPS) at 10 µg/kg over the course of 2 hours was used to induce sepsis. LPS was infused via the femoral vein at a rate of 0.5mL/min. After 2 hours, intervention began depending on the treatment group. Intervention lasted 4 hours. Experiment groups included Sham (without LPS, fluids, norepinephrine (NE), or esmolol), Control (with LPS, no fluids, NE, or esmolol), Standard (with LPS, fluids, and NE), and Experimental (with LPS, fluids, NE and esmolol). Doses: LPS 10 µg/kg, esmolol escalating from 100mg/hr, and NE escalating from 0.4 µg/kg/min. Goals during the intervention included keeping the mean arterial pressure (MAP) above 65mmHg and heart rate below 100. Results: All control pigs died during the 4-hour follow-up. 1 out of 3 standard treatment pigs survived. All esmolol-treated pigs survived. The esmolol group had better MAP, coronary blood flow, myocardial oxygen delivery, and oxygen extraction than the standard treatment group. Conclusion: Esmolol improves survival, coronary perfusion pressure, and myocardial oxygen delivery. This data provides support for our hypothesis and the clinical use of esmolol in sepsis.Item Innate immune system stimulation during pregnancy induces upregulation of thromboxane synthesis in rat maternal heart(2022) Tucker, Selina; Cushen, Spencer; Bradshaw, Jessica L.; Gardner, Jennifer; Ricci, Contessa; Dick, Gregory; Tune, Johnathan; Goulopoulou, StylianiPurpose: Infections during pregnancy are associated with adverse clinical outcomes. We previously showed that exposure to immunostimulatory ODN2395 (synthetic Toll-like receptor 9 agonist) during pregnancy induces maternal vascular inflammation and enhances vascular tone in pregnant rats. These outcomes were mediated in part by activation of the cyclooxygenase/thromboxane A2 (COX/TxA2) pathway. The objective of this study was to investigate the impact of ODN2395-induced immune system stimulation on maternal hearts during pregnancy. We hypothesize that exposure to TLR9-mediated immune system activation during pregnancy upregulates the COX/TxA2 signaling pathway in maternal cardiac tissues in rats. Methods: Rats were treated with a synthetic CpG DNA (ODN2395, 1 mg/kg, intraperitoneal injection) or vehicle (saline) in late pregnancy. Fetoplacental biometrics were recorded after euthanasia on gestational day 20 and maternal hearts were collected to assess COX-1 and COX-2 expression and 6-keto PGF1α (PGI2 metabolic byproduct) and TxB2 (TxA2 metabolic byproduct) production. Results: Left ventricular tissues from dams treated with ODN2395 released higher concentrations of TxB2 compared to tissues from vehicle-treated dams (ODN2395: 0.56 ± 0.06 ng/mg protein vs. Vehicle: 0.31 ± 0.04 ng/mg protein, n5, p=0.0041) but there were no differences in cardiac 6-keto PGF1α release between groups (p=0.16). COX-2 expression was lower in left ventricles from ODN2395-treated rats compared to vehicle-treated rats (p=0.009). There were no differences in cardiac COX-1 expression between groups (p=0.27). Exposure to ODN2395 during pregnancy increased fetal-placental weight ratio (ODN2395: 5.3 ± 0.22 vs. Vehicle: 4.7 ± 0.15, p = 0.04). COX-2 expression was greater in placental tissues from ODN2395-treated rats (p=0.004) but there were no differences in placental 6-keto PGF1α (p=0.51) and TxB2 release (p=0.32). Conclusion: TLR9 activation during pregnancy induces upregulation of TxB2 synthesis in maternal cardiac tissues coupled with a reduction in COX-2 expression. Maternal heart may have enhanced sensitivity to bacterial infections during pregnancy.Item The length-tension characteristics of small coronary arteries vary with transmural origin(2023) Essajee, Sal; Warne, Cooper; Tucker, Selina; Dick, Gregory; Tune, JohnathanThere are transmural differences in the structure of arteries across the left ventricular wall. For example, for arteries of the same size, wall thickness is greater in arteries of the epicardium than those from the endocardium. This observation suggests that there could be differences in their passive and active length-tension relationships, as different amounts of connective tissue or smooth muscle would be expected to alter these characteristics. We tested this hypothesis by studying similarly sized porcine coronary arteries from opposite transmural locations. Endocardial arteries had a diameter of 389 ± 33 µm (n = 8), while epicardial arteries measured 388 ± 50 µm (n = 6). A wire myograph was used to study the mechanical properties of these arteries under isometric conditions in KrebsHenseleit buffer at 37 oC. Arteries were cut into rings with an axial length of 2 mm. Rings were repetitively stimulated to contract at increasing lengths with the addition of high extracellular K + (80 mM). Coronary arteries developed active tension to a plateau level over approximately 3-5 min and K + -induced contractions readily washed out. Arteries from the epicardium were stiffer, as the passive-length tension curve of these vessels was elevated over arteries from the endocardium. Passive tensions at optimal length were 3.2 ± 0.4 vs. 5.6 ± 1.5 mN/mm (p < 0.05). The active tension developed in response to K + depolarization was greater in epicardial arteries. Active tensions at optimal length were 3.4 ± 1.1 vs. 2.4 ± 0.3 mN/mm (p < 0.05). Our results represent the first comparison of transmural differences in coronary arteries under isometric tension. Our findings support the hypothesis that differences exist in the passive and active length-tension relationships of epicardial and endocardial arteries that correlate with wall thickness.Item The impact of healthy pregnancy on maternal cognitive impairment in Sprague Dawley rats(2022) Wilson, E. Nicole; Bradshaw, Jessica L.; Tucker, Selina; Gardner, Jennifer; Goulopoulou, Styliani; Cunningham, RebeccaIntroduction/Background: There is clinical evidence of impaired attention, learning, and memory in pregnant women during pregnancy and in the postpartum period, suggesting an association between pregnancy and maternal cognitive dysfunction. Yet, the effects of pregnancy on memory impairment are unclear. We hypothesized that pregnancy would induce maternal cognitive dysfunction that would persist postpartum in a rat model of healthy pregnancy. Methods: To observe recollective memory, the novel object recognition test was performed using Sprague Dawley female rats with different reproductive histories [non-pregnant virgin, late gestation (gestational day 20, term = 22-23 days), postpartum (28 days after birth), and parous non-pregnant (60 days after birth); n = 7-8/group]. Each rat was placed into an empty arena without objects, to allow for adjustments to the open arena. Thirty-minutes after habituation, each rat was given a period of five minutes to explore the arena with two objects of identical size, color, and texture. Upon completion, one hour was given before the animal was placed back in the arena. To test short term recollective memory, each rat was given three minutes to explore two items: one familiar item and a novel item of different size, color, and texture. The latency to which the animal made the initial contact for each object was recorded, and the number of contacts made with the novel object were tallied and compared with overall contacts to each object. Results: Pregnant rats had increased latency to initial contact of the novel object (p < 0.05) compared to virgin females, postpartum dams, and parous non-pregnant dams. Additionally, parous, non-pregnant dams displayed significantly greater contacts with the novel object (p < 0.05) compared to pregnant rats and postpartum dams. Conclusion: Overall, healthy pregnancy results in decreased short term memory recognition that can be repaired over time. Future directions include evaluating the impact of healthy pregnancy on long term memory recognition, examining underlying mechanisms contributing to cerebral impairments during pregnancy, and determining the effects of pregnancy complications on memory impairment.