Acute Vagotomy Activates the Cholinergic Anti-Inflammatory Pathway

2005 ◽  
Vol 288 (2) ◽  
pp. H977-H979 ◽  
Author(s):  
David van Westerloo ◽  
Tom van der Poll
Keyword(s):  
Proinflammatory Cytokines ◽  
Sprague Dawley ◽  
Proinflammatory Response ◽  
Parasympathetic Innervation ◽  
Afferent Nerves ◽  
Injured Myocardium ◽  
Sprague Dawley Rats ◽  
Tnf Α ◽  
Cervical Vagotomy ◽  
The Brain

Within minutes of acute myocardial infarction (MI), proinflammatory cytokines increase in the brain, heart, and plasma. We hypothesized that cardiac afferent nerves stimulated by myocardial injury signal the brain to increase central cytokines. Urethane-anesthetized male Sprague-Dawley rats underwent ligation of the left anterior descending coronary artery (LAD) or sham LAD ligation after bilateral cervical vagotomy, sham vagotomy, or application of a 10% phenol solution to the epicardial surface of the myocardium at risk. MI caused a significant increase in tumor necrosis factor (TNF)-α and interleukin (IL)-1β in the plasma and heart, which was blunted by vagotomy. MI also caused a significant increase in hypothalamic TNF-α and IL-1β, which was not affected by vagotomy. In contrast, epicardial phenol blocked MI-induced increases in hypothalamic TNF-α and IL-1β without affecting increases in the plasma and heart. These findings demonstrate that the appearance of proinflammatory cytokines in the brain after MI is independent of blood-borne cytokines and suggest that cardiac sympathetic afferent nerves activated by myocardial ischemia signal the brain to increase cytokine production. In addition, an intact vagus nerve is required for the full expression of proinflammatory cytokines in the injured myocardium and in the circulation. We conclude that the sympathetic and parasympathetic innervation of the heart both contribute to the acute proinflammatory response to MI.

Evaluation of Vitamin D3 metabolite (25-OH Vit D3), Neurotransmitter (ACh), and the Expression of Proinflammatory Cytokines (IL-6 and TNF-α) in Tissue Homogenate after Administration of Biofield Energy Healing-based Novel Proprietary Test Formulation and Biofield Treatment per se to the Animals in Vitamin D3 Deficiency Diet (VDD)-induced Sprague Dawley Rats

2021 ◽  
Vol 3 (4) ◽  
pp. 1-11
Author(s):  
Mahendra Kumar Trivedi ◽  
Alice Branton ◽  
Dahryn Trivedi ◽  
Snehasis Jana
Keyword(s):  
Disease Control ◽  
Proinflammatory Cytokines ◽  
Vitamin D3 ◽  
Sprague Dawley ◽  
Test Formulation ◽  
Sprague Dawley Rats ◽  
Tnf Α ◽  
Per Se ◽  
Vitamin D3 Metabolite ◽  
Vitamin D3 Deficiency

