bluuebunny/crossref_metadata_2025_split huggingface dataset:
Adenosine A1 Receptor Elicits Coronary In‐stent Stenosis in Metabolic Syndrome
Authors: Long Xin , Alloosh Mouhamad , Kitsongsermthon Jutarat , He Yuanzu , Park Kinam , Sturek Michael 
Published: June 2021

Adenosine is widely thought to elicit coronary vasodilation and attenuate smooth muscle proliferation, thereby providing cardioprotection. We cloned the porcine adenosine A1 receptor (A1R) subtype and found that it paradoxically stimulated proliferation of cultured coronary smooth muscle cells by extracellular signal‐regulated protein kinases 1 and 2 (ERK1/2) signaling pathways, thus suggesting A1R dysregulation could play a role in coronary in‐stent restenosis. We utilized the Ossabaw swine model of metabolic syndrome (MetS) to test the hypothesis that A1R up‐regulation and A1R‐ERK1/2 signaling play a role in the development of coronary in‐stent stenosis in MetS. Intracoronary stent deployment followed by different durations of recovery from stenting showed A1R upregulation occurred before maximal amount of in‐stent stenosis. Swine were fed standard chow (Lean) or excess calorie atherogenic diet for over 20 weeks, which elicited MetS characteristics. We observed reduced coronary in‐stent stenosis by TAXUS (paclitaxel‐eluting) stents in MetS. Selective A1R antagonism with DPCPX‐eluting stents decreased coronary ERK1/2 activation and decreased in‐stent stenosis comparable to TAXUS. Conclusion: A1R upregulation and A1R‐ERK1/2 activation contributes to coronary in‐stent stenosis in vivo in the setting of MetS. Support: NIH RR013223, HL062552, Purina TestDiet to MS; HL078715 to KP; AHA to XL.Grant Funding Source: NIH
Trefoil factor‐3 is down regulated while CYP24a1 is increased in the ageing rat kidney
Authors: Hultström Michael , Iversen Bjarne M. 
Published: June 2021

The large scale expressional changes in ageing kidneys are not well described. In the present experiment we compared the genome wide expression of mRNAs in both kidneys from five 90 week old rats against five 10 week old rats.The expression from left and right kidneys were compared to determine if the samples should be used as independent samples or as replicates. No significant differences in gene expression were found between left and right kidneys. They showed a homogeneity almost comparable to technical replicates.Pooling results from left and right kidneys produced 20 genes showing a larger than two‐fold change. The most down regulated gene was Trefoil factor‐3, which has been shown to be lower in ageing kidneys previously. The most upregulated gene was cytochrome P450‐24a1, known to hydroxylate Vitamin D3.In conclusion, the left and right kidney cortex show very similar expression patterns, making them very useful for paired experiments but not appropriate as independent samples. Vitamin D3 metabolism is likely changed in the ageing kidney as a result of increased CYP24a1 expression.
Evidence that prenatal steroid exposure produces oxidative stress in the kidney in male sheep
Authors: Bi Jianli , Contag Stephen , Chappel Mark , Rose James C 
Published: June 2021

Prenatal glucocorticoid administration reduces renal function in adult offspring. But little is known about the effect of prenatal steroid exposure on oxidative stress in kidney.The objective of this study was to assess responses of a marker for oxidative stress in the kidney to infusion of angiotensin (ANG) peptides in adult male sheep exposed to steroid prenatally.1–1.5 year old rams exposed to either Betamethasone (B) (n=6) or Vehicle (V) (n=6) at 80–81 days gestation were given intra renal ANG II or ANG 1–7 infusions(1 ng/kg/min) either alone or with an AT 1 R blocker (Candesartan; 0.3 mg/kg), AT 2 R blocker (PD 123319 10ng/kg/min) or Mas receptor blocker (D‐Alaangiotensin 1–7, D‐ALA, 10ng/kg/min) for 3 hours. Urinary 8‐isoprostane(8‐PGF) excretion was measured by EIA kit. ANOVA was used for data analysis.ANG II increased 8‐PGF excretion in B (from1.9±0.1 to 2.8±0.5ng/kg/h) but not in V sheep(p<0.05,F=6.1). Candesartan blocked the response to Ang II but PD didn't. ANG 1–7 infusion decreased the excretion of 8‐PGF in both groups (P<0.05,F=6.6). This response was blocked by D‐ALA.The results suggest that prenatal B exposure promotes an oxidative stress response in kidney. Blockade of the response by candesartan but not by PD suggests that the increased 8‐PGF excretion is mediated through AT1R activation. The decreased 8‐PGF excretion during ANG 1–7 infusion indicates ANG 1–7 might attenuate oxidative damage in B sheep. Supported by HD‐47584 and HD‐17644
Short and Long term Peroxide Removal Modulates Relaxing and Contracting Mechanisms Influencing the Response of Bovine Pulmonary Arteries to Hypoxia
Authors: Ahmad Mansoor , Kelly Melissa R. , Kandhi Sharath , Arudra Sri Krishna Chaitanya , Wolin Michael S. 
Published: June 2021

