bluuebunny/crossref_metadata_2025_split huggingface dataset:
Central Effects of Angiotensin‐(1‐7) Treatment on Medullary MAPK and PI3K Pathways of Antenatal Glucocorticoid Exposed Adult Sheep are Sex Dependent
Authors: Hendricks Alexa S. , Shaltout Hossam A. , Chappell Mark C. , Diz Debra I. 
Published: June 2021

Introduction and HypothesisFetal exposure to betamethasone (BMX) that results from the clinical administration of the glucocorticoid agonist to women threatening premature delivery may lead to deleterious long‐term effects on central autonomic regulation. In the adult offspring of pregnant sheep administered antenatal BMX, mean arterial pressure (MAP) is higher and baroreflex sensitivity (BRS) is impaired. These responses are associated with lower brain medullary expression of Angiotensin‐(1‐7) [Ang‐(1‐7)]. Moreover, we observed sex differences in two key signaling pathways implicated in cardiovascular dysfunction and stimulation of oxidative stress in the dorsal brain medulla (DMM) that include higher mitogen‐activated protein kinase (MAPK) in BMX adult male offspring and an attenuated phosphoinositide 3‐kinase (PI3K) pathway in BMX adult female offspring. To establish whether reduced central Ang‐(1‐7) tone contributes to the BMX‐induced cardiovascular effects, we assessed both MAPK and PI3K pathways in the DMM of BMX sheep following 2‐week intracerebroventricular infusion with Ang‐(1‐7) or artificial CSF (aCSF). We hypothesized that in both BMX male and female sheep, Ang‐(1‐7) therapy will correct the observed disturbances in these two pathways.ResultsAlthough presented before, two weeks of Ang‐(1‐7) administration lowered blood pressure and improved baroreflex sensitivity and heart rate variability. In BMX male sheep Ang‐(1‐7) administration was associated with a significant reduction in MAPK activation in the DMM as detected by phosphorylated ERK 1/2 compared to the aCSF‐treated BMX male controls (0.20 ± 0.07 vs 1.04 ± 0.31; p = 0.01), with no change in the PI3K pathway as determined by comparable phosphorylated Akt expression (0.25 ± 0.088 vs 0.36 ± 0.019; p = 0.34). In contrast, BMX female sheep administered Ang‐(1‐7) showed no change in either phosphorylated ERK 1/2 (0.46 ± 0.16 vs 0.70 ± 0.24; p = 0.31) or phosphorylated Akt expression (0.36 ± 0.06 vs 0.33 ± 0.05; p = 0.50) despite that BMX alone reduced PI3K expression.ConclusionCentral administration of Ang‐(1‐7) constitutes a potential therapeutic approach to improve autonomic dysfunction in both BMX exposed sheep; however, distinctly different signaling mechanisms in the DMM of male and female BMX sheep appear to be stimulated by Ang‐(1‐7).Support or Funding InformationHD 047584This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
Chronic Angiotensin‐(1‐7) Treatment Prevents Obesity Hypertension in Mice
Authors: Miller Amanda Joy , White Melissa C. , Bingaman Sarah S. , Arnold Amy C. 
Published: June 2021

Obesity is associated with overactivation of the renin‐angiotensin system hormone angiotensin (Ang) II, which increases blood pressure via multiple mechanisms. Conversely, Ang‐(1‐7), a vasodilatory hormone that opposes the actions of Ang II, is deficient in animal models of obesity. Our previous data show that in obese mice chronic systemic Ang‐(1‐7) administration can attenuate weight gain by increasing energy expenditure as well as improve insulin sensitivity. In this study, we hypothesized that Ang‐(1‐7) would prevent the hypertension and increased sympathetic tone also associated with this mouse model of obesity. To test this, adult male C57BL/6J mice received 12‐week Ang‐(1‐7) (400 ng/kg/min) or saline infusion via subcutaneous osmotic mini‐pumps. Immediately following mini‐pump implantation, mice were placed on a 60% high fat diet (HFD) or a standard chow diet. The three groups of mice in this study were chow diet saline (chow; n=6), HFD saline (HFD; n=3) and HFD Ang‐(1‐7) [n=8]. Blood pressure was measured during the last week of treatment via a carotid artery catheter connected to a strain‐gauge transducer and blood pressure analyzer. Cardiac sympathetic and parasympathetic tone and sympathovagal balance were calculated from the blood pressure signal using spectral analysis frequency domain methods. Consistent with our previous studies, Ang‐(1‐7) attenuated weight gain in HFD mice (36±2 chow vs. 44±2, HFD vs. 38±1 grams HFD Ang‐(1‐7); P=0.013). Ang‐(1‐7) also prevented the rise in systolic blood pressure with HFD (105±6 chow vs. 134±9 HFD vs. 111±5 mm Hg HFD Ang‐(1‐7); P=0.031), with a similar trend for diastolic blood pressure (P=0.084). There was no significant effect of Ang‐(1‐7) on heart rate (P=0.973). The Ang‐(1‐7)‐mediated blood pressure lowering in HFD mice was not associated with significant changes in cardiac sympathetic tone (P=0.303), parasympathetic tone (P=0.115), or sympathovagal balance (P=0.521). These data suggest that Ang‐(1‐7) prevents obesity hypertension in mice perhaps through autonomic‐independent mechanisms. Overall, these findings provide rationale for targeting Ang‐(1‐7) for treatment of obesity‐related hypertension.Support or Funding InformationHL122507This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
Delayed Therapy with A Hydrogen Sulfide Donor, JK1, Protects against Pressure Overload ‐ Induced Heart Failure
Authors: Li Zhen , Kang Jianming , Xian Ming , Lefer David J. 
Published: June 2021