A novel proprietary test formulation was designed which included minerals, vitamins, β-carotene, cannabidiol isolate,and Panax ginseng extract. This present study was evaluated the impact of the Trivedi Effect® on novel proprietary test formulation in male Sprague Dawley rats, fed with vitamin D3 deficiency diet (VDD). The novel test formulation was divided into two parts; one part was defined as untreated test formulation, while the other part was defined as the Biofield Energy Treated sample, which received the Biofield Energy Healing Treatment by renowned Biofield Energy Healer, Mr. Mahendra Kumar Trivedi. The level of 25-OH Vit. D3 was measured in brain homogenate, which was found to be increased by 20.13%, 24.12%, 45.86%, 14.79%, and 29.96% in the G5 group treated with Biofield Treated test formulation, Biofield Energy Treatment per se to the animals (G6), 15 days pre-treatment of Biofield Energy Treated test formulation (G7), Biofield Energy Treatment per se plus Biofield Energy Treated test formulation from day -15 (G8), and untreated test formulation to the Biofield Energy Treated animals (G9) groups respectively, as compared with the disease control (G2) group. Brain acetylcholine (ACh) level was increased by 61.33% in the G7 group as compared with the untreated test formulation (G4) group. The expression of interleukin-6 (IL-6) was significantly reduced by 43.44% (p≤0.01), 30.93%, 21.42%, 45.99% (p≤0.01), and 60.85% (p≤0.01), respectively as compared with the G4. Lung pro-inflammatory cytokine tumor necrosis factor alpha (TNF-α) level was significantly reduced in the G5, G6, G7, and G8 by 24.86%, 32.55% (p≤0.01), 30.12% (p≤0.01), and 42.69% (p≤0.01), respectively, as compared with the G4 group. Altogether, the Biofield Treated test formulation and/or per se treatment to the animals significantly improved the levels of active form of vitamin D3 metabolite (25-OH Vit D3) and neurotransmitter (ACh); consequently significantly lowered the expression of proinflammatory cytokines (IL-6 and TNF-α). Therefore, the energized test formulation or per se treatment could be effectively useful against neuronal damage and inflammation for the management of brain disorders such as Alzheimer’s disease, dementias, brain cancer, epilepsy and other seizure disorders, mental disorders, and Parkinson’s. Thus, the results showed a significant slowdown of disease progression and all other disease-related complications/symptoms in the preventive Biofield Energy Treatment group per se and the Biofield Energy Treated Test formulation groups (viz. G6, G7, G8, and G9) as compared to the disease control group.

Permeability of the microcirculation in area postrema of rat

1988 ◽  
Vol 46 ◽  
pp. 348-349
Author(s):  
Shams M. Ghoneim ◽  
Frank M. Faraci ◽  
Gary L. Baumbach
Keyword(s):  
Brain Stem ◽  
Area Postrema ◽  
Upper Body ◽  
Sprague Dawley ◽  
Sodium Cacodylate ◽  
Acute Hypertension ◽  
Sprague Dawley Rats ◽  
Ultrastructural Characteristics ◽  
The Brain ◽  
Adjacent Brain

The area postrema is a circumventricular organ in the brain stem and is one of the regions in the brain that lacks a fully functional blood-brain barrier. Recently, we found that disruption of the microcirculation during acute hypertension is greater in area postrema than in the adjacent brain stem. In contrast, hyperosmolar disruption of the microcirculation is greater in brain stem. The objective of this study was to compare ultrastructural characteristics of the microcirculation in area postrema and adjacent brain stem.We studied 5 Sprague-Dawley rats. Horseradish peroxidase was injected intravenously and allowed to circulate for 1, 5 or 15 minutes. Following perfusion of the upper body with 2.25% glutaraldehyde in 0.1 M sodium cacodylate, the brain stem was removed, embedded in agar, and chopped into 50-70 μm sections with a TC-Sorvall tissue chopper. Sections of brain stem were incubated for 1 hour in a solution of 3,3' diaminobenzidine tetrahydrochloride (0.05%) in 0.05M Tris buffer with 1% H2O2.

Ultrastructural changes of Basolateral Amygdaloid nuclei in the Sprague Dawley rats brain following exposure to naphthalene balls

2021 ◽  
Vol 12 (2) ◽  
pp. 1272-1275
Author(s):  
Angu Bala Ganesh K S V ◽  
Sujeet Shekhar Sinha ◽  
Kesavi Durairaj ◽  
Abdul Sahabudeen K
Keyword(s):  
Structural Changes ◽  
Corn Oil ◽  
Chromatin Condensation ◽  
Ultrastructural Changes ◽  
High Dose ◽  
Model Group ◽  
Sprague Dawley ◽  
Sprague Dawley Rats ◽  
The Brain ◽  
Amygdaloid Nuclei