Endothelium removed bovine pulmonary arteries (BPA) contract in the presence of hypoxia due to removal of a basal relaxation mediated by superoxide derived peroxide. Previous studies from our lab have shown that short term removal of peroxide with 0.1mM ebselen (30 minutes before hypoxia) results in increased force development to KCl and an attenuation of hypoxic pulmonary vasoconstriction (HPV) accompanied with decreased 5μM lucigenin and horseradish peroxidase‐luminol detectable superoxide and peroxide levels respectively. Inhibition of the potential source of superoxide Nox‐4 with siRNA treatment results in inhibition of HPV without affecting force development to KCl. Prolonged exposure of BPA to ebselen (beginning 45 minutes before exposing rings to passive tension) resulted in effects similar to siRNA treatment where HPV was attenuated without affecting KCl contraction. Thus short term removal of peroxide results in rapid attenuation of a relaxing mechanism promoting increased KCl force development and attenuating HPV. Prolonged removal of peroxide results in HPV attenuation without affecting KCl force, suggesting that peroxide also maintains a force enhancing mechanism which is not rapidly reversed by hypoxia.Supported by NIH grants HL31069, HL43023 and HL66331.
The magnitude of the hypoxic ventilatory response and ventilatory long‐term facilitation are reduced during sleep when compared to wakefulness
Authors: Gerst D. G. , Syed Z. , Yokhana S. S. , Lin H. S. , Mateika J. H. 
Published: June 2021

PurposeTo determine the impact of arousal state on the magnitude of the hypoxic ventilatory response (HVR − Δ VE/Δ SaO2) and ventilatory long‐term facilitation (vLTF).Methods5 healthy male subjects were exposed to IH on two occasions. The IH protocol consisted of 12‐2 minute episodes of hypoxia (PETO2 – 50 mmHg) in the presence of PETCO2 levels sustained 3 mmHg above baseline. Each episode was followed by a 2 minute normoxic recovery period with the exception of the last recovery period which was 30 minutes in duration. One IH trial was completed during wakefulness, with the other completed during sleep.ResultsThe HVR was greater during wakefulness compared to sleep in all participants (0.8 ± 0.2 vs. 0.5 ± 0.1 L/min/% SaO2, p = 0.06). Moreover, minute ventilation was greater during recovery compared to baseline, during both wakefulness and sleep (Wakefulness – 22.5 ± 1.8 vs. 18.6 ± 1.5 L/min, p = 0.03; Sleep – 15.2 ± 1.8 vs. 14.3 ± 1.8 L/min, p = 0.02). However, the magnitude of vLTF when standardized to baseline was significantly greater during wakefulness compared to sleep (1.21 ± 0.07 vs. 1.07 ± 0.02, p = 0.05).ConclusionsExposure to IH elicits vLTF during both wakefulness and sleep. However, the magnitude of the HVR and vLTF is significantly reduced during sleep compared to wakefulness.Funding: VA‐Merit Award
Impact of acute and chronic intermittent hypoxia on apnea severity
Authors: Yokhana Sanar S , Gerst David G , Badr M. Safwan , Lee Dorothy S , Carney Laura M , Mateika Jason H. 
Published: June 2021

