bluuebunny/crossref_metadata_2025_split huggingface dataset:
Changes on respiratory chemosensitivity after vagotomy in rats
Authors: Moreira Thiago S , Takakura Ana C 
Published: June 2021

Breathing relies on a rhythmically active network of brainstem neurons that is driven by central chemoreceptors and other sources of tonic excitatory drive. The retrotrapezoid nucleus (RTN) contains central respiratory chemoreceptors that are activated by carotid body and inhibited by lung inflation. In the present study, we examined whether the vagus nerve interfere with the activity of RTN chemosensitive neurons in rats. Mean arterial pressure (MAP), pO2, pCO2, pH, phrenic nerve activity (PNA) and RTN CO2‐activated neurons were recorded in urethane‐anesthetized intact or vagotomized male Wistar rats (250–280 g, n = 7/group). In vagotomized rats, without artificial ventilation, pCO2 increased (48 ± 3, vs. intact rats: 44 ± 6%) and pH is reduced (7.27 ± 0.05, vs. intact rats: 7.45 ± 0.05), without change MAP and pO2. The CO2 threshold of RTN neurons (3.2 ± 0.2%, vs. intact rats: 4.5 ± 0.4%) and PNA (4.1 ± 0.2%, vs. intact rats: 5.6 ± 0.3%) was lower in vagotomized rats. After the connection of the vagotomized rats in artificial ventilation, pCO2 (43 ± 4%), pH (7.48 ±0.16) and CO2 threshold of RTN (4.8 ± 0.9%) and PNA (5.7 ± 0.3%) returned to levels observed in intact anesthetized preparations. The present results support the idea of the importance of the vagus nerve on the control of the respiratory chemosensitivity in rats.Financial support: FAPESP (06/60174‐9 to TSM).
Mammary Epithelial Cells Modulate TRPM6 Expression in Response to Variations of Magnesium Availability
Authors: Wolf Federica I , Trapani Valentina , Mastrototaro Lucia , Cittadini Achille 
Published: June 2021

Mammary epithelial cells (HC11) chronically adapted to grow in a low‐magnesium (0.05 mM vs. 0.5 mM) or in a high‐magnesium (40 mM) medium were used to investigate on the mechanisms of cell magnesium transport under conditions of non‐physiological magnesium availability. Magnesium influx was higher in low‐magnesium cells compared to control or high‐magnesium cells, this influx was abolished by Co(III)hexaammine, an inhibitor of magnesium channels. Among the Mg‐transporting channels recently characterized, e.g. MagT1, SLC41A1, transient receptor potential meastatin (TRPM7) was shown to mediate magnesium uptake ubiquitously at cell/tissue level, whereas TRPM6 seems to be responsible for transcellular magnesium absorption or re‐absorption in the intestine and kidney, respectively. We found that HC11 cells grown in low magnesium upregulated mRNA for TRPM6 and not for TRPM7 or MagT1. Consistent with these results, TRPM6 protein level as assessed by western blot, was inversely related to extracellular magnesium, namely low‐magnesium cells > control cells > high‐magnesium cells and was also rapidly up‐ or down‐modulated in HC11 cells acutely deprived of magnesium or in low‐magnesium cells re‐added with magnesium, respectively. These results suggest, for the first time, that TRPM6 contributes to regulating magnesium influx in mammary epithelial cells.Supported by the Italian MIUR‐PRIN 2007ZT39FN.
The Eleven‐nineteen Lysine‐rich Leukemia Gene (ELL) Couples Transcription Elongation with Epigenetic Signaling
Authors: Fufa Temesgen D , Wakano Clay , Byun Jung S , Haggerty Cynthia M , Elenitoba‐Johnson Kojo , Thirman Michael J , Raffeld Mark , Hewitt Stephen , Gardner Kevin 
Published: June 2021