Naphthalene is a bicyclic aromatic constituent commonly used in different domestic and marketable applications comprising soil fumigants, lavatory scent disks and mothballs. Accidentally, workers, children and animals are exposed to naphthalene mothballs, so there is a need to study the pathology behind this chemical toxicity. The current study was carried out to assess the ultra structural changes of basolateral amygdaloid nuclei in the Sprague Dawley rats brain in association to naphthalene toxicity. The toxicity model group was administered with naphthalene (200 and 400mg) using corn oil as a vehicle for 28 days. The post delayed toxicity of naphthalene high dose ingestion was also assessed in rats. After the experimental period, the brain tissue was processed to observe the ultra structural changes using a transmission electron microscope. The alterations in cell organelles, nuclei damage, mitochondrial swelling, chromatin condensation suggested naphthalene induced damage in the neurons of the basolateral amygdala of the brain in the toxicity model group. These experimental trials provide information about the alert of mothball usage in the home and identify risks linked with accidental exposure and misuse.

scholarly journals Ureaplasma urealyticum Modulates Endotoxin-Induced Cytokine Release by Human Monocytes Derived from Preterm and Term Newborns and Adults

2001 ◽  
Vol 69 (6) ◽  
pp. 3906-3915 ◽  
Author(s):  
Winston M. Manimtim ◽  
Jeffrey D. Hasday ◽  
Lisa Hester ◽  
Karen D. Fairchild ◽  
Judith C. Lovchik ◽  
...  
Keyword(s):  
Proinflammatory Cytokines ◽  
Ureaplasma Urealyticum ◽  
Human Monocytes ◽  
Cytokine Release ◽  
Proinflammatory Response ◽  
Pediatr Infect ◽  
High Inoculum ◽  
Tnf Α ◽  
Adult Cells

ABSTRACT We previously observed that Ureaplasma urealyticumrespiratory tract colonization in infants with a birth weight of ≤1,250 g was associated with increases in the tracheal aspirate proinflammatory cytokines tumor necrosis factor alpha (TNF-α) and interleukin-8 (IL-8) relative to the counterregulatory cytokine IL-6 during the first week of life (A. M. Patterson, V. Taciak, J. Lovchik, R. E. Fox, A. B. Campbell, and R. M. Viscardi, Pediatr. Infect. Dis. J. 17:321–328, 1998). We hypothesized thatU. urealyticum alters the host immune response in the presence of a coinflammatory stimulus (e.g., bacterial infection or hyperoxia) by shifting the balance of cytokine expression towards the proinflammatory cytokines. To test this hypothesis, we compared the release of TNF-α, IL-8, IL-6, and IL-10 in vitro by unstimulated andU. urealyticum (with or without lipopolysaccharide [LPS])-stimulated human monocytes from adult peripheral blood and from term and preterm cord blood. U. urealyticum alone and in combination with LPS induced concentration- and development-dependent changes in cytokine release. In vitro inoculation with low-inoculum U. urealyticum (103color-changing units [CCU]) (i) partially blocked the LPS-stimulated IL-6 release by all cells and reduced LPS-stimulated IL-10 release by preterm cells, (ii) stimulated TNF-α and IL-8 release by preterm cells, and (iii) augmented LPS-stimulated TNF-α release in all cells. In preterm cells, high-inoculum U. urealyticum(106 CCU) (i) stimulated TNF-α and IL-8, but not IL-6 or IL-10, release and (ii) augmented LPS-stimulated TNF-α and IL-8 release. High-inoculum U. urealyticum (i) stimulated release of all four cytokines in term cells and IL-8 release in adult cells and (ii) augmented LPS-induced TNF-α, IL-10, and IL-8 release in term cells but did not significantly affect LPS-induced cytokine release in adult cells. We speculate that U. urealyticum enhances the proinflammatory response to a second infection by blocking expression of counterregulatory cytokines (IL-6 and IL-10), predisposing the preterm infant to prolonged and dysregulated inflammation, lung injury, and impaired clearance of secondary infections.

