bluuebunny/crossref_metadata_2025_split huggingface dataset:
The endothelium‐dependent, soluble guanylyl cyclase‐dependent augmentation caused by thymoquinone in isolated porcine coronary arteries is mediated by cIMP (1146.6)
Authors: Detremmerie Charlotte , Leung Susan , Xu Aimin , Alkharfy Khalid , Gao Yuangsheng , Vanhoutte Paul 
Published: June 2021

Aim: Experiments were designed to determine the mechanism underlying the endothelium‐dependent, soluble guanylyl cyclase‐dependent augmentation caused by thymoquinone in isolated arteries.Methods: Rings, with or without endothelium, of porcine coronary arteries were suspended in conventional organ chambers for isometric tension recording. Certain rings were incubated with inhibitors of nitric oxide (NO) synthase inhibitor (L‐NG‐nitroarginine methyl ester, L‐NAME) or soluble guanylyl cyclase (1H‐[1,2,4]oxadiazolo[4,3‐a]quinoxalin‐1‐one, ODQ). They were contracted with phenylephrine (rat arteries) or prostaglandin F2α (porcine coronaries) and exposed to increasing concentrations of thymoquinone. Cyclic nucleotides were measured by HPLC‐MS/MS.Results: Thymoquinone caused a sustained further increase of tension in rings with endothelium. This augmentation was prevented by endothelium‐removal, L‐NAME and ODQ. Incubation with the NO‐donor detaNONOate in L‐NAME‐treated rings restored and even increased the contractile response to thymoquinone. Administration of cIMP restored contractions to thymoquinone in rings without endothelium. By contrast; treatment with pyrophospate did not restore the augmentation by thymoquinone. HPLC‐MS/MS measurements revealed that the latter compound increased the production of cIMP while reducing that of cGMP.Conclusion: The endothelium‐dependent augmentation caused by thymoquinone requires endothelium‐derived NO, activation of soluble guanylyl cyclase and production of cIMP but not the presence of either pyrophosphate or cyclic GMP.
PMA suppresses breast cancer cell proliferation via PKCε‐mediated P‐Rex1 downregulation (1148.5)
Authors: Wong Chuu‐Yun , Xie Yan , Abel Peter , Scofield Margaret , Tu Yaping 
Published: June 2021

Upregulated phosphatidylinositol‐3,4,5‐trisphosphate‐dependent Rac exchange factor 1 (P‐Rex1) promotes tumorigenesis and metastasis of various cancers, and thus could be a potential therapeutic target. The present study was to investigate the role and mechanism underlying phorbol‐12‐myristate‐13‐acetate (PMA), a protein kinase C (PKC) activator, down‐regulation of P‐Rex1 in breast cancer cells. Western blot analysis showed that PMA treatment caused a time‐ and concentration‐dependent decrease in P‐Rex1 protein levels in breast cancer MCF‐7 and BT‐474 cells with a maximum reduction of 87.2 ± 1.1 and 57.0 ± 8.6 %, respectively, at a concentration of 10 ng/ml. Interestingly, either silence of P‐Rex1 by siRNA or PMA treatment inhibits breast cancer cell proliferation by over 70%, which can be attenuated by restoring P‐Rex1 expression. MCF‐7 cells express PMA‐sensitive PKCα, δ, ε, and η. The PKC general inhibitor Gö6983, but not the PKCα‐selective inhibitor Gö6976, blocked the PMA down‐regulation of P‐Rex1 expression and breast cancer cell proliferation. Overexpression of a constitutively active PKCε mutant suppressed P‐Rex1 expression and breast cancer cell proliferation, which was also blocked by Gö6983 treatment. In contrast, overexpression of wild‐type PKCε, wild‐type or constitutively active PKCδ and PKCη had no effect. Together, our data suggest that PMA suppresses breast cancer cell proliferation via PKCε‐mediated P‐Rex1 down‐regulation. Since P‐Rex1 is highly overexpressed in human breast cancers with estrogen receptor (ER) expression, our study may provide a novel strategy for development of chemotherapeutic agents for patients with ER positive tumors that develop resistance to anti‐estrogen therapies.Grant Funding Source: Supported by the National Institutes of Health (CA125661 and 5P20GM103489) and Nebraska State LB595
Expression of hyperoxic bradycardia during hyperbaric exposure in rats prenatally exposed to hypoxia (1150.3)
Authors: Rozloznik Miroslav , Molcan Lubos , Svitok Pavel , Balestra Costantino , Zeman Michal 
Published: June 2021