Background and HypothesisHydrogen sulfide (H2S) protects against heart failure by ameliorating oxidative stress, improving mitochondrial function, increasing nitric oxide bioavailability, and attenuating apoptosis. However, at present there is insufficient evidence supporting the cardioprotective effects of H2S in delayed‐treatment settings which more closely mimics the heart failure in human. In current study, we tested the efficacy of delayed therapy with a novel H2S donor, JK1, in a murine model of transverse aortic constriction (TAC) induced heart failure (HF).MethodsMale C57/BL6J mice at 10 weeks (wks) of age were subjected to TAC for 18 weeks. JK1 (200 μg/kg/d, n=20) or the control compound that is devoid of H2S (200 μg/kg/d, n=18) was administered via i.p. injection twice per day starting at 3 wks post TAC. Echocardiography was performed at baseline and tri‐weekly for 18 weeks post TAC to assess LV structure and function. LV hemodynamics, cardiac fibrosis, vascular reactivity (isolated thoracic aorta), and exercise capacity were measured at the endpoint.ResultsDelayed treatment with JK1 preserved left ventricular (LV) ejection fraction (LVEF 54.6 ± 1.4% vs. 29.7 ± 2.9%, p < 0.01), reduced LV dilation (p < 0.01), and attenuated eccentric hypertrophy (p < 0.01). JK1 treated mice displayed lower LV end‐diastolic pressure (LVEDP 11.4 ± 0.8 mmHg vs. 22.9 ± 1.2 mmHg, p < 0.01) and improved relaxation time constant (Tau 7.2 ± 0.4 ms vs. 10.05 ± 0.6 ms, p < 0.01). Global cardiac fibrosis was markedly reduced in mice received JK1 treatment (5.8 ± 1.5% vs. 17.1 ± 2.4%, p < 0.01). In addition, acetylcholine‐mediated vasorelaxation was significantly improved in mice received JK1 treatment (Max. Relaxation, 66.1 ± 4.6% vs. 31.5 ± 3.6%, p < 0.01; EC50, 605.3 ± 115.9 nM vs. 161.8 ± 31.5 nM, p < 0.01). More importantly, mice received JK1 treatment had greater exercise capacity when compared to those received control (Distance, 0.520 ± 0.083 km vs. 0.089 ± 0.006 km, p < 0.05).ConclusionThese results demonstrate that delayed administration of a novel H2S donor, JK1, significantly preserves systolic LV function, attenuates fibrotic remodeling, and improves LV hemodynamics. JK1 treatment provides benefits beyond the heart as it significantly ameliorates the damage to endothelium caused by HF. In addition, JK1 treatment markedly enhances the exercise capacity in HF. Studies are currently underway to define the molecular mechanisms involved in JK1‐induced cardiovascular protection.Support or Funding Information
Kolaviron abrogates ischaemic heart reperfusion injury through enhancement of Akt/PKB and down‐regulation of p38MAPK/PARP/Caspase 3 signalling pathways
Authors: Oyagbemi Ademola Adetokunbo , Bester Dirk , Esterhuyse Johan , Farombi Ebenezer Olatunde 
Published: June 2021

