bluuebunny/crossref_metadata_2025_split huggingface dataset:
Inhibitory effect of Xanthoceras sorbifolia on TNF‐α‐induced vascular dysfunction in human umbilical vein endothelial cells
Authors: Yoon Jung Joo , Lee Yun Jung , Choi Eun Sik , Ahn You Mee , Han Byung Hyuk , Kang Dae Gill , Lee Ho Sub 
Published: June 2021

Xanthoceras sorbifolia Bunge, which belongs to the Sapindaceae family, is a shrub in Inner Mongolia and China. It has been used as a folk medicine for various diseases including hypertension and enuresis. In human umbilical vein endothelial cells (HUVEC), ethanol extract of seed from the Xanthoceras sorbifolia (EXS) significantly decreased TNF‐α‐induced expression of cell adhesion molecules such as intracellular adhesion molecule‐1 (ICAM‐1), vascular cell adhesion molecule‐1 (VCAM‐1), and endothelial cell selectin (E‐selectin) in a dose‐dependent manner. Pre‐treatment of EXS significantly inhibited the translocation and transcriptional activity of NF‐κB increased by TNF‐α. In addition, EXS also significantly inhibited the formation of intracellular reactive oxygen species (ROS). Furthermore, we found that the vascular protective effects of EXS were linked to the up‐regulation of heme oxygenase‐1 (HO‐1) and nuclear factor E2‐related factor‐2 (Nrf2) expressions in HUVEC. The inhibitory effects of EXS on the TNF‐α‐induced vascular inflammation were partially reversed by an inhibitor of HO‐1, tin protoporphyrin IX (SnPP), while increased by an inducer of HO‐1, cobalt protoporphyrin IX (CoPP).In conclusion, these results suggested that EXS ameliorated TNF‐α‐induced vascular inflammation, possibly through the disturbing ROS/NF‐κB pathway and activation of Nrf‐2/HO‐1. Hence, EXS plays a key role in the vascular inflammation and further prevents the development of atherosclerosis.
Effects of Hydrogen Sulfide on Circulation
Authors: Sonobe Takashi , Haouzi Philippe 
Published: June 2021

Hydrogen sulfide (H2S) has been suggested to relax the vascular smooth muscles and produce a vasodilation. However, it remains unclear whether endogenous H2S produced in the vessels, if any, can produce a vasodilatory effect, which has a relevant physiological or clinical meaning, as concentrations of H2S used in vitro to produce these effects are within a toxic range.In urethane anesthetized mechanically ventilated rats, NaHS was intravenously infused in a stepwise manner to produce an increase in alveolar H2S partial pressure and thus arterial concentration of free H2S (CgH2S) from undetectable up to levels we have previously shown to depress breathing control.Compared to saline infusion, blood pressure started to decrease significantly along with the peripheral vascular resistance by ‐19 ± 5%, (P<0.01) when CgH2S reached ~ 1 microM. As soon as CgH2S exceeded these levels, cardiac output decreased with a decrease in ventricular pressure, along with a significant elevation of blood lactate. Whenever H2S exposure was maintained at a higher level, above 3‐4 microM of CgH2S, a profound inhibition of cardiac contractility occurred leading to cardiac arrest by a pulseless electrical activity.In conclusion, a small reduction in peripheral vascular resistance was found in the rat at relatively low H2S concentrations. These changes were extremely modest with an alarming overlap with the levels of H2S altering cardiac contractility.
Role for DNA damage and epigenetic signaling in coronary artery diseases
Authors: Meloche Jolyane , Henry Sarah , Tremblay Eve , Charbonneau Eric , Provencher Steeve , Bonnet Sebastien 
Published: June 2021

