bluuebunny/crossref_metadata_2025_split huggingface dataset:
In Utero PM2.5 Exposure Contributes to Adult Cardiac Dysfunction
Authors: Tanwar Vineeta , Gorr Matthew , Eichenseer Clayton , Wold Loren 
Published: June 2021

The present study was designed to investigate the effects of in utero exposure to PM2.5 on the adult cardiac functions. Female FVB mice were exposed either to filtered air (FA) or particulate matter (PM2.5) at concentration of 51.69 μg/m3 for 6 h/day, 7 days/wk throughout pregnancy. To examine cardiac function, male offsprings at 12 weeks of age underwent a baseline echocardiographic assessment. Following sacrifice, cardiomyocytes were isolated to assess cardiac dysfunction at cellular level using IonOptix. LV tissue from separate group of mice was used to isolate mRNA and protein to study underlying mechanisms. Mice exposed to PM2.5 in utero demonstrated increased LVESd and LVEDd dimensions and reduced PWTs. Morphological alterations were associated with lower systolic function as indicated by reduced FS in PM2.5 exposed mice compared to FA controls. Cardiomyocytes isolated from PM2.5 exposed hearts showed reduced %PS compared to FA exposed hearts. ‐dL/dt was significantly reduced whereas +dL/dt, TR90 and TPS90 remain unchanged between the groups. qPCR analyses revealed decreased TNF‐α, increased IL‐1ß, collagen I and MMP9 expression in one‐day‐old mice exposed to PM2.5 in utero compared to FA. Western blot analyses demonstrated modified NCX, SERCA and PLN expression in PM2.5 compared to FA exposed hearts. Mass spectrometry revealed differential expression of proteins involved in maintaining cardiac physiological functions in PM2.5 compared to FA exposed hearts.ConclusionsIn utero PM2.5 exposure triggers an inflammatory and profibrotic response and alters Ca2+ homeostasis (through NCX, SERCA and PLN hypophosphorylation) thereby promoting adult cardiac dysfunction.
Western Diet Increases Penile in vivo Reactive Oxygen Species: Investigation of Antioxidant Defense
Authors: La Favor Justin , Luke Nathan , Hannan Johanna , Burnett Arthur 
Published: June 2021

Excessive production of reactive oxygen species (ROS) has consistently been described as a cause of erectile dysfunction (ED), though assessments are often made by indirect byproducts in excised tissue. Under conditions of elevated ROS, many tissues will upregulate the antioxidant defense system as a protective mechanism, though this mechanism is understudied in the penis. The objective of this study was to utilize a novel technique to measure in vivo ROS in the penis of rats, and to investigate the expression of antioxidant and anti‐inflammatory genes following 12 weeks of a control diet (CD) or WD. Following dietary intervention (n = 6 CD; n = 6 WD), a microdialysis probe was inserted into the penis of rats under anesthesia. To measure ROS, probes were perfused with saline containing Amplex Ultrared, horseradish peroxidase, and superoxide dismutase (SOD), and fluorescence measured at the outlet. Penile hydrogen peroxide (1.31 vs. 1.96; p = 0.014) and superoxide (1.86 vs. 2.39; p = 0.029) were elevated in response to the WD. The NADPH oxidase subunit p22phox was increased in WD penes (0.36 vs. 0.51; p = 0.038), while a trend of increased p67phox (0.45 vs. 0.63; p = 0.079) was observed in WD. Of the 11 antioxidant genes investigated, only SOD1 was upregulated in WD (0.98 vs. 1.17; p = 0.03), although expression of the anti‐inflammatory gene heme‐oxygenase 1 (HO‐1) was decreased in WD penes (1.74 vs. 0.96; p < 0.01). In conclusion, NADPH oxidase is a probable source of excessive ROS in WD induced ED, while a modest antioxidant defense response may contribute to redox imbalance in the penis. Downregulation of HO‐1 following WD may exacerbate ED through promotion of inflammation.Supported by a fellowship grant from the Sexual Medicine Society of North America.
Metabolic and Mitochondrial Gene Expression Changes in the Aging Heart
Authors: Barton Gregory , McKiernan Susan , Aiken Judd , Diffee Gary 
Published: June 2021