Intermittent prenatal exposure to hypoxia is associated with postnatal alteration in cardiac and endothelial functions. Hyperoxic exposure has significant effects on the cardiovascular system including bradycardia, vasoconstriction and endothelial dysfunction. The impact of intermittent prenatal hypoxia on cardiac rhythm control during mild hyperoxic conditions is unclear. Thus, expression of hyperoxic bradycardia during normobaric and hyperbaric hyperoxia was investigated telemetrically (PA‐C40, Data Sciences Int) in rats prenatally exposed to hypoxia.Six male Wistar rats prenatally exposed to 10% hypoxia between gestation day 19‐21 (H) and 5 control (C) Wistar rats were exposed for 30 minutes to mild hyperbaric hyperoxia (ppO2 63 kPa, pabs 300 kPa and ppO2 108kPa, pabs 300 kPa) and normobaric hyperoxia (ppO2 67 kPA, pabs 100 kPa).Hyperoxic exposure immediately triggered a bradycardic response in all animals. The bradycardic response was significantly more pronounced (p<0.05) during the hyperbaric exposure to ppO2 108kPa in H rats compared to C rats. Ambient pressure change significantly alternated baroreflex sensitivity (p<0.01) during ppO2 63 kPa exposure in H rats.We conclude that hyperbaric exposure to mild hyperoxia indicates a developmental alteration in cardiac rhythm control in rats prenatally exposed to hypoxia and represents a perspective model to study cardiac rhythm alterations.Grant Funding Source: Supported by grants VEGA 1/0686/12, 2/0107/12 and NOREG and FP7‐PEOPLE‐2010‐ITN
Glucagon like peptide‐1 augments cardiac output during regional myocardial ischemia via increases in ventricular preload, independent of changes in cardiac inotropy (1150.6)
Authors: Goodwill Adam , Casalini Eli , Conteh Abass , Noblet Jill , Sassoon Daniel , Tune Johnathan , Mather Kieren 
Published: June 2021

This study examined the cardiovascular effects of GLP‐1 (7‐36) vs. (9‐36) in normal and ischemic hearts. Swine received systemic infusions of GLP‐1 (7‐36 or 9‐36) at 1.5, 3.0, and 10.0 pmol/kg/min in sequence for 30 min at each dose. Subsequent to this dose response, vehicle or GLP‐1 infusions were maintained at 10.0 pmol/kg/min and the left circumflex artery was ligated to induce regional ischemia. GLP‐1 (9‐36) had no effect on coronary flow, blood pressure, heart rate or indices of cardiac function before or during regional myocardial ischemia. GLP‐1 (7‐36) dose‐dependently increased myocardial glucose uptake (1.3 + 0.8 to 5.5 + 1.9 μmol/min/g; p=0.05), but exerted no other cardiovascular effects prior to ischemia. During ischemia, GLP‐1 (7‐36) increased cardiac output by 2.4 L/min relative to vehicle‐controls (p=0.003). Left ventricular pressure‐volume loops measured during graded IVC occlusion revealed marked increases in end diastolic volume (74 + 1 to 92 + 5 mL;p=0.03) and calculated ventricular volume at zero pressure (8 + 2 to 26 + 8; p=0.05) with GLP‐1(7‐36), while the slope of the end systolic pressure volume relationship was unchanged compared to vehicle and GLP‐1 (9‐36) treatments (p=0.98). These findings indicate that GLP‐1 (7‐36) but not (9‐36) significantly augments cardiac output during regional myocardial ischemia via increases in ventricular preload, independent of changes in cardiac inotropy.Grant Funding Source: Supported by NIH grants HL117620 & T32HL079995. Additional support provided by AHA 13POST1681001813
Effect of berberine on the atrial natriuretic peptide secretion in cardiac atria (1150.9)
Authors: Yoo Hye Rim , Kim Hye Yoom , Kwon Oh Jeong , Cho Kyung Woo , Kang Dae Gill , Lee Ho Sub 
Published: June 2021