This study was designed to determine the impact of intermittent hypoxia (IH) on apnea severity. Thirteen participants with sleep apnea (OSA) completed the study. A baseline sleep study (SS) was completed on day 1. On day 2, participants were exposed to 12 episodes of hypoxia immediately before completing a SS. Thereafter, participants were exposed to IH on nine consecutive days. On day 11, participants were exposed to IH before completing a SS. Five OSA participants completed an identical protocol while exposed to episodes of room air. The hypoxic ventilatory response (HVR − Δ VE/Δ SaO2) and long‐term facilitation of VE (vLTF) were measured each day. The apnea/hypopnea index (AHI) after exposure to IH on day 2 was greater than baseline in the IH but not the placebo group (IH group − 42.0 ± 5.9 vs. 26.6 ± 3.8 events/hr, p = 0.02; Placebo − 37.6 ± 11.3 vs. 30.3 ± 8.0 events/hr, p = 0.3). The AHI on day 11 (39.0 ± 6.2, p < 0.04) was also greater than baseline; however the AHI was similar to that measured on day 2. The HVR measured prior to exposure to IH on day 2 was correlated to the baseline AHI (r = 0.8, p < 0.002). Likewise, on day 2, the AHI was correlated to the HVR measured during the last hypoxic episode and vLTF (r = 0.58, p < 0.04 for both HVR and vLTF). In conclusion, exposure to IH is associated with an increase in the AHI. Increases in the HVR or vLTF might in part be responsible for increases in the AHI.Funding: NIH (HL‐085537)
Regulation of Force Dynamics in Fast Twitch Muscle
Authors: Groenendaal Willemijn , Jeneson Jeroen , Wiseman Robert , Nicolay Klaas , Hilbers Peter , van Riel Natal 
Published: June 2021

Several regulatory steps controlling skeletal muscle force generation have been experimentally demonstrated, and mathematical models have been developed to understand these mechanisms. Here, we investigated the minimal set of mechanisms required to describe both the range in peak force from twitch to tetanus and the characteristics of contraction and relaxation. Hereto, we measured calcium fluorescence using Rhod‐2 and force kinetics in murine EDL muscles at different stimulation frequencies, ranging from twitch to tetanus. Next, we tested available models in literature with a validated spatiotemporal calcium model as input. Monte Carlo simulations, covering a large parameter space, have been performed to test if the evaluated force models could describe the force dynamics.These simulations showed that calcium activation of the cross bridges sufficed to describe the increment in force from twitch to tetanus. In addition, numerical analysis indicated that extending the models with cooperative activation through strongly attached cross‐bridges was required to reproduce the dynamics of contraction and especially of relaxation. Therefore, we hypothesize that the minimal set of mechanisms to describe force dynamics in fast twitch muscle includes both activation by calcium bound to troponin and cooperative activation through strongly attached cross‐bridges.
The inhibition of phosphodiesterase 4 reduces skeletal muscle protein catabolism by suppressing autophagy/lysosomal and proteasomal pathways and atrophy‐specific gene transcription
Authors: Lira Eduardo Carvalho , Parreiras‐e‐Silva Lucas Tabajara , Zanon Neusa Maria , da Costa Neto Cláudio Miguel , do Carmo Kettelhut Ísis , Navegantes Luiz Carlos Carvalho 
Published: June 2021

This work investigated the effect of cAMP through PDE4 inhibition, the major PDE expressed in skeletal muscle, in modulating muscle protein degradation.The protein catabolism was monitored indirectly by measurement of interstitial tyrosine concentration in tibialis anterior muscle from Wistar rats (~250g) by microdialysis. Muscles were perfused with selective PDE 4 inhibitor, rolipram (1mM). Rates of proteolysis were determined by measuring the tyrosine release from extensor digital longus (EDL) and soleus from rats (~70g) incubated with different concentrations of PDE inhibitor. Gene expression was measured by real time‐PCR and cAMP level was estimated by ELISA. In situ muscle perfusion with rolipram reduced interstitial‐arterial tyrosine concentration difference, indicating a reduction in protein catabolism. Rolipram in vitro reduced overall proteolysis in a dose‐dependent manner and increased the muscle level of cAMP. This effect was accompanied by a decrease in the ubiquitin‐proteasome system (UPS) activity and suppression of autophagic and Ub‐ligases (atrogin‐1 and MuRF‐1) gene expression induced by fasting.These findings identify mechanisms by which PDE inhibitors reduces protein degradation, suggesting that inhibition of PDE 4 activates cAMP‐dependent pathway, which leads to the suppression of autophagic and UPS pathways and atrophy‐specific gene transcription.
Mitochondrial function is not the same in rat diaphragm and limb muscles
Authors: Garcia‐Cazarin Mary L , Gamboa Jorge L , Andrade Francisco H 
Published: June 2021