The study was designed to investigate the ameliorative effect of Kolaviron (KV) on ischaemic‐reperfusion injury in experimental rat models. Twenty male Wistar rats were randomly divided into 2 groups: Group one received corn oil as a vehicle and rats in group two were orally administered KV at 200 mg/kg for four weeks. After four weeks of KV pre‐treatment, hearts were excised and mounted on the Working heart perfusion system. Western blot analysis was carried out on frozen heart samples. From this study, there was a significant (p<0.05) reduction in the activity of catalase, superoxide dismutase and glutathione peroxidase with concomitant reduction in oxygen radical absorbance capacity (ORAC) in ischaemic rat heart of animals that received corn oil without KV pre‐treatment. Similarly, pre‐treatment of rats with KV led to a significant (p<0.05) decline in intracellular reactive oxygen species (ROS) and malondialdehyde. Western blots analyses revealed that KV significantly increased the expressions of total Akt/PKB, phosphorylated Akt/PKB at serine 473 and also caused a significant reduction in p38 MAPK, Caspase 3, and cleaved PARP. Combining all, we propose that KV offered notable cardioprotection via quenching of ROS and up‐regulation of pro‐survival sinalling pathways. KV may therefore offer a novel therepeutic window for cardiovascular and other heart related conditionsThis abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
GPER Attenuates Angiotensin II‐Induced Oxidative Stress via cAMP‐Mediated Regulation of NOX4
Authors: OGOLA BENARD O. , Zimmerman Margaret A. , Sure Venkata N. , Katakam Prasad V.G. , Lindsey Sarah H. 
Published: June 2021

Our previous work shows that the G protein‐coupled estrogen receptor (GPER) is protective in the vasculature and kidneys during angiotensin (Ang) II‐dependent hypertension, in part by inhibiting oxidative stress. In addition, we find that acute estrogenic signaling via GPER involves activation of the cAMP signaling pathway in vascular smooth muscle cells. Ang II stimulates the production of reactive oxygen species (ROS) via NADPH oxidase (NOX) complex activation, but whether GPER interferes with NOX activation and whether this occurs through cAMP signaling is not known. Therefore, the goal of the current study was to assess the molecular mechanisms by which GPER attenuates Ang II‐induced oxidative stress in vitro. A7r5 rat aortic smooth muscle cells were treated overnight with 100 nM Ang II in the presence of vehicle or 100 nM of the GPER agonist G‐1. ROS was measured via electron spin resonance spectroscopy (e‐scan) and CellRox™ Green fluorescence. NOX activity and expression were measured by NADP/NADPH ratio, real time RT‐PCR, and immunoblotting. Both e‐scan and CellRox experiments showed that Ang II increased oxidative stress, while co‐administration of the GPER agonist G‐1 prevented this increase (4.3 × 105 vs 1.9 × 105 AU/mg protein, P<0.001, n=7–8). Similarly, NOX activity was elevated in response to Ang II but normalized by G‐1 (189% vs. 83% RLU, P<0.0001, n=5). When the production of cAMP was inhibited with the adenylyl cyclase inhibitor SQ22536, G‐1 was unable to block Ang II‐induced NOX activity (153% vs. 142% RLU, P=0.39, n=6). Ang II increased NOX4 mRNA over time, with a maximum increase at 4h (3.5‐fold change, P<0.05, n=3). Ang II also increased NOX4 protein (1.2 vs 2.1 ADU/β‐actin, P<0.01, n=2). In contrast, administration of G‐1 for 4h decreased NOX4 mRNA by 60% (P<0.05, n=3) with no significant impact on protein expression (P=0.91, n=2). Preliminary studies using male wildtype and knockout mice show higher expression of NOX4 in response to genetic deletion of GPER. These experiments indicate that GPER inhibits NOX4 transcription and suppresses NOX activity, thereby limiting the production of ROS by Ang II. The impact of GPER on NOX activity was dependent on the production of cAMP. Taken together with our previous work, this study provides insight into how acute estrogen signaling provides cardiovascular protection during Ang II‐induced hypertension and potentially other diseases that are characterized by increased oxidative stress.Support or Funding InformationThis study was funded by National Institutes of Health grant HL133619 to S.H.L.This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
Enhanced expression of Egr‐1 in vascular smooth muscle cells from spontaneously hypertensive rats: role of Giα proteins
Authors: Polchtchikov Stephanie , Li Yuan , Anand‐Srivastava Madhu B. 
Published: June 2021

