bluuebunny/crossref_metadata_2025_split huggingface dataset:
Endothelin-1 Enhances Activities of Cav1.2 in Arterial Vascular Smooth Muscle Cells of Peripheral Artery Disease with Hindlimb Ischemia-Reperfusion
Authors: Zhang Xuexin , Qin Lu , Li Jianhua 
Published: May 2023

Background and Objective: The ischemia-reperfusion (IR) injury is a main feature of pathophysiological process in peripheral artery disease (PAD). In PAD, an exaggerated blood pressure response increases cardiovascular and cerebrovascular risks for the disease. Considering that L-type voltage-gated calcium channel (Cav1.2) in arterial vascular smooth muscle cells (VSMCs) plays a crucial role in regulating blood pressure, the purpose of this study was to determine the activities of Cav1.2 following hindlimb IR as well as a contribution of endothelin-1 (ET-1), a potent vasoconstrictor, to the activities of Cav1.2. Hypothesis: We hypothesized that IR injury of PAD upregulates ET-1 signaling pathways in limb muscle and thereby amplifies the activities of Cav1.2 in VSMCs. Methods: An experimental PAD model with IR was induced by 6 hours of ischemia followed by 18 hours of reperfusion in rats (IR18h rats). ELISA and western blot analysis were used to examine the levels of ET-1 in the hindlimb muscle, and protein expression of Cav1.2 and ET-1 receptor ETA in VSM. Patch clamp was used to determine the Cav1.2 currents. Data are presented as mean ± standard deviation. Results: The hindlimb IR increased the levels of ET-1 in the hindlimb muscle, and expression of Cav1.2 and ET-1’s ETA in VSMCs. In particular, compared with the control group, there was a promising trend for the increasing Cav1.2 in VSM of the IR18h group (1.00±0.61 in control/n=4 vs. 8.77±8.04 in IR18h/n=5, P=0.09). Meanwhile, ETA expression was significantly higher in IR18h group than control group (1.00±1.12 in control/n=4 vs. 3.71±1.59 in IR18h/n=5, P<0.05). The hindlimb IR also increased amplitude of Cav1.2. In addition, ET-1 (1 μM) enhanced Cav1.2 current density in VSMCs of control rats from 0.47± 0.14 pA/pF to 0.68 ± 0.14 pA/pF (n=3; P<0.05) and from 0.54 ± 0.17 pA/pF to 0.74 ± 0.15 pA/pF (n=5; P<0.05) in the VSMCs of IR18h rats, respectively. Pretreatment of the VSMCs with an ETA antagonist, BQ-123 (1 μM), prevented the increasing effects of ET-1 on Cav1.2 current. In contrast, an ETB antagonist, BQ-788 (1 μM), had no distinct effects on the ET-1 increased-Cav1.2 current. Conclusions: ET-1 increases the activities of Cav1.2 in VSMCs via ETA receptor and upregulation of ET-1 signaling pathways in VSMCs of PAD is likely to lead to amplified blood pressure response via increasing the activities of Cav1.2. NIH R01 HL141198 & HL164571; and American Heart Association grant # 940567 This is the full abstract presented at the American Physiology Summit 2023 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.
Activation of the optogenetic pumps halorhodopsin and archaerhodopsin result in an unexpected potassium ion redistribution
Authors: Parrish R. Ryley , MacKenzie-Gray-Scott Connie , Jackson-Taylor Tom , Voipio Juha , Trevelyan Andrew 
Published: May 2023