The organum vasculosum laminae terminalis in immune-to-brain febrigenic signaling: a reappraisal of lesion experiments

2003 ◽  
Vol 285 (2) ◽  
pp. R420-R428 ◽  
Author(s):  
Andrej A. Romanovsky ◽  
Naotoshi Sugimoto ◽  
Christopher T. Simons ◽  
William S. Hunter
Keyword(s):  
Side Effects ◽  
Isotonic Saline ◽  
Alternative Interpretation ◽  
Sprague Dawley ◽  
Febrile Response ◽  
Drinking Response ◽  
Organum Vasculosum Laminae Terminalis ◽  
Sprague Dawley Rats ◽  
Organum Vasculosum ◽  
The Brain

The organum vasculosum laminae terminalis (OVLT) has been proposed to serve as the interface for blood-to-brain febrigenic signaling, because ablation of this structure affects the febrile response. However, lesioning the OVLT causes many “side effects” not fully accounted for in the fever literature. By placing OVLT-lesioned rats on intensive rehydration therapy, we attempted to prevent these side effects and to evaluate the febrile response in their absence. After the OVLT of Sprague-Dawley rats was lesioned electrolytically, the rats were given access to 5% sucrose for 1 wk to stimulate drinking. Sucrose consumption and body mass were monitored. The animals were examined twice a day for signs of dehydration and treated with isotonic saline (50 ml/kg sc) when indicated. This protocol eliminated mortality but not several acute and chronic side effects stemming from the lesion. The acute effects included adipsia and gross (14% of body weight) emaciation; chronic effects included hypernatremia, hyperosmolality, a suppressed drinking response to hypertonic saline, and previously unrecognized marked (by ∼2°C) and long-lasting (>3 wk) hyperthermia. Because the hyperthermia was not accompanied by tail skin vasoconstriction, it likely reflected increased thermogenesis. After the rats recovered from the acute (but not chronic) side effects, their febrile response to IL-1β (500 ng/kg iv) was tested. The sham-operated rats developed typical monophasic fevers (∼0.5°C), the lesioned rats did not. However, the absence of the febrile response in the OVLT-lesioned rats likely resulted from the untreatable side effects. For example, hyperthermia at the time of pyrogen injection was high enough (39–40°C) to solely prevent fever from developing. Hence, the changed febrile responsiveness of OVLT-lesioned animals is given an alternative interpretation, unrelated to febrigenic signaling to the brain.

scholarly journals Quantitative Analysis of Diffusion Tensor Imaging in Chronic Hepatitis in Rats

2020 ◽  
Author(s):  
Mengping Huang ◽  
Xin Lu ◽  
Xiaofeng Wang ◽  
Jian Shu
Keyword(s):  
Chronic Hepatitis ◽  
Diffusion Tensor Imaging ◽  
Liver Fibrosis ◽  
Diffusion Tensor ◽  
Control Group ◽  
Sprague Dawley ◽  
Subcutaneous Injections ◽  
Sprague Dawley Rats ◽  
Pathological Stages ◽  
The Brain

Abstract Background Diffusion tensor imaging (DTI) is mainly used for detecting white matter fiber in the brain. From this, DTI has been applied to assess fiber in liver disorders by prior studies. But non-sufficient data has been obtained if DTI could be used for exactly staging chronic hepatitis. This study is to assess the value of DTI for staging of liver fibrosis (F), necroinflammatory activity (A), and steatosis (S) of chronic hepatitis in rats. Methods Seventy male Sprague-Dawley rats were divided into control group(n = 10) and experimental group(n = 60). The rat models of chronic hepatitis were established by abdominal subcutaneous injections of 40% CCl4. All rats underwent 3.0T MRI. ROIs were placed on DTI to estimate MR parameters (rADC value and FA value). Histopathology was the reference standard. Multiple linear regression was used to analyze the association between MR parameters and pathology. The differences in rADC value and FA value among pathological stages were evaluated by MANOVA or ANOVA. LSD was used to test the differences between each two groups. ROC analysis was performed. Results The numbers of each pathology were as follows: F0(n = 15), F1(n = 11), F2(n = 6), F3(n = 9), F4(n = 6); A0(n = 8), A1(n = 16), A2(n = 16), A3(n = 7); S0(n = 10), S1(n = 7), S2(n = 3), S3(n = 11), S4(n = 16). The rADC value had a negative correlation with liver fibrosis (r=-0.392, P = 0.008) and inflammation (r=-0.359, P = 0.015). FA value had a positive correlation with fibrosis (r = 0.409, P = 0.005). Significant differences were found in FA value between F4 and F0 ~ F3 (P = 0.03), while no significant differences among F0 ~ F3 were found (P > 0.05). AUC of FA value in differentiating F4 from F0 ~ F3 was 0.909(p < 0.001) with 83.3% Sensitivity, 85.4% specificity when the FA value was at the cut-off of 588.089(× 10− 6mm2/s). Conclusion FA value for DTI can distinguish early cirrhosis from normal, mild and moderate liver fibrosis.

