bluuebunny/crossref_metadata_2025_split huggingface dataset:
Functional studies of rostral ventrolateral medulla neurons using manganese‐enhanced magnetic resonance imaging in sedentary versus physically active rats (686.36)
Authors: Ingles Judith , Huereca Daniel , Holt Avril , Mueller Patrick 
Published: June 2021

A sedentary lifestyle, a key risk factor in cardiovascular disease (CVD), is linked to increased sympathetic nerve activity (SNA). Control of SNA occurs via bulbospinal catecholaminergic (C1) and non‐C1 neurons primarily in the RVLM. We recently reported that sedentary, but not physically active rats, exhibit increased dendritic branching in bulbospinal C1 RVLM neurons in a specific caudal to rostral pattern. However, regionally specific increases in RVLM neuronal activation have not yet been associated with increased dendritic branching. In many brain regions, manganese (Mn2+), a paramagnetic ion, has been used as a contrast agent to detect neuronal activity via calcium channel uptake. The purpose of this study was to develop MeMRI for in vivo studies of the RVLM, with the hypothesis that sedentary rats would have increased RVLM neuronal activity and greater Mn2+ uptake. One sedentary and one active rat (12 wks wheel running) were administered Mn2+ chloride (66mg/kg, IP), and a control rat was given saline. After 24 hours, rats were imaged (7T, Bruker Avance) and saline values were subtracted from Mn2+ injected animals. Uptake of Mn2+ in the RVLM was greater in the sedentary versus active rat (e.g. 808 vs. 327 avg voxel intensity, respectively). Notably, only the sedentary rat had a pattern of increased uptake in the caudal to rostral RVLM, very similar to our structural studies. These preliminary studies suggest that increased dendritic branching in more rostral RVLM neurons may account for enhanced RVLM neuronal activity and the growing prevalence of CVD in sedentary individuals.Grant Funding Source: Supported by HL096787‐PJM; VA 1l01RX001095‐01‐AGH
Physical (in)activity‐induced changes in tonic excitation and inhibition in the rostral ventrolateral medulla (686.37)
Authors: Laws Maxwell , Mischel Nicholas , Mueller Patrick 
Published: June 2021

The RVLM contains neurons that regulate blood pressure and exhibit (in)activity‐dependent neuroplasticity. Previous studies have found that sedentary animals have enhanced responses to direct activation of RVLM neurons that regulate sympathetic nervous activity (SNA). We hypothesized that sedentary animals have heightened sympathoexcitation due to enhanced glutamatergic and/or attenuated GABAergic neurotransmission. Rats were housed with or without running wheels for 12 weeks and were then anesthetized with Inactin and instrumented to record mean arterial pressure, heart rate, and splanchnic SNA during microinjections into the RVLM. The RVLM was functionally identified by a pressor response to glutamate (30 nl, 100 mM). Bilateral blockade of GABAA receptors with bicuculline (5mM) was performed either alone or following bilateral injection of the ionotropic glutamate receptor antagonist kynurenic acid (40 mM). Sedentary versus active rats displayed a greater SNA response following bicuculline injection alone (Δ62±7% v Δ38±8%, p<0.05). The SNA response to bicuculline after injection of kynurenate was attenuated in sedentary rats (Δ62%±7 v Δ 26%±4, p<0.05). Active rats did not show a significant SNA attenuation (Δ38±8% v Δ31±6%, p>0.05). These findings suggest that the exaggerated SNA increase in sedentary versus physically active rats following GABAA blockade is mediated by enhanced activation of ionotropic glutamate receptors. This study further demonstrates (in)activity‐dependent alterations in the RVLM and these changes may contribute to an increased risk for cardiovascular disease in sedentary individuals.Grant Funding Source: Supported by R01‐HL096787
Differential cardiovascular responses elicited by point‐specific acupuncture during phenylbiguanide‐induced reflex stimulation (686.4)
Authors: Tjen‐A‐Looi Stephanie , Cheng Ling , Li Peng , Longhurst John 
Published: June 2021