The human Eleven‐nineteen Lysine‐rich Leukemia gene (ELL) was first identified as a chromosomal translocation partner for the histone‐methyltransferase mixed lineage leukemia protein (MLL) and was subsequently found to be a RNA polymerase II elongation factor. Though studies in several eukaryotic models including yeast and Drosophila are beginning to shed light on ELL function, just how ELL and its oncogenic fusion with MLL influences gene regulation in mammalian systems remains to be defined. We have profiled the interaction partners of ELL in mammalian cells by sedimentation analysis, immunoprecipitation, mass spectrometry and genome location analysis. These analyses revealed that in addition to the positive transcription elongation factor b (P‐TEFb), ELL associates dynamically with various readers, writers, and erasers of the histone code. These include, the histone acetyltransferase p300, members of the histone deacetylase complex and components of the SET1 methyltransferase complex. Surprisingly, ELL undergoes a dynamic subcellular redistribution in response to mitogen stimulation, forming compartment specific complexes in the nucleus and cytosol. These findings provide new insights into the mechanisms that couple the crosstalk between transcriptional elongation and epigenetic regulation in mammalian cells.Funding: Intramural Research Program of the NCI/NIH, USA
Modulation of Neuropeptide‐Y receptor expression by IGF‐1 and atheroma‐associated cytokines in carotid plaques of symptomatic and asymptomatic patients
Authors: Pankajakshan Divya , Jia Guanghong , Pipinos Iraklis , Agrawal Devendra 
Published: June 2021

Neuropeptide‐Y (NPY) is involved in the induction of immune‐mediated inflammation. But, its role in atherosclerotic plaques is unknown. Here, we examined NPY‐receptor(R) expression in the presence of IGF‐1 and TNF‐α in plaque smooth muscle cells (pSMCs) of symptomatic(S) and asymptomatic(AS) patients with carotid stenosis. IGF‐1 increased NPY‐Y1 and NPY‐Y5 expression in S (1.5 and 1.2‐fold) and AS pSMCs (2 and 1.5‐fold, respectively). TNF‐α significantly decreased NPY‐Y1R (10‐fold) in S with no change in AS pSMCs. NPY‐Y5R expression decreased significantly in both S and AS pSMCs by TNF‐α. The combined stimulation of the cells with IGF‐1 and TNF‐α increased NPY‐Y1 expression by 1.2‐fold in AS pSMCs but no effects in S pSMCs. In both S and AS pSMCs, IGF‐1 increased NPY‐Y5 expression, but the effect of IGF‐1 in the presence TNF‐α was abolished. IGF‐1 increased (80%) NPY‐Y2 receptor expression in AS pSMCs, but had no significant effect in S pSMCs. NPY‐Y2 expression was higher in AS (2.5‐fold) and S pSMCs (3.5‐fold) upon TNF‐α stimulation than respective controls. Thus, IGF‐1 and TNF‐α differentially modulate NPY‐Y1, ‐Y2 and ‐Y5 receptor expression in AS and S pSMCs. A balance between the inflammatory cytokines and IGF‐1 level at the plaque milieu is critical in determining SMC proliferation or apoptosis at the site of fibrous cap leading to the plaque stability/instability in symptomatic patients with carotid stenosis.(Supported by NIH R01HL073349)
Rapid and consistent porcine model for chronic total occlusions in the peripheral vasculature
Authors: Tunev Stefan , Caceres Alejandra , Melder Robert , Wilcox Josiah 
Published: June 2021

Development and testing of treatment options for chronic total occlusions (CTO) still remains one of the last frontiers of vascular interventions. The lack of a consistent CTO animal model is one of the hurdles precluding efficient treatment advances in this field.We describe here a porcine model of a calcified CTO achieved by an intravascular delivery of de‐mineralized bone matrix (DBM) products in the femoral arteries. DBM is essentially de‐mineralized allograft bone particles with osteoinductive properties. In this study, the DBM material was delivered to each vessel via a guide catheter based approach. At 28 days, each treated vessel was evaluated angiographically, the animals were sacrificed and the treated vessels segments were assessed histopathologically. CTO was detected in 73% of the treated vessels. Morphologically, the CTO lesions were characterized by a mixed tissue growth composed of well vascularized collagenous matrix, mineralized and un‐mineralized bone fragments and variable mononuclear inflammation. This tissue reaction appeared well adhered to the vascular tunica media. Vascular channels lined by endothelium were present in vessels with incomplete chronic occlusion.This animal model can provide a platform for 1) development and testing of new CTO crossing devices, 2) evaluation of stents in calcified vessels 3) identification and evaluation of pharmacological entities in context of calcification and 4) development and evaluation of decalcification treatments.
Effects of phytoestrogens from Curcuma comosa Roxb. on rat aorta relaxation
Authors: Intapad Suttira , Saengsirisuwan Vitoon , Suksamrarn Apichart , Piyachaturawat Pawinee 
Published: June 2021