Early growth response, Egr‐1, is known to activate the expression of several genes implicated in the development of vascular dysfunction. Earlier studies have shown that angiotensin II (AngII) enhances the expression of Egr‐1 and Giα proteins in vascular smooth muscle cells (VSMC). In addition, the role of enhanced levels of endogenous Ang II in enhanced expression of Giα proteins in spontaneously hypertensive rats (SHR) has also been shown. The present study was therefore undertaken to examine if VSMC from SHR also exhibit enhanced expression of Egr‐1 proteins and explore the underlying molecular mechanisms mediating this effect. The levels of Egr‐1 protein in VSMC from SHR were not different in 2 weeks old SHR as compared to WKY (Wistar‐Kyoto rats), however, it started increasing at 4 weeks and at 12 weeks, it was significantly increased by 80%. Knockdown of Giα‐2 proteins, using antisense and siRNA treatment, attenuated the enhanced expression of Egr‐1 proteins to control levels. In addition, the knockdown of Egr‐1 by siRNA also attenuated the expression of Giα‐2 and Giα‐3 proteins in VSMC from 12 week old SHR. The enhanced levels of Egr‐1 protein were attenuated by losartan (an AT1 receptor antagonist), BQ123 (an ETA receptor antagonist), BQ788 (an ETB receptor antagonist) but not by PD123319 (an AT2 receptor antagonist) in VSMC from 12 week SHR. These results suggest that VSMC from SHR exhibit an overexpression of Egr‐1 which is due to the enhanced levels of endogenous Ang II, ET‐1 and Giα proteins. In addition, Egr‐1 also regulates the expression of Giα proteins in VSMC from SHR and suggests a cross‐talk between Giα and Egr‐1.Support or Funding InformationSupported by CIHRThis abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
Inhibitory effect and mechanisms of Crossostephium chinensis (L.) Makino on cell proliferation and migration of vascular smooth muscle cells
Authors: Wang Jieyu , Wu Chieh‐Hsi 
Published: June 2021

Percutaneous transluminal coronary angioplasty (PTCA) is a common angioplasty used to relieve the narrowing and obstruction of coronary arteries. Restenosis occurs 30% to 50% of patients after PTCA. The mechanism of restenosis is principally neointinal hyperplasia and inflammatory, as stents resist arterial remodeling. Crossostephium chinensis, a traditional herbal medicine, is indicated on arthralgia, dehumidify and cure rheumatism. Previous studies showed that the extracts of C. chinensis have antioxidant, anti‐proliferative and anti‐inflammatory activities. Thereby, the purpose of this study was to explore the potential effect and mechanisms of C. chinensis on restenosis. Cell viability and migration were examined by MTT and trans‐well assays, respectively. The protein level was monitored by Western blot. Experimental data showed that extracts of C. chinensis can suppress the vascular smooth muscle cells (VSMCs) viability and migration. Protein levels of phospho‐AKT, mTOR, FAK, ERK, PDGFR‐β had been reduced by extract of C. chinensis. Our study suggested that C. chinensis can be a potential inhibitory remedy for restenosis.This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
Focal Inhibition of Thrombin Signaling With Anti‐Thrombin Nanoparticles Reduces Ischemia‐Reperfusion Injury in Acute Myocardial Infarction
Authors: Fazal Jawad , Chen Junjie , Weinheimer Carla , Kovacs Attila , Pan Hua , Wickline Samuel A. 
Published: June 2021

IntroductionAlthough systemic anti‐coagulants are typically administered in acute coronary syndromes (either in anticipation of angioplasty or for secondary prevention of subsequent ischemic events), their role in mitigating potential damage directly associated with reperfusion is not clear. Here we test the hypothesis that inhibition of thrombin signaling selectively at the site of myocardial injury with anti‐thrombotic nanoparticles (NPs; which exert no systemic anticoagulant or platelet effects) could protect myocardium at risk and improve contractile function without bleeding.MethodsAbout 13,000 copies of PPACK (phenylalanine‐proline‐arginine‐chloromethylketone) were conjugated per perfluorocarbon NP (~200 nm) and prepared by microfluidization. 32 mice underwent closed‐chest ischemia (LAD occlusion) for 90 min followed by reperfusion. 15 min before occlusion, either PPACK or control nanoparticles were injected intravenously. Echocardiography was performed (VEVO 2200) 24 hrs pre‐ and post‐ischemic reperfusion injury followed by harvesting heart tissue which was embedded in OCT for histological staining of H&E, Prussian blue, CD144/VE‐cadherin, p65, and thrombin.ResultsPPACK NP treated mice exhibited marked preservation of cardiac functional parameters as early as 24 hours after ischemia as compared to control mice according to changes in contractile metrics: 1) ΔEDV%: 40% ± 21% vs 77% ± 38% for treated vs control (p = 0.02) and 2) ΔESV%: 118% ± 43% vs 216% ± 108%, for treated vs control (p = 0.02) (Fig).ConclusionAnti‐thrombin NP therapy preserves myocardial function in the setting of acute myocardial injury without bleeding risk and implicates thrombin as a promising target for the prevention of ischemia‐reperfusion injury.Support or Funding InformationThis work was supported by NIH grant HL073646‐13.This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
Heparins Derived from Ovine (Sheep) Mucosa are Interchangeable to their Porcine (Pig) Counterparts
Authors: Kouta Ahmed , Abro Schuharazad , Clarizio Destini , Farooqui Ambar , Siddiqui Fakiha , Siddiqui Zafar , Bouchard Olivia , Fareed Jawed 
Published: June 2021