Stimulation of cardiopulmonary receptors with phenylbiguanide (PBG) consequent to vagal activation decreases blood pressure (BP) and heart rate (HR) mediated by the nucleus ambiguus (NA) and nucleus tractus solitarii (NTS). EA at P5‐6 reverses PBG‐induced reflex bradycardia through modulatory actions in the NA. The current study examined effects of EA at P5‐6 (median nerves), ST36‐37 (deep peroneal nerve), LI4‐L7 (branches of median and superficial radial nerves) and G37‐39 (superficial peroneal nerve) acupoints on the PBG reflexes in the NTS. We hypothesized that point specific EA modulation of PBG‐induced vasodepression and bradycardia is related to differential levels of EA‐related somatic and cutaneous afferent evoked activity in cardiovascular and EA‐sensitive NTS neurons. NTS activity and HR and BP responses were recorded every 10 min during either repeated stimulation of the cervical vagus or iv PBG in cats. After two consistent responses, 30 min EA was applied bilaterally at P5‐6, ST36‐37, LI4‐L7 or G37‐39. NTS neurons displayed cardiac rhythmicity, convergence from vagal and baroreceptor afferents, and nerves located under acupoints. Kainic acid into the medial NTS decreased bradycardia from ‐40±10 to ‐18±2 b/m and depressor from ‐32±6 to ‐20±2 mmHg. EA at P5‐6 reduced for over 60 min the depressor by 67% and bradycardia by 60%. Unlike LI4‐L7 and G37‐39, EA at ST36‐37 reduced the depressor by 56% and the bradycardia by 60%. Brief activation of median and deep peroneal nerves showed much greater NTS evoked activity, compared to cutaneous nerves. Unlike LI4‐L7 and G37‐39, EA at P5‐6 and ST 36‐37 reduced vagal evoked NTS activity from 12±2.0 to 2±0.8 and 11.5±1.3 to 2±1.2 spikes/30stim, respectively. Thus at the different acupoints, brief stimulation differentially activates cardiovascular NTS neurons and following 30 min EA elicits point specific responses to PBG stimulation. These data support point specific EA responses that reverse cardiovascular inhibitory reflex responses.Grant Funding Source: HL‐72125, HL‐63313
Melanocortin‐4 receptors in the PVN and RVLM are important in mediating cardiovascular responses to acute stress (686.7)
Authors: do Carmo Jussara , Sessums Price , Ebaady Sabira , Freeman John , Hall John , Silva Alexandre 
Published: June 2021

Our previous studies demonstrate an important role for the brain melanocortin system in regulating sympathetic nervous system activity and blood pressure (BP) as well as in modulating BP responses to stress. However, the brain regions involved in melanocortin‐4 receptors (MC4R)‐mediated modulation of cardiovascular responses to acute stress are unknown. In this study, we examined whether rescue of MC4R specifically in the paraventricular nucleus of the hypothalamus (PVN) or in the rostral ventrolateral medulla (RVLM) of whole‐body MC4R deficient mice (LoxTB‐MC4R mice) restores BP response to acute air‐jet stress. Using Cre‐loxP technology we selectively rescued MC4R in the PVN (LoxTB‐MC4R/Sim1, n=5) or RVLM (Cre‐RVLM/LoxTB‐MC4R mice, n=5). Mice were implanted with telemetry probes for measurement of mean arterial pressure (MAP). After a 10‐day recovery period, baseline MAP was measured for 3 consecutive days and during an acute air‐jet stress test. MAP was continuously measured for 30 minutes before, during and 30 minutes after the stress test. LoxTB‐MC4R mice were slightly heavier (53±2 vs 43±1 and 48±3 g), but had similar baseline MAP (109±1 vs 110±1 and 113±2 mmHg) compared to LoxTB‐MC4R/Sim1 and Cre‐RVLM/LoxTB‐MC4R mice. Acute air‐jet stress significantly increased MAP by 28±2 and 33±2 mmHg in loxTB‐MC4R/Sim1 and Cre‐RVLM/LoxTB‐MC4R compared to only 22±2 mmHg in loxTB‐MC4R mice. These results indicate that MC4Rs in PVN and RVLM neurons participate in the modulation of BP response to acute stress. (NHLBI‐PO1HL51971, NIGMS P20GM104357 and AHA SDG5680016)Grant Funding Source: AHA and NIH
High fat feeding in mice is insufficient to induce cardiac dysfunction and does not exacerbate heart failure (688.11)
Authors: DeMartino Angelica , Brainard Robert , Watson Lewis , Brittian Kenneth , Readnower Ryan , Boakye Adjoa , Zhang Deqing , Hoetker Joseph , Bhatnagar Aruni , Baba Shahid , Jones Steven 
Published: June 2021