Substrate utilization favors fatty acid oxidation in normal healthy hearts. Aging is associated with attenuated mitochondrial biogenesis and fatty acid metabolism in the heart, but the mechanism of these changes remains unclear. Very little information is available on the effects of aging on expression of genes related to fatty acid and glucose metabolism, as well as genes related to mitochondrial function. Exercise has been shown to increase expression ofkey genes related to fatty acid metabolism and mitochondrial metabolism. We determined gene expression differencesin hearts of Young, Old, and Old + Exercise FBN rats, using Qiagen PCR arrays for Glucose, Fatty acid, and Mitochondrial metabolism. Old rats demonstrated decreases (p < 0.05) for key genes in fatty acid transport and β‐oxidation such as (CPT‐1c, CPT‐2, Hadha, Fabp3, Lpl, FATP). Old rats also showed significant decrements in genes involving mitochondrial biogenesis, electron transport, as well as AMPK signaling. There were no differences in the expression of genes involving glucose metabolism with age. Four months of exercise training was unable to attenuate the decline in the gene expression changes in aged hearts. Our data suggest substantial changes to fatty acid and mitochondrial metabolic gene expression with age as a mechanism for alterations in substrate utilization.Supported by NIH AG 030423
RAAS Activation Aggravates Ischemia Reperfusion Injury and Accelerates Progression to Chronic Kidney Disease
Authors: Greite Robert , Chen Rongjun , Baniassad Bita , Rong Song , Thorenz Anja , Meier Martin , Tewes Susanne , Hüper Katja , Güler Faikah 
Published: June 2021

Objective– Ischemia reperfusion injury (IRI) leads to acute kidney injury (AKI) after major surgery and contributes to progressiverenal fibrosis. Activation of the RAAS system and hypertension arecharacteristics of AKI. However, the most frequently used mouse strain (C57Bl6) in IRI research lack blood pressure elevation after IRI. WecomparedCD1 mice with C57Bl/6 mice in the model of IRI induced AKI and the effects of RAAS activation.Methods– IRI was induced by clamping of the renal pedicle for 35 min. Renal function, glomerular filtration rate (GFR) and renal blood flow (RBF) were measured by inulin/PAH‐clearance. Morphology was investigated and immunohistochemistry for myeloid cell infiltration and collagen expression was done. MAPkinase acitvation was analysed by WB. Systemic blood pressure was assessed by tail cuff measurement. Functional MRI to quantify renal perfusion impairment and tissue edema was done.Results– CD1 mice showed severe blood pressure elevation of 20 mmHg after IRI. Creatinine elevation was 4 fold and comparable between C57Bl6 and CD1 mice at d1 after IRI. CD1 mice were more sensitive to hypoxic injury and showed pronounced tissue swelling at d1 correlating with edema formation in the MRI. CD1 mice developed persistent impairment of RBF and rapid progression to CKD. C57Bl6 mice were able to regenerate, normalize RBF and had only minor renal scaring after 4 weeks.ConclusionCD‐1 mice are very sensitive to hypoxic renal injury and develop show severe blood pressure elevation which accelerates the progression to CKD. The CD1 mouse model offers the opportunity to study RAAS activation in the context of IRI.
Angioadaptive Allies: Relationship Between Human Primary Endothelial Cells And Human Skeletal Muscle Myofibroblasts
Authors: Ciccone Joseph , Alinejad Yasaman , Aiken Julian , Despatis Marc‐Antoine , Balg Frederic , Roudier Emilie , Grenier Guillaume , BIROT Olivier 
Published: June 2021