Coronary artery disease (CAD) is the most common cause of heart attacks. Evidence demonstrated that coronary artery stenosis have increased inflammation leading to sustained DNA damage. In cancer, through the activation of poly(ADP)ribose‐polymerase 1 (PARP‐1), a critical enzyme acting as a DNA damage sensor, and the epigenetic reader Bromodomain‐containing protein 4 (BRD4), DNA damage promotes mitochondrial/metabolic dysfunction contributing to cell proliferation. Thus, we hypothesized that increased inflammation‐induced DNA damage in remodeled coronary arteries promotes BRD4 and PARP‐1 expression, triggering CoASMC proliferation. Both coronary arteries (n=10) and primary cultured CoASMC (n=4) from patients with stenosis exhibit increased (p<0.05) DNA damage (γ‐H2AX and 53BP1), PARP‐1 and BRD4 protein expression (western blot). This pathological phenotype significantly increased (p<0.05) cell proliferation (Ki67, MTT assay) through a mitochondrial (TMRM) and metabolic dysfunction (Seahorse XFe24) compared to control cells (n=3). Furthermore, co‐culture of CoASMC with peripheral blood mononuclear cells (PBMC) isolated from symptomatic CAD patients promotes BRD4 expression (qRT‐PCR). Finally, experimental rat model of carotid angioplasty exhibit a similar phenotype that the one seen in CAD patients. Our study suggests an important role for PARP‐1/BRD4 axis in CoASMC proliferation in CAD.A “Fonds de recherche Quebec‐Sante” graduate scholarship to Jolyane Meloche, as well as Canadian Institutes of Health Research grants and a Canadian Research Chair in Vascular Remodeling Diseases to Sebastien Bonnet supported this work.
Aging Selectively Attenuates L‐Type Calcium Currents in Resistance Coronary Arteries
Authors: Mansour Fathi , Hassan Mohammed , Khan Abdul Aleem , Albarwani Sulayma 
Published: June 2021

The current density of L‐type voltage‐gated calcium (L‐VGC) channels was reported to be inversely proportional to the diameter of coronary arteries. Since aging is a major risk factor for coronary artery disease, we investigated if the above relationship is altered with aging. Smooth muscle cells were isolated from coronary arteries of young (3‐4 months) and old (22‐26 months) male F344 rats. Whole‐cell L‐VGC currents were recorded using 10 mM Ba2+ as charge carrier from small (˂100µm) and large (250 to 400 µm) diameter arteries. Student's t‐test was used to compare peak inward current densities (pA/pF; mean± S.E.M) between young and old arteries of similar size and the 2‐way ANOVA was used to compare all four groups (P<0.05). In large arteries, current densities were not significantly different between old (‐5.44 ± 0.92; n=13) and young (‐4.33 ± 0.81, n=13) rats. In small arteries, current densities from old (‐3.66 ± 0.41; n=36) were reduced by 2.4 fold compared to those from young rats (‐8.8 ± 0.88; n=27); with similar V0.5 for both activation and inactivation voltages. Current densities recorded from large arteries of young and old rats and from small arteries of old rats were not significantly different. However, current densities recorded from small arteries of young rats were significantly higher than those from the other three groups. L‐type current density of small resistance arteries of young rats is significantly higher than in large arteries. This inverse diameter‐current density relationship is lost with aging. We conclude that aging selectively affects the density of L‐VGC currents of small resistance coronary arteries.This work is funded by The Research Council of Oman
Upregulation of Orexin Receptor in Paraventricular Nucleus Promotes Sympathetic Outflow Through Non‐selective Cation Channel in Obesity
Authors: Zhou Jing‐Jing , Chen Shao‐Rui , Yuan Fang , Zhang Yi , Li De‐Pei 
Published: June 2021