Feeding high fat diet (HFD) to mice is a commonly used model to investigate the impact of risk factors on cardiovascular physiology and the development of disease. Therefore, we sought to investigate whether a high fat diet (HFD) alone could produce cardiac dysfunction. Mice were fed a normal chow diet, a milk‐based HFD (60% cal from fat), or a lard‐based HFD (60% cal from fat) for a period of 28 weeks. Neither anesthetized (at 18 weeks) nor conscious echocardiography (28 weeks) revealed any evidence of cardiac dysfunction, despite elevated body fat in the two HFD groups. We next evaluated whether a HFD would exacerbate cardiac dysfunction during heart failure. Mice fed a HFD were subjected to myocardial infarction but experienced no more significant ventricular dysfunction than normal diet fed mice. These largely negative results compelled us to investigate a more severe model of hyperglycemia/obesity. Next, db/db mice were subjected to myocardial ischemia‐reperfusion and demonstrated a significant reduction in fractional shortening compared to wild‐type (WT) littermates. Interestingly, when subjected to pressure overload, db/db mice did not exhibit more severe dysfunction than WT littermates. In conclusion, our findings, coupled with several similar reports from other groups, indicate that a HFD may not reliably replicate the pathophysiological impact of a western diet on the murine heart.Grant Funding Source: Supported by the NIH and AHA
Regional variation in the secretory function of visceral fat depots from severely obese women (688.4)
Authors: Mauriege Pascale , Joanisse Denis , Cartier Amelie , Lemieux Isabelle , Bergeron Jean , Biron Simon , Marceau Picard , Richard Denis 
Published: June 2021

Because of its hepatic venous drainage, visceral fat accumulation is an important risk factor for obesity‐related metabolic complications. Objective: To examine the secretory function of a properitoneal fat, the round ligament (RL) in severely obese women. Methods: Metabolic biomarkers, adipogenic, pro‐ vs. anti‐inflammatory, and prothrombotic characteristics were assessed in the RL adipose tissue (AT), and compared to visceral depots, the omental (OME) and mesenteric (MES) fat, in forty‐eight severely obese women (BMI, 54 ± 11 kg/m2), aged 38 ± 9 yrs. Expression of key enzymes involved in lipid metabolism (lipoprotein lipase, LPL; hormone‐sensitive lipase, HSL and phosphodiesterase‐3B, PDE‐3B), and of adipogenic factors (peroxisome proliferator activated receptors‐γ1/2, PPAR‐γ1/2) was measured by real‐time PCR. AT mRNA levels of plasminogen activator inhibitor‐1 (PAI‐1), interleukin‐6 (IL‐6), tumor necrosis factor‐α (TNF‐α) and adiponectin were also determined. Results: AT‐LPL mRNA levels were the highest in the RL depot (0.005<p<0.05), whereas HSL expression did not show regional variation. The highest PDE‐3B and lowest PAI‐1 mRNA levels were observed in the RL and MES fat (0.0001p<0.05). The lowest IL‐6 and TNF‐α as well as the highest adiponectin and PPAR‐γ1/2 mRNA levels were found in the RL AT (0.0001<p<0.05). Conclusion: Despite its anatomic location in the intraabdominal cavity, RL should not be considered as a “classical” visceral AT, as some of its secretory characteristics may contribute to limit the deleterious impact of visceral fat.Grant Funding Source: Supported by the CIHR and CRIUCPQ
CD11c positive cells are prevalent in perivascular adipose tissues of type 2 diabetic mice rather than in the vascular wall (688.7)
Authors: Qiu Tianyi , Li Min , Miles Tanner , Hill Michael 
Published: June 2021