The present study aims to investigate the effect of Curcuma comosa Roxb., family Zingiberaceae, containing phytoestrogens on vascular relaxation. Isolated thoracic aorta from adult female rats were incubated with C. comosa hexane extract, and an isolated diarylheptanoid, [(3R)‐1,7‐diphenyl‐(4E,6E)‐4,6‐heptadien‐3‐ol] which is the major in the extract. Both the extract and diarylheptanoid compound enhanced the endothelium‐dependent relaxation response to acetylcholine. Co‐incubation of C. comosa with ICI182,780 (ER antagonist), L‐NAME (NOS‐inhibitor) or ODQ (guanylase cyclase inhibitor) abolished the enhancing effects. C. comosa extract and the compound also increased the phosphorylation levels of serine 1177‐eNOS and serine 473‐Akt. In addition to the acute exposure, the effects of long‐term treatment (12 weeks) of C. comosa to the ovariectomized rats (OVX) were also investigated. Both C. comosa and diarylheptanoid compound treatments resumed the impairment of endothelium functions, and increased mRNA levels of both ERα and eNOS. The results suggest that the enhancing endothelium‐dependent relaxation by phytoestrogens from C. comosa is both non‐genomic and genomic effects and mediates through ER‐dependent and NO‐pathways.Supported by TRF through RGJ Ph.D. Program (Grant PHD/0094/2547) and research grant from TRF (DBG 5180020)
Embolic potential in symptomatic patients undergoing carotid angioplasty and stenting: evaluation of plaque instability through microscopic quantification of particulate debris
Authors: Chung Christine , Shin Hyun Joo , Shah Tejas R , Faries Peter L 
Published: June 2021

ObjectivePreoperative patient characteristics associated with a higher degree of embolization during carotid angioplasty and stenting (CAS) have yet to be clearly defined. Our aim is to examine whether neurologic symptoms in CAS patients is associated with greater plaque instability as determined by the quantification of intraprocedural embolic debris.Methods/ResultsWe analyzed 162 filters of 233 CAS cases. Particles captured in distal protection devices were visualized by stereomicroscopy along three perpendicular axes, and were subsequently quantified through video imaging software. Due to particle shape heterogeneity, individual particle sizes were determined by greatest length. 56 patients (34%) were symptomatic [transient ischemic attack (TIA): 52%, amaurosis fugax (AF): 21%, cerebrovascular accident (CVA): 34%]. Increased particle number and size were observed in symptomatic (S) vs. asymptomatic (AS) patients: number (S: 14.2 ± 13.9 vs. AS: 7.9 ± 8.8, P<0.001), maximum size (S:1127 ± 1412 μm vs. AS: 744 ± 827 μm, P=0.03), and mean size (S: 473 ± 431 μm vs. AS: 342 ± 262 μm, P=0.02). Furthermore, specific symptoms were associated with particle characteristics to varying degrees. The presence of TIA yielded a significantly greater number (P=0.03) and mean size (P<0.001) of debris, while the occurrence of AF and CVA trended towards the same outcome.ConclusionsThe presence of neurologic symptoms increases the number and size of embolized debris in CAS patients, which may place them at greater risk for perioperative embolic complications.Grant Funding Source: National Institute of Health K08HL073313.
Fabry and fmf diseases: more that eyes can see
Authors: Vasto Sonya , Castiglia Laura , Nuzzo Domenico , Rizzo Claudia , Duro Giovanni , Caruso Calogero 
Published: June 2021