Angioadaptation is the ability of capillaries to adapt to physiological changes. This is influenced by interactions between endothelial cells (EC) and supporting cells such as myofibroblasts (MF).ObjectiveWe examined a possible pro‐angiogenic paracrine interaction between newly identified MF progenitors in human skeletal muscle and primary EC, and how this interaction may be altered under hyperglycemic conditions.MethodsHuman skeletal muscle MF progenitor cells (CD90+) were sorted by FACS and differentiated into MF using TGFb under normo‐(NG) or hyperglycemic (HG) conditions. The expression level of 55 angioadaptive proteins was measured by proteome array in the conditioned media (secretome). Human microvascular EC were treated with secretome. VEGF‐A and TSP‐1 mRNA levels were measured by qPCR in these cells. EC migration was evaluated in the Boyden Chamber assay.ResultsThe secretome from differentiated MF was enriched in pro‐angiogenic factors compared to CD90+ cells. VEGF‐A mRNA expression was increased in EC when treated with MF secretome and their migration was stimulated. In contrast, CD90+ cell differentiation under HG resulted in decreased pro‐angiogenic factor secretion in MF secretome and reduced EC migration.ConclusionMF exert some pro‐angiogenic stimulation on primary EC compared to progenitor cells. This pro‐angiogenic effect is attenuated when cell differentiation occurs under HG. Funding: CIHR/NSERC.
Activation of Retrotrapezoid Nucleus (RTN) Maintains Normal Breathing in Hyperoxia Despite the Loss of Carotid Body (CB) Input
Authors: Basting Tyler , Burke Peter , Stornetta Daniel , Stornetta Ruth , Guyenet Patrice 
Published: June 2021

Rationale and objectives: the CBs contribute greatly to resting ventilation in conscious mammals. For example, their excision produces large and long‐lasting breathing reductions. Yet sustained hyperoxia, which silences the CBs, produces minimal breathing reductions in conscious rats and mildly activates breathing in man. RTN is a major cluster of central respiratory chemoreceptors (CRCs). Here we tested whether, under hyperoxia, breathing might be maintained by a compensatory increase in RTN activity.Methods: RTN and nearby C1 neurons were bilaterally transduced with archaerhodopsin (PRSx8‐ArchT‐EYFP‐LVV). We first showed that RTN neurons were instantly silenced by green light in anesthetized rats. We then measured the effect of RTN inhibition (10s) on breathing (fR, VT) and BP in conscious rats exposed to normoxia (21% FiO2) or hyperoxia (65% FiO2). Arterial blood gases (PO2, PCO2), pHa and HCO3 were measured under both conditions.Results: hyperoxia produced a very mild respiratory acidosis. RTN inhibition elicited a much larger fR and VT reduction in rats exposed to hyperoxia than to normoxia. BP was unaffected under hypoxia or hyperoxia suggesting that the C1 neurons were minimally impacted by the light.Interpretation: in conscious rats hyperoxia activates RTN, which maintains ventilation at control level (normoxia) despite the presumed loss of CB activity. RTN activation by hyperoxia probably results from several mechanisms including mild respiratory acidosis, Haldane effect and CNS vasoconstriction, the latter causing reduced CO2 wash‐out and brain parenchymal acidification. Funding: HL074011 (PGG), 5T32HL007284‐38 (TMB).
Greater β‐Adrenergic Vasodilation in Healthy Men Versus Women: Cyclooxygenase Suppresses Nitric Oxide
Authors: Peltonen Garrett , Johansson Rebecca , Limberg Jacqueline , Harrell John , Ernst Brady , Kellawan Jeremy , Crain Meghan , Eldridge Marlowe , Sebranek Joshua , Walker Benjamin , Schrage William 
Published: June 2021