The optogenetic pumps halorhodopsin and archaerhodopsin are now common tools for directed silencing of specific neuronal cell classes. Halorhodopsin achieves neuronal silencing by pumping chloride ions into cells while archaerhodpsin silences cells by pumping out protons. Though these pumps are often targeted to specific cells within the neuronal network, the differential movement of ions across neuronal membranes can exert significant effects on neighboring cells. Furthermore, these ionic movements often result in secondary ion movements as the cells attempt to maintain electroneutrality. We, therefore, sought to determine to what extent these optogenetic pumps might result in secondary, unexpected movements of other ions. We hypothesized that there would be potassium redistribution occurring with both optogenetic pumps and secondary effects on cells not expressing the opsins. We explored this hypothesis through activation of these pumps, while recording with ion-selective microelectrodes and with current clamp recordings on cells not expressing the opsins. We found that both the chloride pump and the proton pump led to secondary redistribution of K+ ions into the cell, through tonically open, “leak” K+ channels. After the end of the activation with halorhodopsin, there was a large rise in extracellular K+, mediated by both the removal of K+ that had been driven into the cells, as well as by the cell’s extrusion of Cl- ions by the potassium chloride cotransporter, which uses the K+ gradient to remove Cl- ions from the cells. This secondary rise in extracellular K+ was much less with archaerhodpsin, presumably due to its activation not involving chloride loading of the neurons. We further found that during halorhodopsin activation, neighboring cells not expressing the opsin had greatly reduced excitability during illumination, likely due to the observed decrease in extracellular K+. Surprisingly, halorhodopsin also triggered cortical spreading depolarizations during and following illumination, when extracellular K+ was below physiological levels, an observation not replicated with archaerhodpsin activation. These results demonstrate that there are unexpected and significant effects on the neuronal network with use of optogenetic pumps. Despite the confounding issues inherent with using these tools, our results demonstrate new and exciting ways to address physiological questions with optogenetic tools. Medical Research Council (UK) This is the full abstract presented at the American Physiology Summit 2023 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.
Hypoxemia in individuals with mild-to-moderate obesity at simulated altitude: implications for an exaggerated ventilatory response
Authors: Balmain Bryce , Ri-Li Ge , Levine Benjamin , Babb Tony 
Published: May 2023

Introduction: Individuals with obesity are more hypoxemic (lower PaO2) relative to those without obesity. Rapid ascent to high altitude also causes hypoxemia. However, the magnitude of hypoxemia in individuals with obesity at high altitude is unknown but could be more severe compared with those without obesity due to the additive effects of obesity- and altitude-related causes of hypoxemia. To test this hypothesis, we compared PaO2 in individuals with vs. without obesity at a simulated altitude of 12,000ft. Methods: 19 younger otherwise healthy individuals were studied for 24 hours in a hypobaric environmental chamber: 10 without obesity (age: 35±7yr; BMI: 25.0±3.8 kg/m2) and 9 with mild-to-moderate obesity (age: 35±6yr; BMI: 37.3±4.2kg/m2). PaO2 (arterial puncture), ventilation (V̇E, pneumotachograph), and self-reported symptoms of acute mountain sickness (AMS, Lake Louise score) were measured at sea level (Pb: ~760mmHg) and at a simulated altitude of 12,000ft (Pb: ~483mmHg). Results: PaO2 was lower (p<0.001) in those with (84.5±8.0mmHg) vs. without obesity (96.1±6.8 mmHg) at sea level; however, PaO2 was not significantly different between groups at 12,000ft (with obesity: 47.8±6.0mmHg; without obesity: 51.2±5.6mmHg, p=0.265). While V̇E was similar between groups at sea level (with obesity: 14.8±5.0L/min; without obesity: 11.3±3.3L/min, p=0.114), V̇E was higher (p=0.029) in those with (58.3±8.4L/min) vs. without (47.2±9.0L/min) obesity at 12,000ft, which may reflect a greater hypoxic ventilatory response in those with obesity relative to those without obesity. Lastly, seven individuals with obesity and four individuals without obesity had AMS scores of ≥4 at 12,000ft. Conclusion: We demonstrated that the magnitude of hypoxemia at high altitude was similar between those with and without obesity, but this was at the expense of an exaggerated ventilatory response in those with obesity. While perhaps an appropriate compensatory ventilatory response to a hypoxic stimulus, this finding could have implications for younger healthy individuals with mild-to-moderate obesity traveling to higher elevations where they could be more likely to develop severe dyspnea and/or AMS. Further investigation of the degree of hypoxemia at high altitude is required in older individuals with a greater magnitude of obesity. This is the full abstract presented at the American Physiology Summit 2023 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.
What is the role of ATP in the hypertensive carotid body?
Authors: Felippe Igor , Pen Dylan , Bose Aabharika , Moraes Davi , Ponnampalam Anna , Paton Julian 
Published: May 2023