Effect of Berberine on the Atrial Natriuretic Peptide Secretion in Cardiac AtriaHye Rim Yoo 1,2, Hye Yoom Kim 1,2, Oh Jeong Kwon 1,2, Kyung Woo Cho 2, Dae Gill Kang 1,2, and Ho Sub Lee 1,2*1College of Oriental Medicine and Professional Graduate School of Oriental Medicine, Wonkwang University, Iksan, Jeonbuk 570‐749, Republic of Korea; 2Hanbang Body‐fluid Research Center, Wonkwang University, Shinyong‐dong, Iksan, Jeonbuk, 570‐749, Republic of KoreaThe aim of the present study is to identify the effects of berberine on the secretion of atrial natriuretic peptide (ANP) from the atrium. Experiments were performed in perfused beating rat left atria paced electrically. Atrial dynamics, atrial pulse pressure, was measured with physiograph. ANP was measured using radioimmunoassay. As a result, berberine increased ANP secretion and atrial dynamics in a concentration‐ dependent manner. Atropine‐non‐selective muscarinic receptor antagonist, methoctramine‐selective M2 muscarinic receptor antagonist, and hemicholinium 3‐inhibitor of choline transporter which inhibits acetylcholine synthesis had no effects on the berberine‐induced changes in ANP secretion and pulse pressure. Berberine is known to activate AMP‐activated protein kinase (AMPK), experiments were performed to identify involvements of this possibility on the berberine‐induced changes in ANP secretion and pulse pressure. Compound C, an inhibitor of AMPK activation, slightly inhibited the berberine‐induced increase in ANP secretion and pulse pressure. These findings suggest that berberine increases ANP secretion and atrial pulse pressure via, at least in part, activation of AMPK signaling.
The SIRT3 deacetylase blocks cardiac fibrosis by targeting TGFβ1‐Smad3 signaling (1152.6)
Authors: Gupta Mahesh , Sundaresan Nagalingam , Gupta Madhu 
Published: June 2021

Cardiac fibrosis after myocardial injury is a major challenge in the medicine today to preserve heart function. At the cellular level, activation of TGFβ1 signaling is considered a major contributor of cardiac fibrosis. However, the underlying mechanism of TGFβ activation is not yet completely understood. SIRT3 is a mitochondrial deacetylase which is activated by exercise and calorie restriction. SIRT3 regulates variety of mitochondrial functions, including metabolism, ROS synthesis and apoptosis. SIRT3KO mice spontaneously develop cardiac fibrosis with age. This study was undertaken to test the hypothesis whether SIRT3 deficiency leads to transformation of cardiac fibroblasts (CF) into myofibroblasts (myoFB) and excessive synthesis of extracellular matrix (ECM). CF obtained from adult rat hearts were subjected to SIRT3 knockdown (KD) by using siRNA. Differentiation of CF to myoFB was determined by increased expression of myoFB markers, like smooth muscle α‐actin, fibronectin and collagen1. The results showed robust expression of myoFB markers in SIRT3KD cells. To test whether SIRT3 deficiency contributed to this phenotype, we re‐expressed SIRT3 and found that this intervention changed back myoFB phenotype of SIRT3‐deficient cells to normal CF. Similar results were obtained when TGFβ1‐induced myoFB were over expressed with SIRT3, thus demonstrating the ability of SIRT3 to block transformation of CF into myoFB and synthesis of excessive ECM. Mechanistic studies showed increased levels of TGFβ1 and Smad3 in SIRT3KD cells, which were resistant to use of the anti‐oxidant, N‐acetyl cysteine. These data thus demonstrated an anti‐fibrotic role of SIRT3, which is independent of its ability to regulate cellular oxidative stress.Grant Funding Source: NIH‐NHLBI
Vascular endothelial growth factor‐C: its unrevealed role in fibrogenesis (1152.9)
Authors: Zhao Tieqiang , Zhao Wenyuan , Meng Weixin , Liu Chang , Chen Yuanjian , Sun Yao 
Published: June 2021