Type 2 diabetes is associated with chronic systemic inflammation and the recruitment of immune cells. In this study, we postulated that CD11c positive cells, a specific subset of lymphocytes, are increasingly expressed with age in perivascular adipose tissues from diabetic mice. Homozygous Type 2 diabetic (db/db) and heterozygous control (DbHET) mice from the same strain were purchased from Jackson Laboratory, and divided into four age groups: 6‐10, 12‐16, 18‐22, and greater than 24 weeks. Epididymal (EAT), mesenteric (MAT), pericardial (PCAT), and periaortic (PAAT) adipose tissues were collected from the db/db and DbHET mice along with spleen, thoracic aortas (TA), mesenteric (MA), and left anterior descending coronary (LAD) arteries. All samples were used to detect CD11c m RNA level using quantitative real‐time PCR. Our data show an age‐dependent increase in CD11c expression of EAT, MAT, PCAT and PAAT adipose tissues from db/db mice. In contrast, CD11c expression remained constant among all four age groups of DbHET mice. Within each age group, higher adipose tissue CD11c levels were observed in db/db mice, compared to those of the DbHET mice. No significant changes of CD11c expression were detected in spleen, TA, MA or LAD. Overall, our data support the conclusion that in a mouse model of Type 2 diabetes, CD11c positive cells accumulate in a duration of diabetes‐dependent manner in the perivascular adipose tissues, rather than in the vascular wall. The impact of these cells on vascular function therefore likely occurs through paracrine regulated mechanisms.Grant Funding Source: NIH HL085119
Garlic attenuate hypertension and renal clearance in streptozotocin‐diabetic rats: a possible role of plasma and kidney angiotensin converting enzyme 1 (689.1)
Authors: Al‐Qattan Khaled , Thomson Martha , Ali Muslim , Mansour Mohamed , J Divya 
Published: June 2021

Objective: The effect of garlic on the blood pressure and renal clearance in relation to plasma and kidney angiotensin converting enzyme 1 (ACE‐1) concentration in conscious early streptozotocin‐diabetic rats was investigated. Method: Normal rats (n=10) received 0.5 ml normal saline (NR/NS), diabetic rats (n=10) received 0.5 ml NS (DR/NS) and diabetic rat (n=10) received 500 mg/ml/kg garlic extract (DR/GE) as daily intraperitoneal injections for eight weeks. Results: After treatment, NR/NS, DR/NS & DR/GE: blood glucose = 8.1±0.4, 26.7±0.8a & 12.4±0.2a,b mmol/l; serum insulin = 1.12±0.09, 0.12±0.02a & 0.52±0.04a,b ng/ml; blood pressure = 105±2, 175±3a & 155±2a,b mmHg; water intake = 29±1, 190±2a & 175±1a,b ml/24 h; urine output = 8±1, 93±1a & 79±1a,b ml/24 h; plasma ACE‐1 = 550±7, 755±10a & 689±8a,b pg/ml, kidney ACE‐1 = 1917±3, 1003±6a & 1646±5a,b pg/mg protein; serum albumin = 1.93±0.01, 0.86±0.03a & 1.34±0.04a,b g/dl; urine albumin = 0.017±0.001, 0.042±0.001a & 0.013±0.001a,b g/dl; serum creatinine = 83±2, 117±a & 91±2a,b µmole/l; urine creatinine = 1.3±0.06, 13.0±1.0a & 7.4±0.71a,b mmol/24 h, respectively. a: sig. different compared to NR/NS, b: sig. different compared to DR/Ns. Conclusion: Garlic may attenuate changes in diabetic blood pressure and renal clearance partially by minimizing changes in systemic and kidney ACE‐1 concentrations.Grant Funding Source: KU #SL09/10
Diabetic renal injury is not prevented or reduced by increasing renal arginine availability (689.11)
Authors: Awad Alaa , You Hanning , Gao Ting , Cooper Timothy , Morris Sidney 
Published: June 2021