ATP acting on P2X2/3 receptors within carotid bodies (CBs) underpins chemoreflex hyperreflexia and hypertonicity of sympathetic activity in Spontaneously Hypertensive rats (SHR). As the exact mechanisms remain elusive, we hypothesized either a greater release and/or decreased breakdown of ATP in CBs of SHR versus Wistar rats, and that high concentrations of exogenous ATP in the CB of normotensive rats would produce the sensitised motor responses portrayed by SHRs. Three experiments were performed to investigate the generation, breakdown and physiological responses of ATP in the CB: First, we sought to quantify the amount of ATP released from CBs of male Wistar and SHRs (N=10 for each strain; 4-5 weeks old) using an in vitro colorimetric technique; second, in both strains (Wistar, N=10; SHR, N=12), we used digital droplet polymerase chain reaction (ddPCR) for quantitative analysis of gene expression of six enzymes, which are all involved with the extracellular metabolism of ATP (Enpp1-3, Entpd 2-3, and Nt5e); we also quantified the levels of gene expression for tyrosine hydroxylase (TH) and Panx-1 channel, which are markers for CB type I (or glomus cells) and type-II cells, respectively. Third, we used the working heart-brainstem preparation (WHBP) for analysis of the CB chemoreflex responses evoked by ATP stimulation in Wistar rats (N= 25, 60-80g). Stimulation of CBs was carried out with local intra-arterial injection of potassium cyanide (KCN 20-100 μL, 0.04%; i.a.), and direct intra-CB injection of ATP (10-100 μL, 50 μM - 5 mM) or α, β-methylene ATP (10 μM, 450 μM, and 5mM).Although no rat strain differences in Enpp1 and Entpd2-3 were detected, Enpp2-3 and Nt5e expression were increased in SHR (p<0.05) versus Wistar rats suggesting greater breakdown of ATP in SHR CBs. However, ATP released from the CB at baseline and with KCN stimulation was two-fold greater in SHR (P<0.05). KCN stimulation of the CB, evoked hyperpnoea, bradycardia and sympathoexcitation in Wistar rats, whereas ATP produced hypopnoea/apnoea, repetitive burst discharge of post-inspiratory activity and elevations in both abdominal motor activity and SNA. We found that the ATP-induced hyponoea/apnoea was prevented by ipsilateral nodosectomy suggesting activation of non-CB afferent/s. Microinjecting either ATP or α, β-methylene ATP directly into the CB produced hyperpnoea and sympathoexcitation. Despite upregulation of some ATP degrading enzymes in the SHR, CB release of ATP is higher in this strain and produces activation of respiratory and sympathetic systems. Health Research Council of New Zealand This is the full abstract presented at the American Physiology Summit 2023 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.
Effect of Dohongsamul-tang on Cardiac Function in Chronic Myocardial Infarction Rats
Authors: Jang Youn Jae , Hong Mi Hyeon , Yang Sun Ryo , Lee Ho Sub , Kang Dae Gill 
Published: May 2023

Myocardial infarction (MI) is a frequent and severe manifestation of ischemic heart disease. We investigated the changes of protein in chronic MI which was occurred with long-term ischemia, without reperfusion. Guaruhaebaekbaekju-tang(瓜蔞薤白白酒湯, GHT) is an established traditional Chinese medicine that is widely used for the treatment of cardiac function, although its mechanisms remain unclear. GHT (100 or 200 mg/kg/day) was administered to rats immediately after coronary artery ligation for 8 weeks. After being sacrificed, the effect of GHT on cardiac fibrosis was confirmed by cardiac function and histological studies. As a result, the biomarker for detecting MI, lactate dehydrogenase (LDH), creatine kinase myocardial band (CK-MB) and Creatine Phosphokinase (CPK) enzymes, were significantly decreased by GHT. Heart function was evaluated by cardiac ultrasound to determine the effect of GHT on left ventricular dysfunction. MI group have decreased EF (Ejection fraction) as well as FS (Fractional shortening), compared to HT group. Additionally, left-ventricular (LV) dysfunction and dilatation were attenuated in the GHT group compared with MI group. In addition, protein expression levels the effect of GRT on cardiac fibrosis was confirmed by reducing the expression of transforming growth factor β (TGF-β) and collagen 1. This is thought to appear through inhibition of the TGF-β/p-Smad 2 pathway. Additionally, GHT reduced the Masson's trichrome and picrosirius red staining intensity in left ventricle of the MI group. Therefore, these findings suggest tha GHT has protective effects via inhibition of TGF-β/p-Smad 2 pathway, which is associated with improvement of myocardial fibrosis in rats with MI. These results suggest that GHT has a protective effect on heart failure by alleviating cardiac hypertrophy, myocardial fibrosis, cardiac dysfunction caused in MI model. This study was supported by a National Research Foundation of Korea (NRF) Grant funded by the Korean government (MSIP) (2017R1A5A2015805) (2021R1A2C1010859). This is the full abstract presented at the American Physiology Summit 2023 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.
Investigating respiratory simplification caused by prenatal RAGE upregulation
Authors: Clarke Derek , Curtis Katrina , Wendt Ryan , Stapley Brendan , Clark Evan , Campbell Kennedy , Black Joe , Hill Nate , Arroyo Juan , Reynolds Paul 
Published: May 2023