AbstractElevated sympathetic outflow contributes to hypertension in obesity. Orexins importantly regulates autonomic function. Presently we determined the role of orexin in the paraventricular (PVN) nucleus of hypothalamus in controlling sympathetic outflow in obese Zucker rats (OZRs) and lean Zucker rats (LZRs). Orexin A microinjection into PVN significiantly dose‐dependently elevated arterial blood pressure (ABP) and renal sympathetic nerve activity (RSNA) manner in anesthetized OZRs than LZRs, which eliminated by SB‐334867, orexin receptor 1 receptor (OX1R) antagonist, but not TCS‐OX2‐29, OX2R antagonist. Furthermore, SB‐334867 reduced basal ABP and RSNA in OZRs but not LZRs. Compared with LZRs, OX1R expression in PVN was significantly higher in OZRs, while no difference for OX2R. OX1R immunoreactivity was positive in retrogradely labeled PVN‐spinal neurons. Compared with LZRs, the basal firing rate in the PVN‐spinal neurons was higher in OZRs, and orexin A excited firing activity in PVN‐spinal neurons in OZRs, which eliminated by SB334867. SB334867 also decreased basal firing activity of these neurons in OZRs. In addition, orexin A induced larger currents in PVN spinal neurons in OZRs. These data suggest that upregulation of OX1R in the PVN promotes hyperactivity of PVN presympathetic neurons and sympathetic outflow in obesity.This work was supported by National Institutes of Health (Grants MH096086 to D.‐P. L.) and National Natural Sciences Foundation of China (31271223 and 31071002).
Electrical Stimulation of Carotid Sinus in Conscious Normotensive and Spontaneously Hypertensive Rats
Authors: Domingos Gean , Santos‐Almeida Fernanda , Silva Luiz Eduardo , Dias Daniel , da Silva Carlos Alberto , Castania Jaci , Salgado Helio , Fazan Rubens 
Published: June 2021

Electrical stimulation (ES) of the carotid sinus (CS) has been used to treat resistant arterial hypertension. Our aim was to evaluate, in conscious normotensive and spontaneously hypertensive rats (SHR), the effect of sustained (60 min) ES of CS on arterial pressure (AP), heart rate (HR) and heart rate variability (HRV). Male Wistar rats (n=8) and SHR (n=8) had the left CS surrounded by a pair of electrodes and insulated from adjacent tissues. A catheter was introduced into the femoral artery and exteriorized together with the CS electrodes. On the next day, conscious rats under continuous recording of AP had their CS stimulated with square pulses of 1 mA, 1 ms, and 30 Hz, delivered randomly, continuously or intermittently (20/20 s ON/OFF), during 60 min. On the following day the type of CS stimulation was inverted. To analyze HRV, segments of 5 min were selected immediately before, at the onset, middle and end of ES period. Greater sustained fall in AP due to ES of CS was observed in SHR (‐50±7 vs ‐11±2 mmHg). A conspicuous bradycardia was also elicited by sustained ES of the CS (‐62±15 and ‐32±11 bpm in SHR and Wistar rats). No difference was observed between continuous or intermittent ES of CS. Overall, HRV was increased by ES of CS only in SHR (from 4.8±0.6 to 11.7±3.2, 7.0±0.6 and 6.7±1.0 bpm at the onset, middle and end of ES). Surprisingly, no differences were observed in HR spectra during ES of CS in both groups. We conclude that ES of the CS was more effective to reduce AP and HR in SHR as compared to normotensive rats. Moreover, despite a marked effect of ES in overall HRV in SHR, no changes in HR spectra were observed.Financial Support: FAPESP, CAPES and CNPq.
Chronic Heart Failure Blunts the Low Pressure Baroreflex Induced Biphasic Change of Sympathetic Nerve Activity
Authors: Oga Yasuhiro , Kishi Takuya , Saku Keita , Kakino Takamori , Nishizaki Akiko , Arimura Takahiro , Fujii Kana , Tohyama Takeshi , Nishikawa Takuya , Sunagawa Kenji 
Published: June 2021