scholarly journals THERAPEUTIC PROFILING OF NANO ENCAPSULATED DIOSGENIN VIA ATTENUATING HORMONAL STATUS, CELL PROLIFERATION, INFLAMMATORY RESPONSES, AND APOPTOSIS IN AN ANIMAL MODEL OF MAMMARY ONCOGENESIS

2021 ◽  
pp. 126-132
Author(s):  
MANOBHARATHI VENGAIMARAN ◽  
KALAIYARASI DHAMODHARAN ◽  
MIRUNALINI SANKARAN
Keyword(s):  
Cell Proliferation ◽  
Molecular Docking ◽  
Cyclin D1 ◽  
Inflammatory Responses ◽  
Chitosan Nanoparticles ◽  
Hormonal Status ◽  
Sprague Dawley ◽  
Therapeutic Impact ◽  
Sprague Dawley Rats ◽  
Tnf Α

Objective: The central motive of this study is to explore the therapeutic impact of Diosgenin encapsulated Chitosan nanoparticles (DG@CS-NP) on mammary carcinogenesis in female Sprague Dawley rats via modulating hormonal status, cell proliferation, inflammatory responses, and Apoptosis. Methods: 7,12-dimethylbenz(a)anthracene (DMBA) was administered subcutaneously near the mammary gland (25 mg/kg b. wt) to provoke mammary tumor in female Sprague Dawley rats. Following the progress of a tumor, DMBA-induced tumor-bearing rats were medicated orally with 5 mg/kg b. wt of DG@CS-NP. Consequently, the expression of ER, PR, PCNA, Cyclin D1, NF-κB, TNF-α, Bcl-2, Caspases-3, and p53 in experimental rats were revealed via architectural immunohistochemistry. Further, Diosgenin interactions with these proteins were evidently confirmed by molecular docking analysis. Results: As a result, we noticed diminished levels of ER, PR, PCNA, Cyclin D1, NF-κB, TNF-α, and Bcl-2 expressions in DG@CS-NP medicated rats as well as with elevated levels of Caspases-3 and p53 expressions. In DMBA rats, the expressions were vice versa. Additionally, molecular docking analyses support these outcomes by highlighting the strong interaction between Diosgenin and breast cancer targets. Conclusion: These reports prove that DG@CS-NP imposes its therapeutic impact by hormonal adjustments, downregulating proteins involved in inflammation and cellular proliferation, and thereby promotes apoptosis by impeding apoptotic inhibitors.