Receptors for advanced glycation end-products (RAGE) are multi-ligand cell surface receptors of the immunoglobulin superfamily predominantly expressed by lung epithelium. Previous experiments showed that RAGE upregulation throughout pregnancy caused significant fetal lung hypoplasia via elevated apoptosis and misregulation of the transcription factors thyroid transcription factor 1 (TTF1) and forkhead box protein A2 (Fox-A2). Our current research focused on characterizing the contributors to these abnormalities. We confirmed poor development of murine lungs through a time course of RAGE upregulation from conception to sacrifice on embryonic day (E)15.5, E16.5, E17.5, E18.5, and specific upregulation from E15.5 to E18.5 only. H&E staining confirmed significant simplification. We hypothesized that this malformation was in part due to aberrant levels of inflammation and apoptosis. Blotting revealed significantly increased levels of phosphorylated AKT and ERK1/2 in RAGE TG pups which cause NF-κB mediated transcription of inflammatory genes. Due to potential roles for these signaling intermediates, we sought to assess RAGE-mediated impact on mitochondrial efficiency. Oxidative phosphorylation was assessed in lungs from RAGE TG pups and controls by measuring oxygen consumption per unit mass when lungs were exposed to the substrates malate, glutamate, ADP, succinate, and FCCP which activate sequential components of the electron transport chain. We discovered significantly increased levels of oxidative phosphorylation in transgenic pups compared to controls. Levels of ATP and reactive oxidative species (ROS) in relation to altered oxidative phosphorylation and inflammation provided additional mechanistic clarity. These results support the importance of proper RAGE regulation in the development of lung tissue and elucidate mechanisms possibly causing such damage. This work was supported by funding from the National Institutes of Health (NIH 1R15-HL152257, PRR and JAA). This is the full abstract presented at the American Physiology Summit 2023 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.
Reciprocal Regulation of Na/K-ATPase and Sodium Glucose Co-Transporter 2
Authors: Gao Yingnyu , Correa Pessoa Marco Tulio , Liu Jiang , Pierre Sandrine , Tian Jiang 
Published: May 2023

Sodium Glucose Co-Transporter 2 (SGLT2) is the major driving force for glucose reabsorption and inhibition of SGLT2 improves renal and cardiac function in patients with chronic kidney disease (CKD). Since SGLT2 uses the sodium gradient established by Na/K-ATPase (NKA) for glucose reabsorption, we hypothesize that there is link between SGLT2 and NKA in regulation of renal and cardiac functions. To demonstrate this hypothesis, we measured the SGLT2 expression level in LLC-PK1 cells (a porcine proximal tubule cell line), PY-17 cells (a cell line derived from LLC-PK1 cells with NKA α1 knockdown), and AAC-19 cells (a cell line that re-introduce a rat NKA α1 into the PY17 cells). The RT-PCR result showed that reduction of NKA in PY17 causes significant increase in SGLT2 expression (about 1.7-fold change compared to that in LLC-PK1 cells), while reintroduction of NAK in AAC-19 cells brought down the SGLT2 expression level that comparable to LLC-PK1 cells. Reciprocally, we found that inhibition of SGLT2 blocked NKA related signaling pathway. Specifically, treatment of LLC-PK1 cells with ouabain at 10 or 100 nM induced Src activation while pretreatment of the cells by 1 μM EMP (a specific SGLT2 inhibitor) for 24h blocked ouabain-induced Src activation. Our previous work has demonstrated that the plasmalemmal NKA/Src complex serves a scaffolding and signaling function beyond its well-known ion pumping role and blocking NKA/Src signaling attenuates cardiac hypertrophy and improves heart function in animal model of CKD. Based on these findings, we demonstrated a functional link between SGLT2 and NKA and postulate that the renal and cardiovascular benefit of SGLT2 inhibition may reside within their capacity for regulation of NKA signaling, which need to be further validated in animal models. Marshall Start up Funding to Jiang Tian, NIH R15HL164682-01 to Jiang Liu and Jiang Tian, NIH R01 DK129937 to Sandrine Pierre and Jiang Liu. This is the full abstract presented at the American Physiology Summit 2023 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.
Mitochondrial Rieske iron-sulfur protein is a crucial molecule in COPD-associated pulmonary hypertension
Authors: Truong Lillian , Zheng Yun-Min , Wang Yong-Xiao 
Published: May 2023