The mitochondrial content of skeletal muscles is proportional to their activity levels, supposedly to match ATP supply to demand. This view excludes the existence of intrinsic differences in mitochondrial function. The diaphragm is a constantly active respiratory muscle with high mitochondrial content. This study tested the hypothesis that mitochondrial function differs in rat diaphragm and triceps surae (TS, limb muscle). Mitochondria isolated from diaphragm and TS muscles of adult male Sprague Dawley rats were used to measure O2 consumption with polarography, the content of respiratory complexes, uncoupling protein 2 and 3 (UCP2 and UCP3) and voltage dependent anion channel 1 (VDAC1) by western blot, and complex IV activity by spectrophotometry. Respiration states 3 (substrate‐ and ADP‐driven) and 5 (uncoupled) were 27±8% and 24±10% lower in diaphragm than in TS mitochondria (p<0.05 for both). However, the contents of respiratory complexes III, IV and V and VDAC1 were higher in the diaphragm than in TS (23±6%, 30±8%, 25±8% and 18±8% respectively, p≤0.02 for all comparisons). Likewise, complex IV activity was 64±16% higher in diaphragm mitochondria (p=0.01). UCP2 and UCP3 content was not different. These data indicate that diaphragm mitochondria respire at lower rates, despite a higher content of respiratory complexes. The results support our initial hypothesis and suggest that in the diaphragm mitochondrial content is not the only determinant of aerobic capacity. We propose that VDAC1 influences ATP production in the diaphragm by regulating mitochondrial respiration.Research supported by R01 EY012998‐08A1 to FHA.
Coordinated maintenance of the size control of muscle cells by AMP‐activated protein kinase
Authors: Lantier Louise , Mounier Rémi , Leclerc Jocelyne , Melki Judith , Pende Mario , Bertrand Luc , Foretz Marc , Viollet Benoit 
Published: June 2021

Skeletal muscle mass is regulated by signaling pathways that govern protein synthesis and cell proliferation, the mammalian target of rapamycin (mTOR) playing a key role in these processes. Recent studies have suggested the crucial role of AMP‐activated protein kinase (AMPK) in the inhibition of protein synthesis and cell growth. Here, we address the role of AMPK in the regulation of muscle cell size in vitro and in vivo. The size of myotubes lacking both AMPKα1 and α2 catalytic subunits was 1.5‐fold higher than for controls. A marked increase in p70S6K Thr389 and rpS6 Ser235/236 phosphorylation was observed concomitant with an up‐regulation of protein synthesis rate. Inhibition of mTOR pathway by AMPK activators (AICAR, metformin, A‐769662) was blunted and was correlated with altered raptor phosphorylation. However, treatment with rapamycin prevented both p70S6K phosphorylation and cell hypertrophy. Moreover, in skeletal muscle‐specific deficient AMPKα1/α2 KO mice, soleus muscle showed a higher mass with myofibers of larger size and was correlated with enhanced p70S6K and rpS6 phosphorylation. Our results demonstrate the cross talk between AMPK and mTOR/p70S6K pathways in muscle cell size control.ANR‐06‐PHYSIO‐026
Functional muscle analysis of the Tcap knockout mouse
Authors: Markert Chad David , Childers Martin K. 
Published: June 2021