Ammonia reduction with ornithine phenylacetate restores brain eNOS activity via the DDAH-ADMA pathway in bile duct-ligated cirrhotic rats

2012 ◽  
Vol 302 (1) ◽  
pp. G145-G152 ◽  
Author(s):  
Vairappan Balasubramaniyan ◽  
Gavin Wright ◽  
Vikram Sharma ◽  
Nathan A. Davies ◽  
Yalda Sharifi ◽  
...  
Keyword(s):  
Bile Duct ◽  
Protein Expression ◽  
Ammonia Concentration ◽  
Sham Operation ◽  
Sprague Dawley ◽  
Sprague Dawley Rats ◽  
Duct Ligation ◽  
Tnf Α ◽  
No Signaling ◽  
Brain Water

Ammonia is central in the pathogenesis of hepatic encephalopathy, which is associated with dysfunction of the nitric oxide (NO) signaling pathway. Ornithine phenylacetate (OP) reduces hyperammonemia and brain water in cirrhotic animals. This study aimed to determine whether endothelial NO synthase activity is altered in the brain of cirrhotic animals, whether this is associated with changes in the endogenous inhibitor, asymmetric-dimethylarginine (ADMA) and its regulating enzyme, dimethylarginine-dimethylaminohydrolase (DDAH-1), and whether these abnormalities are restored by ammonia reduction using OP. Sprague-Dawley rats were studied 4-wk after bile duct ligation (BDL) ( n = 16) or sham operation ( n = 8) and treated with placebo or OP (0.6 g/kg). Arterial ammonia, brain water, TNF-α, plasma, and brain ADMA were measured using standard techniques. NOS activity was measured radiometrically, and protein expression for NOS enzymes, ADMA, DDAH-1, 4-hydroxynonenol (4HNE), and NADPH oxidase (NOX)-1 were measured by Western blotting. BDL significantly increased arterial ammonia ( P < 0.0001), brain water ( P < 0.05), and brain TNF-α ( P < 0.01). These were reduced significantly by OP treatment. The estimated eNOS component of constitutive NOS activity was significantly lower ( P < 0.05) in BDL rat, and this was significantly attenuated in OP-treated animals. Brain ADMA levels were significantly higher and brain DDAH-1 significantly lower in BDL compared with sham ( P < 0.01) and restored toward normal following treatment with OP. Brain 4HNE and NOX-1 protein expression were significantly increased in BDL rat brain, which were significantly decreased following OP administration. We show a marked abnormality of NO regulation in cirrhotic rat brains, which can be restored by reduction in ammonia concentration using OP.

Abstract 17: Early Life Stress Sensitizes The Angiotensin II-elicited Hypertensive Response

Hypertension ◽  
2020 ◽  
Vol 76 (Suppl_1) ◽  
Author(s):  
Baojian Xue ◽  
Terry Beltz ◽  
Fang Guo ◽  
David M Pollock ◽  
Jennifer S Pollock ◽  
...  
Keyword(s):  
Mrna Expression ◽  
Proinflammatory Cytokines ◽  
Life Stress ◽  
Early Life ◽  
Early Life Stress ◽  
Male Rats ◽  
Sprague Dawley ◽  
Cns Inflammation ◽  
Wide Range ◽  
The Brain

Separation of neonatal rodent pups from their mothers has been used as a model to study the effects of early life stress (ELS) on behavioral and physiological responses in adults. Using an Induction-Delay-Expression experimental paradigm, our previous studies demonstrate that a wide range of stressors administered during an induction period produces hypertensive response sensitization (HTRS) in response to a subsequent pro-hypertensive stimulus. HTRS is accompanied by activation of the brain renin-angiotensin system (RAS) and CNS inflammation. The present study investigated whether ELS induces HTRS and changes in brain-related underlying mechanisms. Rat neonates from Sprague-Dawley breeders were subjected to ELS by separating them each morning from their mothers for 3 h on postnatal days 2 to 14. Pups from non-handled litters formed control groups. At 10 weeks of age, male rats were used to evaluate blood pressure and autonomic function using telemetric probes and pharmacological methods. In addition, in separate control and ELS groups, the lamina terminalis (LT) structures and the hypothalamic paraventricular nucleus (PVN) were analyzed for mRNA expression of RAS components and proinflammatory cytokines. Adult ELS rats as compared to non-separated controls exhibited 1) HTRS during expression testing using 2 week ANG II infusions (120 ng/kg/min s.c.; ELS animals, Δ45.5±4.5 mmHg vs. controls, Δ22.4±3.1 mmHg); 2) a greater reduction in mean arterial pressure following ganglionic blockade (hexamethonium, 30 mg/kg, ip), 3) increased sympathetic drive to the heart (atenolol, 8 mg/kg, ip), 4) decreased vagal tone (atropine, 8 mg/kg, ip), and 5) increased mRNA expression of several components of the brain RAS and proinflammatory cytokines in the LT and PVN. These results suggest that maternal ELS may predispose individuals to hypertension that is mediated by upregulation of the brain RAS and proinflammatory cytokines and increased sympathetic drive to the cardiovascular system.