Fabry disease is an X‐linked disorder resulting from a deficiency of the lysosomal enzyme alpha‐galactosidase leading to the accumulation of glycolipids in the cells. It has been demonstrated that polymorphisms of alfa‐galactosidase might influence the onset and development of inflammatory cardiovascular age related disease.Familiar Mediterranean fever (FMF) is a autosomal recessive inflammatory based disease, characterized by recurrent fever, peritonitis, arthritis, pleuritis, and cardiac problems. MEFV encodes the pyrin protein it has been suggested to play a role in the innate immunity regulating the inflammatory response. Several data suggest a role of FMF polymorphisms in worsening recurrent inflammatory diseases. The aim of this study is to analyze the interaction between polymorphisms of this two diseases in order to find possible association. We have analyzed 46 patients with cardiac and neurological diseases holding Fabry's disease polymorphisms. Surprisingly, we have found that out of the 46 patients 9 individuals were bearing also Pyrin allelic mutations (more that 19.6%). Since the percentage of Pyrin mutation in a healthy population is more or less 5%, we can conclude that the presence of these mutations might load of further inflammatory burden the status on Fabry's patients.
Epigenetic regulation of high glucose‐induced proinflammatory cytokine production in monocytes by curcumin
Authors: Yun Jung‐Mi , Jialal Ishwarlal , Devaraj Sridevi 
Published: June 2021

Diabetes is a pro‐inflammatory state. We have shown increased monocyte proinflammatory cytokines in patients with diabetes. High glucose (HG) induces inflammatory cytokines via epigenetic changes. Curcumin is anti‐inflammatory and may regulate chromatin remodeling by inhibiting histone acetylation. In this study, we tested the effect of curcumin on histone acetylation and inflammatory cytokine secretion under HG conditions in monocytes. THP‐1 cells were cultured in presence of normal glucose (NG, 5.5 mmol/L) or HG(25 mmol/L) conditions in absence or presence of curcumin (1.5–12.5μM) for 72h. Cytokine level, NFκB transactivation, histone deacetylases (HDACs) activity, and histone acetylases (HATs) activity were measured by immunoblotting, ELISA and immunofluorescence. HG activates HAT which in turn acetylates p65 and suppresses HDAC2 resulting in NFκB activation and increased transcription of IL‐6 and TNF‐α in monocytes. Curcumin induces HDAC2 and decreases HAT (p300) activity, thereby resulting in decreased NFκB activation and decreased inflammatory cytokine release (p<0.001) in HG conditions. These results indicate that curcumin decreases HG‐induced cytokine production in monocytes via epigenetic changes involving NFκB. In conclusion, curcumin supplementation by reducing vascular inflammation may prevent diabetic complications.Grant Funding Source: N/A
Sympathetic Preganglionic Neurons Modulation by Nitric Oxide in The Spinal Cord
Authors: Sabino Joao Paulo J , Bombarda Gabriela , Silva Carlos Alberto Aguiar , Fazan Rubens , Salgado Maria Cristina Oliveira , Salgado Helio Cesar 
Published: June 2021

The role played by the nitric oxide/cyclic guanosine monophosphate pathway (NO/cGMP) on sympathetic preganglionic neuron (SPN) modulation still deserves a thorough investigation. Therefore, the role played by NO/cGMP pathway of the spinal cord in the control of mean arterial pressure (MAP) and heart rate (HR) was examined in conscious rats (N= 56) equipped with catheters into the subarachnoid space (intrathecal) and femoral artery. Intrathecal administration of L‐NAME (an inhibitor of NO synthase) caused an increase in MAP but did not affect HR. Intrathecal ODQ (an inhibitor of soluble guanylyl cyclase) did not change MAP and HR. Intrathecal L‐arginine (a precursor of the synthesis of NO) decreased both MAP and HR, while ODQ given before L‐arginine prevented these effects. AP5 (an antagonist of NMDA receptor) did not attenuate the increase in MAP promoted by L‐NAME. Although the hypotensive and bradycardic responses induced by Intrathecal administration of L‐arginine was dependent of cGMP, our results indicate that NO acts as a tonic inhibitory neuromodulator of SPN, independent of either cGMP or NMDA receptors.Research support: CAPES, CNPQ e FAPESP.
Relationship between birth weight and the autonomic nervous system
Authors: Chiba Haruka , Nagai Mizuki , Haga Mayu , Sasaki Konosuke , Maruyama Ryoko 
Published: June 2021