BackgroundWe previously showed that volume loading activates low pressure baroreflex (L‐BARO) and causes biphasic change in sympathetic nerve activity (SNA). We examine if chronic heart failure (CHF) blunts the L‐BARO regulation of SNA.MethodsWe used 10 anesthetized Sprague‐Dawley rats. CHF was induced by myocardial infarction. We vascularly isolated carotid sinuses and kept carotid sinus pressure constant to abolish the arterial baroreflex which is the major regulator of SNA. We infused or withdrew blood (3ml/kg) stepwise to activate L‐BARO and recorded SNA and hemodynamics.ResultsIn the control group (n=5), volume loading evoked biphasic changes in SNA with a maximal response of 61±43%. In contrast, CHF (n=5) markedly reduced the maximum response (10±13% from baseline) and blunts L‐BARO induced SNA alteration. In both group, vagotomy totally abolished the L‐BARO regulation of SNA. Regarding hemodynamics, L‐BARO attenuated the increases in AP and LV end‐diastolic pressure (LVEDP) against volume infusion in control group, whereas did not affect either in CHF.
imageConclusionsCHF blunted L‐BARO modulation of SNA in rats. The mechanism and pathophysiological significance of L‐BARO failure in CHF remains to be seen.
The Effect of Multiple Sclerosis on Carotid Baroreflex Control of Heart Rate and Blood Pressure
Authors: Huang Mu , Allen Dustin , Keller David , Davis Scott 
Published: June 2021

Multiple sclerosis (MS), a progressive neurological disease, can result in impairments in autonomic control of cardiovascular function. We tested the hypothesis that patients with MS (n=5) exhibit a blunted response following baroreflex perturbation compared to sex and age matched healthy controls (CON: n=5). At rest, 5‐sec pulses of neck suction (NS; ‐60 Torr) and neck pressure (NP; +40 Torr) were applied to simulate carotid hypertension and hypotension, respectively. Mean arterial pressure (MAP; finger photoplethysmography) and heart rate (HR) were continuously measured in response to the perturbations. Following NS, responses in MAP (MS: ‐11±5 mmHg, CON: ‐10±3 mmHg; p=0.59) and HR (MS: ‐8±3 BPM, CON: ‐8±4 BPM; p=0.93) were similar between groups. While HR response (MS: 5±5 BPM, CON: 5±4 BPM; p=0.94) following NP was no different, a difference in MAP approached significance (MS: 6±2 mmHg, CON: 8±2 mmHg; p=0.09). These data suggest that patients with MS demonstrate a diminished ability to increase MAP to hypotensive stimuli compared to healthy controls. Supported by NIH R15HL117224 and National MS Society RG4696A
Maternal Obesity and the Developmental Programming of Hypertension: The role of Leptin in the Central Nervous System
Authors: Lim Joon (Kyungjoon) , Burke Sandra , Head Geoffery 
Published: June 2021

The obesity in women among child baring age is increasing and this has been reported to be parallel to the increase in obesity in general population. We determined the trans‐generational ‘programming’ of leptin signalling in the central nervous system (CNS) following an initiation of a high fat diet (HFD) in mothers. Female New Zealand White rabbits were fed a high fat (13%) diet (mHFD) or a normal fat diet (mNFD) prior mating and during pregnancy. Offspring from mNFD rabbits were subdivided and fed a HFD for 10days (mNFD10dHFD) to mimic adulthood obesity. All rabbits received an intracerebroventricular (ICV) catheter into the lateral ventricle and a recording electrode on the left renal nerve. Experiments were conducted in conscious rabbits and animals received increasing doses of melanocortin receptor antagonist (SHU9119), α‐Melanocortin stimulating hormone (αMSH) and a single dose of Leptin antagonist via ICV. BP, HR and RSNA were measured. ICV SHU9119 reduced BP (‐5.8±0.7mmHg and ‐4.1±0.9mmHg) and RSNA (‐2.4±0.3 nu and ‐0.7±0.3 nu) in mHFD and mNFD10dHFD rabbits (P<0.001). Leptin antagonist reduced BP and RSNA only in mHFD rabbits (‐2.1±0.5mmHg and ‐2.7nu, respectively). αMSH injection increased BP, HR and RSNA in both mHFD and mNFD10dHFD rabbits (P<0.05). Total % fat was increased (50%) in all rabbits that had HFD. Obesity during pregnancy ‘programs' leptin signalling pathway in the CNS of the offspring during development. Leptin via activation of melanocirtin pathway plays a key role in the CNS contributing to the pressor and tachycardic effects as well as renal sympathetic nerve activity in the pathophysiology of obesity.
Relation Between Diaphragm EMG and Ventilation in Rats Acclimatized to Hypobaric Sustained Hypoxia
Authors: Moya Esteban , Berruecos Steve , Fu Zengxing , Powell Frank 
Published: June 2021