Data suggest women exhibit greater β‐adrenergic receptor (β‐AR) mediated regulation of blood pressure than men. We tested the hypothesis that peripheral β‐AR vasodilation is greater in women, due in part to nitric oxide synthase (NOS) and cyclooxygenase (COX) signaling. In 22 healthy adults (10 men, 12 women; 24±2 yrs) forearm blood flow (FBF) was measured by Doppler ultrasound during graded brachial artery infusion of the β‐AR agonist isoproterenol (ISO: 3, 6, and 12 ng 100 ml lean tissue‐1 min‐1). Three ISO trials were performed: 1) ISO (control), 2) ISO with NOS or COX inhibition [L‐NMMA (n=10) or ketorolac (n=12), respectively, in counterbalanced order] followed by, 3) ISO with combined NOS + COX inhibition (double blockade – DB, n=22). Forearm vascular conductance was calculated (FVC = FBF/MAP) and the rise in FVC with ISO infusion (DFVC; infusion – baseline) quantified β‐AR vasodilation. Contrary to our hypothesis, DFVC with ISO was greater in men than women (p=0.02). L‐NMMA decreased DFVC from control (p=0.02) but did not eliminate the sex difference (p=0.01). Ketorolac increased DFVC above control (p<0.01), and abolished the sex‐difference (p=0.39). DB decreased DFVC below control (p=0.03) such that DFVC was again greater in men than women (p=0.01). We conclude: 1) β‐AR vasodilation is greater in young men vs women, 2) COX signaling limits β‐AR vasodilation more in women, and 3) COX appears to suppress NOS in both sexes, but more in women. These data are the first to demonstrate COX‐mediated restraint of β‐AR vasodilation in humans, and highlight sex differences in β‐AR control.Support: NIH R01 HL105820
Effects of Long‐term Voluntary Exercise on the Respiratory Muscles in Young Type 2 Diabetic Rats
Authors: Ichinoseki‐Sekine Noriko , Tsuzuki Takamasa , Yoshihara Toshinori , Takamine Yuri , Kobayashi Hiroyuki , Naito Hisashi 
Published: June 2021

This study investigated the effects of long‐term voluntary exercise on the respiratory muscles in young type 2 diabetic rats. Twenty‐two Otsuka Long‐Evans Tokushima Fatty (OLETF) rats, a model of type 2 diabetes mellitus, and 18 non‐diabetic control Long‐Evans Tokushima Otsuka (LETO) rats were assigned randomly to sedentary or exercise groups subjected to 20 weeks of voluntary wheel running from 5 weeks of age. A strip of diaphragm was used to measure the contractile properties and the rest was frozen and stored for immunohistochemical analysis. The total running distance did not differ between groups. The voluntary exercise significantly reduced the fasting blood glucose and serum triglyceride in OLETF rats. The mean fiber cross‐sectional area (CSA) was significantly greater in OLETF rats at both 5 and 25 weeks of ages. Type IIb fibers comprised 4–8% in OLETF rats, while little or none was expressed in LETO rats. At 25 weeks of age, muscle force production in OLETF rats was significantly lower than in LETO rats at stimulation frequencies of 1 (OLETF: 6.86 ± 0.96, LETO: 8.16 ± 1.25 N/cm2) and 30 Hz (OLETF: 16.35 ± 0.69, LETO: 18.55 ± 1.56 N/cm2). There was a slight, but non‐significant, tendency for voluntary exercise to increase fiber CSA and force production. Our results indicated that voluntary exercise in the young can improve glucose tolerance and hyperlipidemia, but has little effect on respiratory muscle.This work was supported by grants from the MEXT‐Supported Program for the Strategic Research Foundation at Private Universities (S1101008).
Effect of Low Dose Dopamine on Ventilatory Stability in Healthy Adults
Authors: Veldhoven Lisa , Holbein Walter , Johnson Blair , Limberg Jacqueline , Joyner Michael 
Published: June 2021