Background and PurposeHeparin is the most widely used anticoagulant drug for parenteral indications including surgical, interventional, and medical usage. Currently available heparin is obtained from porcine (pig) intestine. For Muslim countries, an alternate source of heparin, such as ovine (sheep) heparin, from non‐porcine origin may be more acceptable for religious reasons. The purpose of this study is to compare ovine heparin with currently available porcine heparin to demonstrate their biosimilarity.Materials and MethodsSeveral batches of powdered porcine heparin were commercially obtained. Powdered ovine heparins were provided by Ronnsi Pharmaceutical Co., China. These heparins were compared for the anticoagulant (ACT, aPTT, TT), antiprotease (Anti‐Xa, Anti‐IIa), and USP potency cross‐referenced against USP reference heparin. Molecular profile studies were carried out as specified by U.S. FDA. Protamine titration studies were carried out for both preparations using various tests. The relative interactions of these heparins with HIT antibodies were also investigated using HIT antibodies obtained from patients employing platelet aggregation studies. Thrombin generation inhibition studies were also carried out.ResultsThe molecular profile of porcine heparins were comparable and ranged from 15–18 kDA(p<0.05). However, the ovine heparins showed a slightly lower molecular weight in comparison to porcine heparins (14–16 kDA). The anticoagulant activities in all the assays were also comparable for the ovine and porcine heparins. The USP potency of several batches of porcine heparin ranged from 170–200 U/mg (mean=182+/−12) whereas the ovine heparin exhibited 160–210 U/mg (mean=184+/−16) potency (p<0.05). In the ACT studies both the bovine and porcine heparin provided similar results. In the protamine titration curves, both heparin preparations provided superimposable results. Similarly, in the HIT antibody assays, the behavior of ovine and porcine heparin was identical.ConclusionsThese studies clearly demonstrated that the ovine heparins exhibit comparable molecular profiles and anticoagulant activities. Furthermore, in the USP assay, the potency of these preparations were similar. Thus, ovine heparin should be considered biosimilar to its porcine counterpart and is expected to provide similar results in various clinical indications.This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
Heat shock protein 90 promotes morphine anti‐nociception in the spinal cord, but not in the brain, in a murine cancer induced bone pain model
Authors: Stine Carolyn , Lei Wei , Streicher John M. 
Published: June 2021

Heat shock protein 90 (Hsp90) is a ubiquitous and highly expressed regulator for various signaling pathways. Hsp90 has been well studied as a potential cancer therapeutic target, and Hsp90 inhibitors such as 17‐AAG have been tested as anti‐cancer therapeutics in preclinical studies and clinical trials. However, there have been no reported studies as to whether or not treatment with an Hsp90 inhibitor could affect pain or opioid therapy in cancer patients. Our laboratory previously found that Hsp90 promotes opioid‐induced anti‐nociception in the brain and represses it in the spinal cord in tail flick, paw incision, and HIV neuropathic pain models, suggesting potential effects in cancer pain treatment. This study was designed to investigate the regulatory activity of Hsp90 on opioid induced anti‐nociception in cancer pain using a model of cancer induced bone pain (CIBP). To achieve this goal, female Balb/c mice were injected with 66.1 murine breast cancer cells in the intramedullary space of the right femur. Pain behaviors, including mechanical allodynia, spontaneous flinching, and guarding, were assessed prior to, 7 days, and 13 days after the surgery. Thirteen days after the injection with cancer cells, mice were given intracerebroventricular (icv) or intrathecal (it) injections with either 0.5 nmol 17‐AAG or 1% DMSO vehicle, followed by a 24 hour recovery. After 24 hours, all of the mice were subcutaneously injected with 10 mg/kg morphine and pain behaviors were assessed for two hours. We found that it administration of 17‐AAG greatly reduced morphine anti‐nociception in mechanical allodynia (~64% reduction) without changing spontaneous pain. Meanwhile, treatment with 17‐AAG via icv showed no effect on von Frey, flinching, or guarding. These results indicate that Hsp90 in the spinal cord, but not in the brain, modulates opioid‐induced anti‐nociception in cancer pain. These results also suggest that Hsp90 inhibitors given for cancer therapy could make opioid treatment less effective in cancer patients.This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.