BackgroundEpidemiological studies have suggested that low or high birth weight is a risk factor for hypertension in later life. Generally, blood pressure is regulated by several factors, including the number of nephrons, hypothalamic pituitary adrenal function, and the autonomic nervous system (ANS). However, the mechanism by which low or high birth weight leads to hypertension has barely been elucidated. To address this lack of research, we studied the relationship between birth weight and ANS.PurposeThe aim of this study was to investigate the effect of birth weight on heart rate variability (HRV) and cardiovascular responses.MethodsIn nonsmoking, healthy volunteers aged 20 to 30 years, we measured ECG and blood pressure (BP) in the right arm by autonomic sphygmomanometer after stabilization for 5 min throughout the experiment. We allocated participants to a low‐birth‐weight group, normal‐birth‐weight group, and high‐birth‐weight group.ResultBirth weight was inversely correlated with systolic BP and the ratio of low‐frequency to high‐frequency (LF/HF) power, an index of sympathetic nerve activity. There was a positive relationship between systolic BP and LF/HF.ConclusionLow birth weight probably has an influence on autonomic nervous system regulation.
Acute glutathione supplementation enhances endothelial‐mediated coronary artery dilation
Authors: Levy Andrew S , Smith Christopher S , Rush James WE 
Published: June 2021

Reports from both human and animal studies demonstrate that acute thiol manipulation influences both vascular function and nitric oxide (NO) production. To this end acute glutathione (GSH) administration has been used to enhance coronary vasodilation; however, the mechanisms have not been fully resolved. The purpose of this investigation was to determine how acute GSH administration alters NO‐mediated coronary artery dilation. Endothelial function was assessed in isolated, perfused hearts using a Langendorff apparatus. GSH was administered at concentrations of 0 (CON), 1 or 10 μM and dose‐response curves to bradykinin (BK) were constructed. The sensitivity to BK was enhanced at the 10 μM concentration (p<0.01) and no differences were seen in maximal dilation. In the presence of LNAME (0.1 mM) and/or sGC inhibition (ODQ, 3 μM) the sensitivity to BK remained enhanced in the presence of GSH (10 μM) (p<0.05). Treatment with TEMPOL (0.1 mM) enhanced the sensitivity to BK in CON similar to the effect of GSH (10 μM) and GSH (10 μM)+TEMPOL (0.1 mM). TEMPOL enhanced the sensitivity to exogenous NO (SNP), whereas GSH slightly reduced maximal dilation to SNP. Collectively, these results suggest GSH enhances BK mediated dilation through an antioxidant‐dependent mechanism unrelated to NO production or utilization.Supported by Heart and Stroke Foundation & Natural Science and Engineering Research Council
Perfusion Territory of Embolized Coronary Artery Vasa Vasorum
Authors: Moritz Regina , Eaker Diane R. , Anderson Jill L. , Kline Timothy L. , Jorgensen Steven M. , Ritman Erik L. 
Published: June 2021

Occlusion of coronary vasa vasorum (VV) leads to hypoperfusion of the arterial vessel wall (AVW) possibly resulting in impaired solute transport. We hypothesize that high cholesterol (HC) facilitates development of atherogenesis in hypoperfused areas.Swine (40) underwent injection of gold‐coated μspheres (100μm) in left coronary artery. After the procedure 13 swine were studied immediately, 13 were fed a standard (C) and 14 a HC diet for 3 months prior to study. The LADs were harvested and snap‐frozen (cryo micro‐CT scanning). Hypoperfused areas in the AVW were defined by local reduction of CT‐values. The distance of μsphere to lumen (x) was measured, and foam/fat cells/mm2 (f/fc) in hypoperfused and perfused areas were counted using histology.
Linear relationship between x and hypoperfused AVW.
In HC the f/fc # in media of hypoperfused areas is higher than in C (p=0.001).
In HC f/fc # is higher in hypoperfused AVW areas compared to adjacent perfused areas (p<0.05).
In C there is no difference in f/fc # between hypoperfused and perfused areas (p=0.92).
In C and HC the f/fc # in intima of perfused, as well as in hypoperfused, areas is not different (p=0.9/0.5).
Occlusion of VV leads to increased susceptibility of hypoperfused AVW areas for precursors of atherosclerosis with HC diet. The linear relationship of hypoperfused area to μsphere distance suggests that VV function as a plexus rather than a vascular tree.This study was supported by NIH grant HL065342.
ACE2 over‐expression regulates oxidative stress gene expression in the brainstem
Authors: Xu Ping , Lazartigues Eric 
Published: June 2021