BackgroundIn models of congestive heart failure, carotid body denervation decreases ventilatory oscillations, thereby increasing ventilatory stability. Low‐dose dopamine can acutely blunt carotid body chemosensitivity assessed by a reduction of the hypoxic ventilatory response (HVR), but whether it affects ventilatory stability was previously unknown. We hypothesized ventilatory oscillations [as assessed by coefficient of variation of tidal volume (%CV Vt) and breathing frequency (%CV Fb)] would be reduced when the carotid chemoreceptors were desensitized by low‐dose dopamine.MethodsHealthy adults (n=20, 6F/14M, 31±2 years) rested quietly for 5‐min and breath‐by‐breath ventilation was measured during normoxia under 2 IV infusion conditions: 1) saline, 2) an individualized dose of dopamine (1‐4 ug/kg/min) shown to result in a nadir HVR.ResultsDopamine infusion increased breathing frequency (13±1 to 14±1 breaths/min, p=0.03) with no change in mean tidal volume (740±65 to 700±68 mL, p=0.18). Infusion of dopamine in young healthy adults increased ventilatory oscillations (%CV Vt: saline = 21±2, dopamine = 30±4, p=0.01; %CV Fb: saline = 17±1, dopamine = 21±2, p=0.07). There was no relationship between the decrease in HVR and the increase in ventilatory oscillations (Vt: r=0.15, p=0.54; Fb: r=0.33, p=0.16).ConclusionContrary to our hypothesis, IV dopamine (at an individualized dose that attenuates HVR) significantly increases ventilatory oscillations in healthy subjects. These data suggest the effect of low‐dose dopamine on ventilatory oscillations in healthy adults is in contrast to that seen with carotid body denervation in disease.Funding: NIH DK090541
The Effects of Perinatal Androgen Deprivation on Locomotor Activity in Male Rats
Authors: Jeong KumHwa , Yn Alicia , Khan Talha , Fickes Dane , Vang Pakou , Yousaf Faeeq , Shah Binita , Taylor George , Gopalan Chaya 
Published: June 2021

Testosterone and its metabolites—estrogen and dihydrotestosterone— are involved in the brain sex differentiation during the perinatal period by binding to androgen receptors (AR) or estrogen receptors (ER). However, in the presence of flutamide (FLU), testosterone that is metabolized to estrogen will only bind to ER. Blockade of AR using FLU during the perinatal period could alter the levels of estrogen, which in turn, may modulate the sex differentiation of the brain. This study tested perinatal androgen deprivation on estrogen levels and, in turn, its effects on locomotor activity in male rats.Long‐Evans rats (N=37) were divided into two groups: Group 1 received FLU (20 mg/kg; SC) during perinatal period (prenatal day 4 ‐ postnatal day 4) & Group 2 served as control. On postnatal day 65, these groups were divided into 3 subgroups (injected 5 days/week x 7 weeks): A. finasteride (20 mg/kg, SC), an α‐reductase inhibitor, B. letrozole (2 mg/kg, SC), an aromatase inhibitor and C. vehicle.Open Field (OF) Paradigm: Each animal was tested every week in an OF apparatus where the rat was allowed to explore the OF for 6 minutes. The time spent in the center of the field was compared with the time spent in the periphery using Any‐Maze. In addition, serum estrogen levels were measured using ELISA.Animals receiving FLU not only had high serum estrogen levels but also showed increased locomotor activity by spending significantly more time in the center field. These results suggest that perinatal androgen deprivation results in high levels of estrogen that may contribute to their willingness to explore freely.
Angiotensin II–Dependent Increase in the b=Bone Marrow Sympathetic Drive Initiates the Inflammatory and Endothelial progenitor Cell Imbalance and Precedes Blood Pressure Increase
Authors: Ahmari Niousha , Santisteban Monica , Baekey David , Raizada Mohan , Zubcevic Jasenka 
Published: June 2021

IntroductionDysfunctional brain‐bone marrow (BM) communication is associated with overactive brain RAS, leading to elevated sympathetic drive (SNA) to the BM and increased blood pressure (BP). Here, we hypothesized that angiotensin II (Ang II)‐dependent increase in BM SNA directly initiates the endothelial progenitor (EPC) and inflammatory cell (IC) imbalance, independently of its effects on BP.MethodsSubpressor dose of Ang II (15 ng/kg/min ICV) was infused in Sprague‐Dawley rats for 3, 7 and 21 days. The in situ decerebrated artificially‐perfused preparation was used to determine femoral BM SNA (fSNA) in control and Ang II rats. Fluorescence‐activated cell sorting (FACS) investigated the levels of EPCs and ICs in blood and BM.ResultsElectrophysiology revealed a 20% increase in the fSNA peak firing as early as 7 days of Ang II infusion. This was associated with elevation in BM IC levels (CD4+:2fold; CD4+.CD25+:4fold; CD3+:2fold; CD3+.CD45+:4fold; CD68+:2fold) and EPCs (CD90+:1.5fold). Femoral BM sympathectomy significantly decreased levels of Ang II‐dependent ICs but not EPCs in the BM. No change was observed in circulating cells at any time point.ConclusionThese observations demonstrate that Ang II‐dependent increase in BM fSNA directly affects the BM EPC/IC balance, independent of the blood pressure effects. Thus, elevated BM fSNA may initiate early impaired BM activity, but additional prohypertensive signals may be needed for fully blown immune response and development of hypertension‐related pathophysiology. AHA 14SDG18300010.
P2X3 Receptor Antagonism Reduces Peripheral Chemoreceptor Reflex Hypersensitivity and Blood Pressure in the Spontaneously Hypertensive Rat
Authors: Pijacka Wioletta , Ford Anthony , Paton Julian 
Published: June 2021