Autosomal recessive limb‐girdle muscular dystrophy type 2G (LGMD2G) is an adult‐onset myopathy characterized by distal lower limb weakness, calf hypertrophy, and progressive decline in ambulation. The disease is caused by mutations in Tcap, a z‐disc protein of skeletal muscle, although the precise mechanisms resulting in clinical symptoms are unknown. To provide a model for preclinical trials and for mechanistic studies, we generated knockout mice carrying a null mutation in the TCAP gene. Here we present the first report of a Tcap knockout mouse model for LGMD2G and the results of an investigation into the effects of Tcap deficiency on skeletal muscle function in 4‐month‐ and 12‐month‐old mice. Muscle histology of Tcap‐null mice revealed abnormal myofiber size variation with central nucleation, similar to findings in the muscles of LGMD2G patients. An analysis of a Tcap binding protein, myostatin, showed that deletion of TCAP was accompanied by increased protein levels of myostatin. Our Tcap‐null mice exhibited a decline in the ability to maintain balance on a rotating rod, relative to wild‐type controls. No differences were detected in force or fatigue assays of isolated extensor digitorum longus (EDL) and soleus muscles. Finally, a mechanical investigation of EDL and soleus indicated an increase in muscle stiffness in knockout animals. We are the first to establish a viable knockout mouse model of Tcap deficiency and our model mice demonstrate a dystrophic phenotype comparable to humans with LGMD2G.Support: M.K. Childers Laboratory Startup Fund
Effect of combined inhibition of adenosine and nitric oxide on compensatory vasodilation during exercise with acute hypoperfusion
Authors: Casey Darren P. , Walker Branton G. , Roberts Shelly K. , Knutson Jean N. , Joyner Michael J. 
Published: June 2021

Nitric oxide (NO) contributes to compensatory vasodilation in the contracting human forearm subjected to hypoperfusion during exercise. We tested the potential for adenosine/NO interaction in the compensatory dilation. Eight males (25 ± 2 yrs) performed forearm exercise (20% of max) during intra‐arterial balloon inflation. Each trial included; exercise, exercise with balloon inflation, and exercise after deflation (3 min each). Forearm blood flow (FBF; ultrasound) and brachial artery catheter pressure (BAP) were measured. Exercise was repeated during NO synthase inhibition (L‐NMMA) alone and with the combination of L‐NMMA/aminophylline (adenosine receptor blockade). Forearm vascular conductance (FVC; ml/min/100mmHg) was calculated from BF (ml/min) and BAP (mmHg). The % recovery in FVC during inflation was calculated as (steady state inflation plus exercise value – nadir)/[steady state exercise (control) value‐nadir]. FVC fell acutely with balloon inflation during all trials (P < 0.01). During the control trial, the % recovery in FVC was 111 ± 8%. The % recovery in FVC was attenuated with NOS inhibition alone (80 ± 9%; P < 0.001 vs. control) and attenuated further with combined inhibition of NO/adenosine (63 ± 9%; P < 0.05 vs. L‐NMMA). Thus, adenosine has an NO independent role in the compensatory vasodilatation during exercise with acute hypoperfusion.NIH HL46493 (MJJ), AR55819 (DPC) and RR‐024150.
A Single Nucleotide Polymorphism (SNP) in Titin (TTN) Decreases Muscle Soreness and Strength Deficits after Eccentric Exercise in Women
Authors: Moeckel‐Cole Stephanie Anne , Zambraski Edward , Gordish‐Dressman Heather , Hoffman Eric , Devaney Joe , Clarkson Priscilla 
Published: June 2021

There is significant and unexplained variability in muscle damage indicators following eccentric exercise, differences that might be due to genetic alterations in muscle structural genes. We determined whether SNP rs11693372 in the promoter of TTN was associated with strength loss and muscle soreness following eccentric exercise.Methods75 women and 79 men performed 50 eccentric actions of the elbow flexors. Strength was measured pre/post‐exercise, and 4d, 7d and 10d post‐exercise. Soreness was assessed via a visual analog scale at similar time points. Associations were compared between the TTN SNP and strength loss and soreness.ResultsAnalyses revealed significant differences in strength loss and soreness between genotypes for women only. Compared to T allele carriers, women possessing the ancestral CC genotype experienced: 1) less strength loss post‐exercise (CC, N=13, −44.8% ± 4.9; CT, N=31, −63.2% ± 3.2; TT, N=31, −55.9% ± 3.2; p<=0.01) and after 4d (CC, −26.0% ± 7.7; CT, −51.4% ± 4.9; TT, −39.9% ± 4.9; p<0.01); and 2) less muscle soreness at 3d (CC, 40.0mm ± 5.9; CT, 54.1mm ± 3.9; TT, 63.9mm ± 3.9; p=0.01) and 4d (CC: 30.2mm ± 6.8; CT: 50.3mm ± 4.4; TT: 51.4mm ± 4.4; p<0.01) post‐exercise.ConclusionsThese observations suggest that, for women, possession of the CC alleles mitigated strength loss and the development of muscle soreness following damaging eccentric exercise compared to T allele carriers.
Telmisartan inhibits sympathetic nerve activity through the reduction of oxidative stress and release of GABA in RVLM of hypertensive rats
Authors: Kishi Takuya , Hirooka Yoshitaka , Sunagawa Kenji 
Published: June 2021