Our recent publication showed that pharmacological blockade of arginases confers kidney protection in diabetic nephropathy via a nitric oxide synthase 3 (NOS3)‐dependent mechanism. Arginases compete with NOS for the common substrate L‐arginine. L‐arginine or L‐citrulline supplementation showed beneficial effect in patients with hypertension, angina and erectile dysfunction by improving endothelial function with enhanced NO synthesis. Therefore, we hypothesized that L‐arginine or L‐citrulline supplementation would prevent or reduce diabetic renal complication.DBA mice injected with multiple low doses of vehicle or streptozotocin (STZ; 50 mg/kg ip for 5 days) were provided drinking water (DW) supplemented with L‐arginine, L‐citrulline, isonitrogenous nonessential amino acid control or no amino acids (DW control) for 9 weeks.Diabetic mice with DW control showed significant increases in urine albumin excretion (p<0.05), albumin/creatinine ratio (p<0.05), kidney weight/body weight ratio (p<0.05), plasma creatinine (p<0.05), blood urea nitrogen (p<0.05), glomerular histopathological changes (p<0.001), kidney macrophage recruitment (p<0.001), kidney arginase activity (p<0.05), kidney argnase‐2 protein expression (p<0.05), kidney TNFα (p<0.01) and fibronectin (p<0.01) mRNA expression compared to normal mice after 9 weeks of diabetes. Isonitrogenous amino acid supplementation in diabetic mice was similar to DW control diabetic mice. Interestingly, neither L‐arginine nor L‐citrulline supplementation in diabetic mice affected any of these renal parameters despite increasing kidney arginine levels (6‐ and 8‐fold; respectively).These findings indicate that chronic L‐arginase or L‐citrulline supplementation does not prevent or reduce diabetic renal injury.Grant Funding Source: Supported by NIH R01 DK094930
Hepatocyte nuclear factor 4α negatively regulates STIM1 protein expression in human glomerular mesangial cells (689.15)
Authors: Wang Yanxia , Wu Peiwen , Chaudhari Sarika , Ma Rong 
Published: June 2021

Store‐operated Ca2+ signaling pathway plays an important role in physiological and pathological processes in glomerular mesangial cells. STIM1 is a key component of this Ca2+ entry pathway. We have recently demonstrated that high glucose (HG) significantly increased the expression level of STIM1 protein in cultured human mesangial cells (HMCs). However, the underlying mechanism for the HG response is unknown. Hepatocyte nuclear factor 4α (HNF4α) is a nuclear receptor expressed mainly in the kidney and liver, and regulates transcription of many genes. The present study was carried out to determine if HNF4α regulated STIM1 expression in response to HG treatment in HMCs. In cultured HMCs, HG treatment (25 mM for 6 days) significantly inhibited HNF4α‐DNA binding determined by electrophoretic mobility shift assay. Chromatin immunoprecipitation assays showed that HNF4α binding to STIM1 promoter region was attenuated by HG treatment. Knockdown of HNF4α using siRNA increased STIM1 mRNA and protein expressions. Furthermore, inhibition of store‐operated Ca2+ entry or knockdown of STIM1 increased fibronectin and collagen IV protein expressions in HMCs. Knockdown of HNF4α decreased the expression levels of both fibronectin and collagen IV proteins. These results suggest that HNF4α represses STIM1 transcription in HMCs.Grant Funding Source: NIH/NIDDK
Expression of amphiregulin in various models of polycystic kidney disease (690.1)
Authors: Bunni Marlene , Steele Stacy , Bell P Darwin 
Published: June 2021

In polycystic kidney disease (PKD) there is the continual expansion of cysts throughout the time course of this disease. The mechanisms that control the rate of cystic growth are not fully known. In PKD, the epidermal growth factor (EGF) receptor is mislocalized to the apical membrane of epithelial cells that line cystic structures. The findings that cystic fluid contains various hormones and signaling molecules further suggests that growth factors may play a role in regulation of cystic growth. The purpose of this study was to determine which EGF receptor dependent growth factors are elevated in PKD. Growth factors from human cystic fluid and mouse models of PKD were measured with an Elisa assay and RT‐PCR. Amphiregulin (Areg), epiregulin (Ereg), transforming growth factor alpha (TGFα), heparin binding EGF (HBegf) and egf were measured. In the IFT88 knockout mouse model where cilia are deleted, there was a four‐fold increase in Areg mRNA expression in mice that lacked cilia compared to mice with cilia. All other growth factors were the same between cilia minus versus cilia plus mice. In mice with a knockout of polycystin 2 there was a 5 fold increase in only Areg compared to mice with polycystin 2. In mice that lacked polycystin 1 there was 3 fold increase in Areg and an 8 fold increase in Ereg. Other growth factors were unchanged by the presence or absence of these proteins that cause autosomal dominant PKD (ADPKD). In fluid collected from individual cysts from human ADPKD kidneys we found that Areg concentration varied between 49 to 250 pg\ml and also varied between cysts from the same kidney. These results suggest that Areg and possibility Ereg may play a role in cystogenesis in PKD.Grant Funding Source: P30DK074038 and VA Merit
Hypoxia inducible factor‐1α mediates the profibrotic action of albumin in renal tubular cells (690.12)
Authors: Hu Junping , Zhu Qing , Han Weiqing , Li Xiaoxue , Li Pin‐Lan , Li Ningjun 
Published: June 2021