Arterial hypertension is associated with increased peripheral chemoreceptor reflex sensitivity. We have shown that bilateral carotid body (CBR) resection in spontaneously hypertensive (SH) rats reduces arterial pressure (AP). Since ATP is a major participant in CB transduction signalling, and P2X3 receptors are associated with visceral afferent sensitisation, we hypothesized that P2X3 antagonism would reduce chemoreflex hypersensitivity and lower AP in SH rats.SH and Wistar rats were implanted with telemeters to record AP. Doses of a P2X3 receptor antagonist (AF‐219) were administered as an i.v. bolus: 0.5 (n=4), 1 (n=4), 2 (n=5), 4 (n=5) and 8 mg/kg (n=4), and changes in both basal AP and chemoreflex sensitivity assessed. The chemoreflex was stimulated with sodium cyanide (NaCN; 120 μg/kg i.v.).At all doses, AF‐219 diminished NaCN evoked AP responses (P=0.084) in SH rats. In SH rats, basal AP was reduced by AF‐219 (P<0.05): ‐8±3 mmHg, 0.5mg/kg; ‐16±1 mmHg, 1mg/kg: ‐18±3 mmHg, 2mg/kg; ‐13±1 mmHg, 4mg/kg; ‐13±2 mmHg, 8mg/kg. In normotensive Wistars, AF‐219 did not reduce AP vs. baseline (‐4±2 mmHg, 1 mg/kg; P>0.05). Injections of vehicle had no effect in either rat strain (n=4). In SH rats, CBR blunted the 1 mg/kg AF‐219 induced fall in AP vs. non‐CBR rats. However, the fall versus baseline in AP in SH‐CBR rats remained significant (‐8±1 mmHg,P<0.01).P2X3 receptor antagonism depresses chemoreflex hypersensitivity and lowers AP in SH rats to a level observed after selective CBR. P2X3 receptor antagonism may provide a novel way to attenuate CB tonicity in SH rats and as such become a novel target for controlling hypertension.Supported by: British Heart Foundation and the NIH
The Rev1‐Pol ζ Mutasome
Authors: Burgers Peter , Makarova Alena , Binz Sara 
Published: June 2021

Rev1 and DNA polymerase ζ (Pol ζ) play key roles in DNA translesion synthesis (TLS) and are largely responsible for both spontaneous and damage‐induced mutagenesis in eukaryotic cells. Pol ζ is a 4‐subunit complex (Rev7‐Rev3‐Pol31‐Pol32). The Pol31 and Pol32 subunits of Pol δ bind the Rev3 catalytic subunit of Pol ζ, and those subunits are required for PCNA‐dependent TLS by Pol ζ.The catalytic activity of Rev1 is largely dispensable for mutagenesis, however the interactions of Rev1 with mono‐ubiquitinated PCNA and with Pol ζ are essential. This suggests that Rev1 may act as a scaffold for TLS. We have identified a conserved regulatory motif (M1) in Rev1 that, when mutated results in a large stimulation of Pol ζ replication activity. Stimulation requires the interaction domains between Rev1 and Pol ζ, and is absolutely dependent on the presence of PCNA. However, the catalytic activity of Rev1 is not required. We hypothesize that the M1 motif participates in a negative regulation of Pol ζ‐mediated TLS that is relieved upon Rev1 modification during DNA damage response, which then leads to the initiation of mutagenesis.