BackgroundWe have demonstrated that angiotensin II‐dependent reactive oxygen species (ROS) and ƒÁ‐amino butyric acid (GABA) in the rostral ventrolateral medulla (RVLM) play a major role in regulating sympathetic nerve activity (SNA) in hypertensive rats. The aim of this study was to determine whether oral administration of angiotensin II type 1 receptor (AT1R) blocker, telmisartan, decreases SNA via the reduction of ROS and release of GABA in the RVLM of hypertensive rats.Methods and ResultsWe divided stroke‐prone spontaneously hypertensive rats (SHRSP), as a hypertensive model with enhanced SNA, into 2 groups, telmisartan‐group (TLM) and hydralazine‐group (HYD). Telemetered mean blood pressure (MBP) was reduced in both groups to a similar level. SNA and heart rate (HR) were significantly decreased in TLM, whereas increased in HYD. ROS in the RVLM were significantly lower in TLM than in HYD. The release of GABA measure by microdialysis was significantly higher in TLM than in HYD (15.1±0.7 vs 8.2±1.1 pmol/sample, n=5 for each, P<0.01). Microinjection of angiotensin II into the RVLM increased MBP and HR, and decreased GABA in the RVLM in HYD to a greater extent than in TLM.ConclusionTelmisartan decreases AT1R‐dependent ROS and increases GABA in the RVLM, thereby decreases SNA as well as blood pressure in SHRSP.
Angiotensin (1‐7) into rostral ventrolateral medulla is enhanced in spontaneously hypertensive rats
Authors: Nakagaki Toshiaki , Hirooka Yoshitaka , Ito Koji , Hoka Sumio , Sunagawa Kenji 
Published: June 2021

BackgroundAngiotensin‐(1‐7) (Ang‐(1‐7)) is recognized as an important mediator of renin angiotensin system. Ang‐(1‐7) is a peptide of ligand for Ang‐(1‐7)‐Mas receptor, and has opposite actions of angiotensin II in the vasculature. In the central nervous system, however, it has been shown that microinjection of Ang‐(1‐7) into rostral ventrolateral medulla (RVLM), one of vasomotor centers of brainstem increased blood pressure in normotensive rats. The aim of the present study was to determine the possible involvement of Ang‐(1‐7) in the RVLM in hypertension.Methods and ResultsIn anesthetized Wistar‐Kyoto (WKY) rats and spontaneously hypertensive rats (SHR), we microinjected Ang‐(1‐7) (100 pmol) and a Mas receptor antagonist (A‐779: 100 pmol) into the RVLM. Microinjection of Ang‐(1‐7) increased blood pressure in both strains. The changes were, however, significantly greater in SHR than WKY rats (13.3 ± 1.3 mmHg, n=7 vs. 6.6 ± 0.8 mmHg, n=5; p<0.05). In contrast, microinjection of a Mas receptor antagonist (A‐779) deceased blood pressure significantly greater in SHR than WKY rats (‐26.4 ± 1.7 mmHg, n=5 vs. ‐13.7 ± 0.8 mmHg, n=5; p<0.05).ConclusionBoth exogenous and endogenous Ang‐(1‐7) in the RVLM are enhanced in spontaneously hypertensive rats. The Ang‐(1‐7)‐Mas receptor pathway in RVLM may contribute to the mechanisms of blood pressure elevation in spontaneously hypertensive rats.