Pulmonary hypertension (PH) often occurs in chronic obstructive pulmonary disease (COPD) and is the major cause of death in COPD patients. Molecular mechanisms for PH in COPD remain poorly understood, and clinical treatments are neither specific nor effective. Cigarette and e-cigarette smoking (CS) account for up to 90% of COPD cases, in which nicotine is the major active component and causes COPD-like cellular responses; moreover, hypoxia is a known key factor in the development of PH. In this study, we aim to develop a PH in COPD animal model and determine the underlying molecular mechanisms. Our findings revealed that co-exposure of nicotine (or CS) and hypoxia synergistically elevated PH (i.e., right ventricular pressure and weight) compared to nicotine, CS, or hypoxia alone. We also found that mitochondrial reactive oxygen species ([ROS]m), assessed using mitochondrial-specific ROS indicator MitoSOX, was significantly increased in pulmonary artery smooth muscle cells (PASMCs) from CS patients with COPD compared to normal PASMCs from non-CS patients. The increased [ROS]m was blocked by lentiviral short hairpin RNA (shRNA)-mediated knockdown of Rieske iron-sulfur protein (RISP) in mitochondrial complex III. More importantly, SMC-specific RISP gene knockout blocked nicotine/hypoxia exposure-induced PA remodeling and hypertension, whereas SMC-specific RISP overexpression exacerbated PH in mice. We further discovered that RISP regulated DNA damage following nicotine/hypoxia co-exposure via ataxia telangiectasia-mutated (ATM) signaling. RISP also mediated nuclear factor (NF)-κB inflammatory signaling. Together, our studies for the first time demonstrate that nicotine/hypoxia co-exposure leads to RISP-dependent [ROS]m, ATM-mediated DNA damage-dependent NF-κB-associated inflammation, PA vasoremodeling and PH in COPD in a sex-dependent manner. Moreover, RISP, ATM, and NF-κB may serve as novel and effective molecular targets in treating COPD and its associated PH. NIH R01 HL122865, NIH R03AG070784, and NIH R01 HL108232 This is the full abstract presented at the American Physiology Summit 2023 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.
Aerobic exercise training improves left ventricular chamber compliance in Göttingen minipigs
Authors: Duncker Dirk , Heinonen Ilkka , van Drie Ruben , Zandbergen Lotte , van der Velden Jolanda , Merkus Daphne , Sorop Oana 
Published: May 2023

Introduction: Exercise training is known to improve left ventricular (LV) function, but the mechanisms remain incompletely understood. Here we investigated the structural and functional adaptations in the LV in response to 2-months of aerobic exercise training in Göttingen minipigs. Methods: Adult male Göttingen minipigs were randomized to an aerobic exercise training regimen of running on a treadmill 3 times per week (N=8, EX) or sedentary housing (N=8, untrained, UT). Structural, functional and molecular measurements were performed in the LV of pigs from both groups at the end of the 2-months period. Results: EX did not affect body weight (35±1 kg vs 37±2 kg EX vs UT) but improved endurance running capacity (75±6 min vs 38±4 min until exhaustion in EX vs UT, P<0.05 by t-test) at the end of the 2-month period, which was associated with enhanced endothelium-dependent vasodilation to bradykinin of small arteries isolated from skeletal small arteries (AUC: 438±46 in EX vs 292±37 in UT, P <0.05 by t-test). EX had no significant effect on LV systolic function (data not shown), but resulted in an increase in LV end-diastolic compliance as the slope of the end-diastolic pressure-volume relationship was lower in EX vs UT ( P<0.05 by 2-way ANOVA). This increase in LV chamber compliance was not due to changes in LV structure as the LV weight to body weight ratio (3.10±0.17 vs 3.15±0.10 g/kg), cardiomyocyte cross-sectional area (100±10 vs 104±8 mm2) and collagen content (7.6±0.3 vs 6.6±0.4% myocardium area) were not significantly different between UT and EX. In contrast, single LV cardiomyocyte stiffness was reduced in EX compared to UT ( P<0.05 by 2-way ANOVA), likely caused by a shift in titin isoform towards the more compliant N2BA isoform (N2BA/N2B ratio: 1.22±0.03 vs 0.95±0.05; P<0.05 by t-test). Conclusion: Two months of aerobic exercise training 3 times per week increased LV diastolic chamber compliance, which was mediated, at least in part, through a titin isoform shift and a decreased myocyte stiffness, in the absence of LV structural changes. Dutch CardioVascular Alliance: An initiative with support of the Dutch Heart Foundation (Grants 2017B018 ARENA-PRIME and 2020B008 RECONNEXT) This is the full abstract presented at the American Physiology Summit 2023 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.