Exposure to chronic sustained hypoxia in healthy subjects, for example during acclimatization to high altitude, increases ventilation in normoxia and increases the ventilatory response to acute hypoxia or hypercapnia. Laboratory rodents have proved to be a useful model for studying the mechanisms of such ventilatory acclimatization to hypoxia. However, it is not known if all respiratory muscles contribute similarly to increases in ventilatory drive and chemoreflexes with acclimatization. Here we tested the hypothesis that the diaphragm contributes to increases in ventilatory responses to hypoxia and hypercapnia equally before and after acclimatization. Therefore, we measured diaphragm electromyogram activity and related the amplitude of the rectified and integrated signal (EMGdia) to tidal volume (Vt) in rats exposed to one week of sustained hypoxia. We made an abdominal incision in male Sprague‐Dawley rats and implanted a two‐electrode transmitter to telemeter EMG activity from the diaphragm muscle. After recovery, we simultaneously measured ventilation with barometric pressure plethysmography and EMGdia with telemetry in awake, unrestrained rats before and after 7 days of exposure to hypobaric hypoxia (PO2 = 80 Torr). EMGdia positively correlated with Vt when breathing was stimulated by hypoxia, hypercapnia or both, and this relationship was not changed after chronic hypoxia. This shows that ventilatory acclimatization to hypoxia does not change the contribution of the diaphragm to ventilatory drive and chemoreflexes. Supported by NIH RO1 HL‐081823.
Phrenic Long‐term Facilitation (pLTF) Following Acute Intermittent Hypoxia is NADPH Oxidase Independent in a Rat Model (SOD1G93A) of ALS
Authors: Nichols Nicole , Mitchell Gordon 
Published: June 2021

Acute intermittent hypoxia (AIH; 3, 5‐min episodes, 11% O2) elicits a form of respiratory plasticity known as pLTF. In normal rats, pLTF requires NADPH oxidase activity and superoxide formation. Since enhanced pLTF is observed in SOD1G93A rats at disease end‐stage (Nichols et al., 2011) despite increased superoxide dismutase‐1 expression and decreased superoxide accumulation in phrenic motor neurons (Satriotomo et al., 2008), we tested the hypothesis that AIH‐induced pLTF is NADPH oxidase independent in anesthetized,paralyzed and ventilated end‐stage SOD1G93A rats (versus age‐matched, wild‐type littermates). Following intrathecal injections of vehicle (control) or an NADPH oxidase inhibitor (apocynin; 600μM; 12μL), pLTF was abolished in wild‐type (7±3%, n = 4; controls: 40±4%, n=5; p<0.05), but not end‐stage SOD1G93A rats (78±15%, n = 4; controls: 92±18%, n=4; p>0.05). Since pLTF is no longer dependent on NADPH oxidase activity in end‐stage SOD1G93A rats, we suggest that key molecular targets of reactive oxygen species that normally constrain pLTF (e.g. protein phosphatases) are down‐regulated with disease progression in ALS.[Supported by NIH K99 HL119606, R01 HL080209 and R01 HL069064]
Acute caspase inhibition attenuates progressive vascular remodeling in established Pulmonary Arterial Hypertension
Authors: Happé C M , Szulcek R. , Rol N. , Schalij I. , Westerhof N. , Vonk‐Noordegraaf A , De Man F.S. , van Nieuwe Amerongen G.P. , Bogaard H.J. 
Published: June 2021