Angiotensin (Ang) I converting enzyme type 2 (ACE2) cleaves Ang II into the vasodilator Ang‐(1–7). We previously reported that ACE2 is expressed in the brain and involved in the prevention of hypertension via regulation of autonomic function. We also showed that ACE2 KO mice have increased levels of reactive oxygen species (ROS) in the brain. To clarify the role of ACE2 in the regulation of ROS levels, we performed an oxidative stress PCR array using brainstems from SA mice, with brain‐specific ACE2 overexpression, and control littermates (NT).In SA mice, the main ROS‐producing enzyme, NADPH oxidase, subunits genes Nox1 (gp91phox homolog), Nox4, p22phox and p67phox were downregulated by −3.1, −1.6, −13.4 and −11 folds respectively, compared to controls. The NADPH oxidase activator 1 (Noxa1) and the dual oxidase1 (Duox1), which generates hydrogen peroxide, were also decreased by −2.6 and −1 fold, respectively. Anti oxidant stress enzymes like glutathione peroxidase 1, 3, 6, 8 subunits were downregulated by −180, −3, −2.4, −3.1 folds and so were SOD 1 (−1.2 fold) and 3 (−1.8 fold). Moreover, there was a trend to a reduction in lipid peroxidation (Tbars assay) in the brainstem of SA mice. These data show that ACE2 is regulating the expression of multiple genes involved in the formation and removal of ROS in the brainstem, which may contribute to the prevention of hypertension in this model. NIH RR018766 and HL093178
Investigation of the Association of SCN1B with Cardiac Junctional and Ion Channel Proteins at the Intercalated Disc
Authors: Gatt Jessica Lane , Isom Lori L. 
Published: June 2021

Voltage‐gated Na+ channels (VGSCs), located in cardiac intercalated discs, are heterotrimeric molecules containing a central, pore‐forming α subunit and two multifunctional β subunits, associated with multiple proteins to ensure rapid, synchronous electrical transduction of action potentials through cardiac myocytes. Mutations in genes encoding VGSC α and β subunits can lead to cardiac arrhythmias, including Long‐QT and Brugada Syndromes.We propose that VGSC β1, encoded by SCN1B, plays an integral role in forming multimolecular signaling complexes in heart. Our aim was to use the SCN1B null mouse model to investigatec interactions of Nav1.5 with junctional and ion channel proteins that are dependent on β1. This information will provide insight into how SCN1B mutations lead to cardiac arrhythmia. Using co‐immunoprecipitation, we investigated the association of Nav1.5 with Kv4.3, N‐cadherin, and connexin‐43, in solubilized SCN1B null and wildtype heart membranes.Previous studies showed that β1 associates with Nav1.5, N‐cadherin, and connexin‐43 in transfected cells. The present in vivo results suggest that Nav1.5 and Kv4.3 form a macromolecular complex in wildtype heart. Nav1.5 and N‐cadherin associate in wildtype but not SCN1B null heart, suggesting that β1 is critical for Nav1.5‐N‐cadherin interactions. Nav1.5 and Cx‐43 remain associated in the SCN1B null heart, suggesting this interaction does not depend on β1. Our results suggest that VGSC β1 is an integral molecular adaptor, organizing and linking Nav1.5 complexes to key junctional and ion channel proteins in the intercalated disc.