scholarly journals 2251

2017 ◽  
Vol 1 (S1) ◽  
pp. 60-60
Author(s):  
Andrea Lee Frump ◽  
Margie Albrecht ◽  
Sandra Breuils-Bonnet ◽  
Bakhtiyor Yakubov ◽  
Mary Beth Brown ◽  
...  
Keyword(s):  
Western Blot ◽  
Knockout Mice ◽  
Sprague Dawley ◽  
Protein Receptor ◽  
Morphogenetic Protein ◽  
Sprague Dawley Rats ◽  
Tnf Α ◽  
Study Population ◽  
Direct Binding ◽  
17Β Estradiol

OBJECTIVES/SPECIFIC AIMS: Women with pulmonary arterial hypertension (PAH) exhibit superior right ventricular (RV) function and survival compared with men, a phenomenon attributed to poorly understood cardioprotective effects of 17β-estradiol (E2). We hypothesize that E2, through ERα, attenuates PH-induced RV dysfunction by upregulating the pro-contractile and pro-angiogenic peptide apelin. This ERα-mediated increase in apelin is mediated by the myocardial remodeling effector bone morphogenetic protein receptor 2 (BMPR2). METHODS/STUDY POPULATION: ERα, BMPR2, and apelin were measured (western blot) in RVs from patients with PAH-induced RV failure and in RV homogenates from male or female Sprague-Dawley rats with sugen/hypoxia (SuHx) or monocrotaline (MCT)-induced PH. H9c2 rat cardiomyoblasts and cardiac endothelial cells were stressed with TNF-α (10 ng/mL) or staurosporine (50 nM)±E2 (100 nM; 24 h). ERα-, BMPR2-, and apelin-dependence were evaluated by siRNA (5 pM). Downstream apelin target and pro-survival factor ERK1/2 expression was measured (western blot). p<0.05 by ANOVA was considered significant. RESULTS/ANTICIPATED RESULTS: ERα correlated positively with BMPR2 and apelin expression in SuHx-RVs and human RVs. Treatment of SuHx-PH rats with E2 or ERα agonist increased RV BMPR2 and apelin, whereas RV apelin was decreased in E2-treated hypoxic ERα knockout mice (p<0.05), but not in ERβ knockout mice. In H9c2 cells, E2 or ERα agonist attenuated TNF-α- or staurosporine-induced decreases in BMPR2, apelin, and phospho-ERK1/2 (p<0.05 for all endpoints). E2 protection was lost in presence of siRNA directed against ERα, BMPR2, or apelin (p<0.05). ERα was necessary for E2-mediated increases in BMPR2, apelin, and ERK1/2, and BMPR2 was required for the E2-mediated increase in apelin (p<0.05 for siRNA vs. scramble). ERα, BMPR2, and apelin protein was increased in decompensated human RVs but downstream phospho-ERK signaling was disrupted. DISCUSSION/SIGNIFICANCE OF IMPACT: E2, via ERα, increases BMPR2 and apelin in the failing RV and in stressed rat cardiomyoblasts. The E2-mediated increase in apelin is BMPR2-dependent and likely occurs through direct binding of ERα to the BMPR2 promoter. Harnessing this E2-ERα-BMPR2-apelin axis during RV compensation may lead to novel, RV-targeted therapies for PAH patients of either sex.

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