Proteinuria is closely associated with the progression of chronic kidney diseases (CKD) by producing renal tubulointerstitial fibrosis. Over‐activation of hypoxia inducible factor (HIF)‐1α has also been implicated in the progression of CKD. The present study tested whether HIF‐1α mediated albumin‐induced profibrotic action in cultured rat renal proximal tubular cells. Western blot assay showed that incubation of the cells with albumin (20 μg/ml) for 48 hrs significantly increased HIF‐1α protein level by 2.26 ± 0.33 fold, collagen‐I by 2.13 ± 0.037 fold and tissue inhibitor of metalloproteinase (TIMP)‐1 by 1.99 ± 0.12 fold, respectively. HIF‐1α shRNA blocked albumin‐induced increases in collagen‐I (0.54 ± 0.037 vs. 2.13 ± 0.037) and TIMP‐1 (0.76 ± 0.093 vs. 1.99 ± 0.12) protein levels. Furthermore, overexpression of prolyl‐hydroxylase 2 (PHD2) transgene, an enzyme promoting the degradation of HIF‐1α, significantly attenuated albumin‐induced increases in collagen‐ I(0.53 ± 0.21 vs. 1.81 ± 0.30) and TIMP‐1 (0.59 ± 0.19 vs. 1.23 ± 0.16) levels, whereas silencing of PHD2 gene remarkably enhanced albumin‐induced increase in collagen‐I level (2.48 ± 0.77 vs. 1.81 ± 0.30). It is suggested that HIF‐1α mediates albumin‐induced profibrotic effects in renal tubular cells and that manipulating PHD2/HIF‐1α pathway may be used as a therapeutic strategy in chronic kidney diseases.Grant Funding Source: support by NIH grant HL089563 and HL106042
The effect of rutin on overactive contractility of bladder smooth muscle in the model of cyclophosphamide‐induced cystitis in rats (690.15)
Authors: Celebi Fikret , Gelen Volkaan , Cınar Dursun , Sengul Emin 
Published: June 2021

The effect of rutin on overactive contractility of bladder smooth muscle in the model of cyclophosphamide‐induced cystitis in rats Fikret Çelebi, D.Ali Cınar, Emin Sengül, Volkan Gelen.Department of Physiology, Faculty of Veterinary Medicine, University of Atatürk, Erzurum, Turkey Cyclophosphamide (CYP) is a widely used chemotherapeutic agent in the treatment of cancer and renal disease.However, CYP often leads to hemorrhagic cystitis. Hemorrhagic cystitis increases the frequency and amplitude of spontaneous contractions in the bladder muscles.A flavonoid derivative, rutin, has been reported to have antimicrobial, antihepatotoxic, antiviral, and anti‐hypertensives effects. The aim of this study was to investigate the effects of rutin, which is known to have a potent antioxidant and anti‐inflammatory effect, on bladder smooth muscle contractility in a cyclophosphamide (CYP)‐induced cystitis rat model.24 adult female Sprague Dawley rats (200‐250 g) were used throughout experiments. Rats were divided into four groups (1: control, 2: CYP, 3: routine and 4: routine + CYP ).Bladder smooth muscle strips isolated from groups, were placed in isolated organ bath. Contraction response curves of smooth muscles of the bladder induced by ACh (10‐4M) and KCl (60 mM), and spontaneous contractions of smooth muscles of the bladder obtained.The amplitüde and frequency of conrtactions were higher in CYP induced cystitis group than control group (p< 0,05). Group 4 (routine + CYP ) has lower amplitüde and frequency than CYP induced cystitis group (p< 0,05).As a result of this study, the spasmolytic effect of the rutin was found on bladder smooth muscle contractility in a cyclophosphamide (CYP)‐induced cystitis rat model.