Vascular endothelial growth factor (VEGF)‐C is a key mediator of lymphangiogenesis. Our recent study shows that VEGF‐C/VEGF receptors (VEGFR)‐3 are significantly increased in the infarcted rat myocardium, where VEGFR‐3 is expressed not only in lymph ducts, but also in myofibroblasts, indicating that VEGF‐C has an unrevealed role in fibrogenesis during cardiac repair. The current study is to explore the regulation and molecular mechanisms of VEGF‐C in fibrogenesis. The potential regulation of VEGF‐C on myofibroblast differentiation/growth/migration, collagen degradation/synthesis and TGF‐β/ERK pathways was detected in cultured cardiac myofibroblasts. Our results showed that VEGF‐C significantly increased myofibroblast proliferation, migration and type I/III collagen production. Matrix metalloproteinase (MMP)‐2 and ‐9 were significantly elevated in the medium of VEGF‐C treated cells, coincident with increased tissue inhibitor of metalloproteinase (TIMP)‐1 and TIMP‐2. Furthermore, VEGF‐C significantly elevated TGF‐β1 synthesis and ERK phosphorylation in myofibroblasts, which was significantly suppressed by TGF‐β or ERK blockade. This study indicates that in addition to lymphangiogenesis, VEGF‐C is also involved in fibrogenesis in the repairing heart through stimulation of myofibroblast proliferation, migration and collagen synthesis, via activation of the TGF‐β1 and ERK pathways.Grant Funding Source: NIH
Chronic hyperinsulinemia impairs insulin signaling and downregulates uncoupling protein 3 in mouse heart (1155.4)
Authors: Harmancey Romain , Haight Derek , Taegtmeyer Heinrich 
Published: June 2021

Chronic hyperinsulinemia is a consequence of insulin resistance and one of the main features of type 2 diabetes. To investigate the effect of hyperinsulinemia on myocardial insulin signaling and gene expression, C57BL/6 mice were treated twice daily for 15 days with gradually increasing concentrations of intermediate‐acting insulin (0.14 to 1.68 U Novolin N per day). Diet was supplemented with sucrose cubes and 5% glucose in the drinking water to prevent hypoglycemia. While chronic insulin treatment raised plasma insulin levels from 0.88 to 2.07 ng/ml (P < 0.01), it decreased Akt activity by 39% (P < 0.05) when compared to untreated mice. This was accompanied by a dramatic decrease in mitochondrial uncoupling protein 3 (UCP3) mRNA (‐51%; P < 0.001) and protein levels (‐28%; P < 0.05). Conversely, acute stimulation of the Akt pathway with a single injection of short‐acting Humulin R (1 U/kg body weight) in overnight‐fasted mice induced a 3‐fold increase in myocardial UCP3 mRNA levels. We conclude that chronic hyperinsulinemia impairs insulin signaling in the heart, which, in turn, impairs UCP3 expression. The decrease in UCP3 may link insulin resistance to mitochondrial dysfunction in the heart.Grant Funding Source: Supported by K99 HL112952 (to R.H.) and R01 HL061483 (to H.T.)
Hemodynamic effects of β1‐ and β2‐adrenoceptor stimulation in conscious Zucker diabetic fatty rats (1155.7)
Authors: Cook Rosalind , Bussey Carol , Cragg Patricia , Lamberts Regis 
Published: June 2021