In pulmonary arterial hypertension (PAH) a phenotypic switch of the endothelium results in exuberant cell growth and vascular remodeling. Recent animal models of PAH show a high cell turnover with coexisting high rates of apoptosis and proliferation. In vitro experiments suggest that high shear stress induces a loss of PAH patient derived microvascular endothelial cells (MVEC). We tested whether an impaired response to increased shear stress and ongoing apoptosis are involved in vascular remodeling in PAH. Rats with progressive PH were treated for 2 weeks with the pan‐caspase inhibitor Z‐Asp. PAH patient derived MVECs were treated with Z‐Asp and subjected to increased levels of fluid shear stress to simulate the hemodynamics of the PAH lung. Analysis revealed a significant decrease in cleaved caspase 3 positive cells in lung endothelial cells (0.6±0.1 vs. 0.2±0.1, p=0.02) and smooth muscle cells (2.2±0.2 vs. 1.2±0.5, p=0.02). A reduction in pulmonary vascular resistance (0.9±0.2 vs. 0.5±0.1, p=0.01) with Z‐asp was associated with a decrease in intima thickness (24±4 vs. 14±2, p=0.001). Detailed analysis showed a decrease in the proliferative marker PCNA in endothelial cells (1.5±.4 vs. 0.8±0.2, p=0.05). Mechanistically, Z‐Asp in MVECs improved shear adaptation and prevented shear‐induced cell loss by restoring protein surface levels of the mechanosensor CD31. In conclusion, we showed that caspase inhibition in experimental PAH attenuates vascular remodeling by restoration of endothelial shear adaptation and apoptosis reduction. Our data suggests that new PAH treatment concepts should consider apoptosis prevention instead of induction.
The Chaperone Protein Hsp90 is Upregulated in Human Pulmonary Hypertension
Authors: Ruffenach Gregoire , Le Guen Marie , Chabot Sophie , Breuils‐Bonnet Sandra , Tremblay Eve , Provencher Steeve , Bonnet Sebastien 
Published: June 2021

INTRODUCTIONHuman and animal pulmonary arterial hypertension (PAH) is characterized by a selective activation of several transcription factors including STAT3, NFAT and HIF‐1α, which regulates pulmonary artery smooth muscle cells (PASMC) proliferation and apoptosis. The activation mechanisms of these factors in PAH remain elusive. Hsp90 is a major molecular chaperone that is plays a pivotal role in assisting correct folding and functionality of its client proteins. The Hsp90 client proteins include a wide variety of transcription factors like NFAT, STAT3 and HIF‐1α. Recent evidences have shown that miR‐223 may regulates HsP90 expression in cancer, which share many similarities with PAH. We thus hypothesized that the miR‐223/Hsp90 axis is aberrantly expressed in PAH patients, contributing to PAH‐PASMC phenotype.METHODS and RESULTSUsing immunoblot, we showed that Hsp90 is upregulated in lungs, and PASMC of PAH patients compared to non‐PAH donors. This upregulation in Hsp90 is associated with a significant downregulation of miR223 in PAH; upregulation of HIF‐1α, NFAT and STAT3 activation measured by immunoblot and nuclear translocation assay. In primary cultured PASMC from 3 PAH and 3 control patients, we demonstrated that miR‐223 upregulation using mimic or Hsp90 molecular inhibition using siRNAs significantly reduces PAH‐PASMC proliferation and resistance to apoptosis. Finally, using monocrotaline‐induced PAH, we showed that miR223 nebulization decreases total pulmonary resistance by decreasing distal PA wall thickness.CONCLUSIONThe miR223/Hsp90 may represent a new signal hub in PAH, accounting for the activation of several transcription factors contributing to PAH‐PASMC phenotype and thus vascular remolding seen in PAH.