The β‐adrenoceptor (β‐AR) functional responsiveness and β1‐AR expression, key components of blood pressure regulation, are reduced in many cardiomyopathies. Chronic heart failure in vitro models suggests that β2‐AR redistribution might compensate for the decreased β1‐AR function. Whether similar β‐AR subtype changes contribute to cardiovascular dysfunction in diabetes is unknown. Therefore, we aimed to determine the hemodynamic effects of specific β1‐ and β2‐AR stimulation in type II diabetes in vivo.Male Zucker Diabetic Fatty (ZDF) rats and paired lean littermates (20 week old n=8 per group) were implanted with a radiotelemeter and vascular access port to measure arterial blood pressure, derive heart rate (HR) and inject drugs intravenously under stress‐free conscious conditions. Cumulative doses of isoproterenol (non‐selective β1‐ and β2‐AR agonist, 0.001‐3µg/kg) or fenoterol (non‐selective β2‐AR agonist, 0.001‐3µg/kg) in the presence of atenolol (selective β1‐AR antagonist, 2000µg/kg) were injected.The increase in HR due to non‐selective β‐AR stimulation was not significantly different between ZDF and lean rats for all doses (at 0.1µg/kg: 106±10 vs. 109±13 bpm). However the HR response to specific β2‐AR stimulation was significantly reduced in ZDF rats (25±4 vs. 2±4 bpm and 47±7 vs. 20±2 bpm; p<0.002 at 0.03 and 0.1µg/kg, respectively).Thus, in conscious diabetic ZDF rats the functional β‐AR responsiveness was not affected, whereas the sensitivity to specific β2‐AR stimulation was reduced. Therefore, hemodynamic regulation by β1‐ and β2‐AR is altered in diabetes, and furthermore β1‐AR signalling might play a compensatory role in maintaining β‐AR reactivity.
Increases in rat adipose blood flows following bolus intraperitoneal injection of glucose (1156.2)
Authors: Yang Hsiaotung , Rector Scott , Thorne Pamela , Chen Xinyue , Laughlin Harold 
Published: June 2021

The purpose of this study was to determine the magnitude of increased blood flow (BF) to rat adipose tissue depots that is signaled by hyperglycemia. BF was measured in adult SD rats (422±2.6 g, n=6) after 5 hr fasting with stable isotope labeled microshereres. > 4 hr recovery from arterial catheterizing surgery, BF was determined in conscious rats confined to cage activity at before and 15 min after bolus dextrose (2 g/kg b.w.) intraperitoneal injection (i.p.). Blood glucose level was increased from 144±10.1 to 463±36.3 mg/dl (p<0.001). Arterial blood pressure (BP) (141±5.8 mm Hg), and heart rate (460±10.0 bpm) remained unchanged by hyperglycemia. BFs (ml/min/100 g) in adipose tissues prior to glucose i.p. were as follows: epididymal (22±2.4), retroperitoneal (200±36.4), omental (47±5.4), subcutaneous (38±2.9), and brown fat (369±66.7). Fifteen min post i.p. glucose, BFs showed 11.3, 5.3, 13.1, 3.8, and 1.4 fold increase in those adipose tissues respectively (p<0.01). In addition, hyperglycemia also induced 4‐6 fold increases in BFs in the hind limb muscles, spleen, kidney, and duodenum (p<0.01), BF to the liver was 13.0 fold higher (p<0.001) in the post compared to prior glucose i.p. (22±2.6 ml/min/100 g). The independent effects of insulin were not assessed, but could have contributed to observed changes in BF. These results demonstrate the dramatic effects of 3.2 fold elevated circulating glucose on increases in BFs in adipose, skeletal muscle, and some visceral organs.Supported by NIH HL 36088 (MHL) , VA‐CDA2 (1299‐02) (RSR), and CVM Research Grant of MU (MHL and HTY)Grant Funding Source: NIH HL 36088 (MHL), VA‐CDA2 (1299‐02) (RSR), and CVM Research Grant of MU (MHL and HTY)
Brain endocannabinoids modulate lung Inflammation during sepsis (1157.4)
Authors: Peng Jianya , Russo Vincenzo , Gertzberg Nancy , Neumann Paul , Johnson Arnold , Feleder Carlos 
Published: June 2021

Sepsis is a systemic inflammatory response caused by infection which can lead to shock and lung injury. Previous studies indicate that septic shock is mediated by brain endocannabinoid 1 (CB1) receptors. Hence, this study tested the hypothesis that the brain CB1 receptors regulate LPS‐induced lung inflammation. Male Sprague‐Dawley rats received an intracerebroventricular (ICV) injection of either the CB1 receptor antagonist Rimonabant (2 µg/kg) or vehicle, 5 minutes prior to IV injection of either LPS (5 mg/kg) or saline. Lungs were removed 0.5 h or 4 h after IV injection of LPS and isolated for assessment of pulmonary capillary pressure (Ppc), lung wet/dry weight ratio (W/D), TLR4 activation, α7nicotinic acetylcholine (α7nAch) pathway, IL‐6 and VCAM.LPS‐ 0.5 h induced a decrease in lung levels of IRAK1 and IκBα indicating activation of TLR4, and decreased phosphorylated Src‐Y416 family kinases (pSFK) and phosphorylated Raf1‐S259 (pRaf1) suggesting decreased α7nAch signaling all which were prevented by Rimonabant. In addition, Rimonabant prevented the LPS‐induced 4 h increase in the W/D/Ppc and IL‐6 and Rimonabant reduced the LPS induced increase in VCAM expression. The data indicates that the brain CB1 receptor mediates, in part, the lung inflammation response to LPS.Grant Funding Source: Supported by NIH R01 HL059901 to A. Johnson and NIH R15A1072744 to C. Feleder
Impaired lung mitochondrial oxidative capacity following perinatal nicotine exposure in rats (1159.2)
Authors: Cannon Daniel , Liu Jie , Sakurai Reiko , Rossiter Harry , Rehan Virender 
Published: June 2021

Perinatal smoke and nicotine exposure predisposes to chronic lung disease and morbidity. As the PPARγ pathway is implicated in structural and functional airway deficits in a well‐established rat model of perinatal nicotine exposure, mitochondrial derangement may accompany these deficits. Therefore, we hypothesized that perinatal nicotine exposure would result in lung mitochondrial dysfunction.Sprague‐Dawley dams received either placebo (CON) or nicotine (NIC, 1 mg.kg‐1) daily from embryonic day 6 to postnatal day 21. Postpartum, pups were breast feed ad libitum. Parenchymal lung sections (~10mg) were taken from adult males for mitochondrial assessment in situ (O2K, Oroboros).Body mass was not different at 5 months between CON and NIC (637±65 vs. 624±49 g; p=0.71). ADP‐stimulated O2 consumption (JO2) was ~50% less in NIC (n=6) compared to CON (n=6) (4.5±0.8 vs.8.8±2.5 pmol.s.mg‐1, respectively; p<0.05). Uncoupled JO2 was ~60% less in NIC (6.4±1.5 vs. 15.4±5.7 pmol.s.mg‐1; p<0.05), each with excess complex IV capacity. Flux control ratios were not different between conditions (p>0.05).These data suggest reduced mitochondrial density, rather than respiratory chain complex dysfunction, with perinatal nicotine exposure. Low maximal JO2 with nicotine exposure, possibly via suppressed mitochondrial biogenesis, may predispose towards increased oxidative stress and chronic lung disease.Grant Funding Source: Supported by NIH HD51857, HD71731
Systemic factors associated with adipose tissue remodeling after severe burn injury in children (1160.2)
Authors: Saraf Manish , Porter Craig , Chao Tony , Finnerty Celesete , Chondronikola Maria , Borsheim Elisabet , Herndon David , Sidossis Labros 
Published: June 2021

The chronic adrenergic stress response to severe burn injury a causes plethora of metabolic abnormalities. However, the impact of burn injury on adipose tissue (AT) metabolism remains largely unknown. Here, we studied the effect of severe burn injury on systemic biomarkers thought to be involved in AT remodeling (i.e. White‐to‐brown transdifferentiation).Ten severely burned children (age 12±4 years; % total burn surface area 49±20) and ten healthy children (age 12±5 years) participated in this study. Hormones levels were measured by luminex multiplex magnetic assay kit and ELISA kit in plasma samples obtained in the fasted state (2‐4 weeks post injury in burned patients).Plasma fibroblast growth factor 21 (634 vs 40 pg/ml, (p=0.07), leptin (9 vs 1.2 ng/ml; p=0.055), interleukin ‐ 6 (68 vs 4.8 pg/ml; p=0.03) and amylin (65 vs 24 ng/ml, p=0.06) were all increased systemically in burn patients vs. healthy subjects. Irisin also showed a trend to be increased in burn patients (116 vs 83 ng/ml, p=0.24), however this was not statistically different. These findings suggest that severe chronic inflammatory stress alters the systemic hormonal profile of burn patients in a similar manner to that observed during adrenergic stimulation in rodents that has been shown to result in white‐to‐brown transdifferentiation.Grant Funding Source: NIH (P50‐GM60338, R01‐GM05668) and SHC (84090, 84080, 71008 and 71006) g