bluuebunny/crossref_metadata_2025_split huggingface dataset:
Cerebral oxidative metabolism during exhaustive exercise and recovery at sea level and high altitude (853.12)
Authors: Smith Kurt , Macleod David , Willie Christopher , Lewis Nia , Tymko Mike , Macleod Nicholas , Ikeda Keita , Day Trevor , Ainslie Philip 
Published: June 2021

Cerebral oxidative carbohydrate metabolism (OCI) is reduced during moderate and exhaustive exercise at sea‐level (SL) and restored rapidly during recovery. In contrast, in normobaric hypoxia OCI remains unchanged at rest and during moderate exercise. It is unknown what happens to OCI during exhaustive exercise and recovery following partial acclimatization to high altitude (HA; 5050m). Therefore, we hypothesized that OCI will be reduced at HA compared with SL during rest, exercise and recovery. Cerebral metabolism was calculated from the arterial and jugular venous differences for oxygen (Ca‐vO2), glucose (Glua‐v), and lactate (Laca‐v) at 20,40,60,80,100% of the maximum achieved wattage (%Wmax) and during 1,2,4,6,8,10,15,20,25, and 30 minutes of recovery at both SL and HA. The OCI was calculated as an index of the cerebral molar carbohydrate uptake ratio: OCI = Ca‐vO2/Glua‐v + ½ Laca‐v. Resting OCI at HA was ~40% reduced compared with SL (4.0 ± 0.5 vs 6.7±1.0 µmol.100g‐1.min‐1, respectively). Compared to SL, exercise at HA resulted in an ~14, and 8% greater reduction in OCI from rest at 20 and 40%Wmax, an equal reduction at 60% Wmax and an ~ 25, and 29% lesser reduction at 80, and 100% Wmax. During recovery from exercise at SL, OCI remained below baseline values until 25 min whereas at HA the OCI return to baseline at 6 min. It appears that during exhaustive exercise and recovery at sea level the brain relies more on non‐oxidative metabolism than at high altitude.Grant Funding Source: Canadian Graham‐Bell Scholarship, National Science and Engineering Research Council
An anatomical basis for interaction between acid‐sensing ion channel 1 and neuronal nitric oxide synthase in rat and human cerebral arteries (853.8)
Authors: Lin Li‐Hsien , Jin Jingwen , Nashelsky Marcus , Dailey Morris , Talman William 
Published: June 2021

Acid‐sensing ion channel type 1 (ASIC1), which may play contribute to synaptic plasticity, memory, fear conditioning and ischemic brain injury, is found primarily in brain; but it is also expressed in isolated mouse cerebrovascular smooth muscle cells. However, ASIC1 has not been shown in intact cerebral arteries. In contrast, neuronal nitric oxide synthase (nNOS), which is responsible for synthesis of NO, is found in human and animal cerebral arteries where NO may modulate protein activity. In that NO also modulates proton‐gated currents in cultured cells expressing ASIC1, we hypothesized that ASIC1 and nNOS may be expressed in close proximity in cerebral arteries. By Western blot analysis we found that ASIC1 is expressed in cerebral arteries in rat and human. Using confocal microscopy we found that ASIC1‐immunoreactivity (IR) was present in the anterior cerebral artery (ACA), middle cerebral artery (MCA), posterior cerebral artery (PCA) and basilar artery (BA) of rat and human. Colocalization of ASIC1‐IR with IR of alpha‐smooth muscle actin confirmed that ASIC1 was located in the smooth muscle layer of cerebral arteries while nNOS‐IR was found in neighboring endothelial and adventitial layers of the ACA, MCA, PCA and BA in rat and human. The proximity of ASIC1‐IR and nNOS‐IR provides an anatomical basis for possible interactions between ASIC1 and nNOS in regulating vasomotor tone of cerebral arteries.Grant Funding Source: Supported by NIH RO1 HL 088090 and a VA Merit Review
Heme oxygenase‐1 counteracts contrast media‐induced endothelial cell dysfunction (855.1)
Authors: Chang Chao‐Fu , Liu Xiao‐ming , Peyton Kelly , Durante William 
Published: June 2021

Endothelial cell (EC) dysfunction contributes to the pathogenesis of contrast media (CM)‐induced acute kidney injury, which is a major adverse event following coronary angiography. In this study, we evaluated the effect of CM on human EC proliferation, migration, and inflammation, and determined if heme oxygenase‐1 (HO‐1) influences the biological actions of CM. We found that three distinct iodine‐based CM, including high‐osmolar (diatrizoate), low‐osmolar (iopamidol), and iso‐osmolar (iodixanol), stimulated the expression of HO‐1 protein and mRNA. The induction of HO‐1 was dependent on the concentration and duration of CM exposure and associated with an increase in NF‐E2‐related factor‐2 (Nrf2) activity and reactive oxygen species (ROS) production. CM also stimulated HO‐1 promoter activity and this was prevented by mutating the antioxidant responsive element or by overexpressing dominant‐negative Nrf2. In addition, the CM‐mediated induction of HO‐1 and activation of Nrf2 was abolished by N‐acetyl‐L‐cysteine. Finally, CM inhibited the proliferation and migration of ECs and stimulated the expression of intercellular adhesion molecule‐1 and the adhesion of monocytes on ECs. Inhibition or silencing of HO‐1 exacerbated the anti‐proliferative and inflammatory actions of CM but had no effect on the anti‐migratory effect. In conclusion, the present study demonstrates that the induction of HO‐1 via the ROS‐Nrf2 pathway counteracts the anti‐proliferative and inflammatory actions of CM. Therapeutic approaches targeting HO‐1 may provide a promising approach in preventing CM‐induced endothelial and organ dysfunction.Grant Funding Source: Supported by NIH grant HL59976 and a grant from the Department of Health, Taipei City Government
BK channel β‐1 subunit deficiency exaggerates vascular fibrosis and organ damage in high fat diet‐induced obesity in mice (857.10)
Authors: Xu Hui , Garver Hannah , Phelps Jeremiah , Fernandez Roxanne , Galligan James , Fink Gregory 
Published: June 2021

BK channels regulate arterial tone. Studies done in humans and animals suggest that impaired BK channel function contributes to obesity associated hypertension due to higher myogenic tone and increased norepinephrine (NE) reactivity. In current study, we continually measured mean arterial pressure (MAP) and heart rate (HR) using radiotelemetry in high fat (HF) diet fed wild type (WT) and BK channel β1‐subunit knockout (BK β1‐KO) mice during last 11 weeks of HF‐fed. After 24 weeks on HF‐fed, body weight and blood glucose levels were similar in all mice. All mice were normotensive, but BK β1‐KO mice showed a progressive fall in HR when compared to WT mice. Atenolol (oral) or hexamethonium (ip) treatment reduced MAP and HR similarly in all mice, prazosin (oral) decreased MAP and increased HR in BK β1‐KO only. Mesenteric arteries (MA) from BK β1‐KO mice exhibited increased sensitivity to NE and BayK 8644, higher myogenic tone, increased wall thickness and smaller wall/lumen ratio compared to WT mice. BK β1‐KO mice also exhibited left ventricular hypertrophy, lower hematocrits and higher plasma creatinine levels than WT mice. Histological studies revealed more extensive collagen deposition in MA, coronary and renal arteries, myocardium and kidneys of BK β1‐KO compared to WT mice. Our results indicate that BK channel deficiency does not cause hypertension, but does promote vascular fibrosis and organ damage in HF‐fed mice.Grant Funding Source: Supported by NIH and AHA
Novel role of HIF‐1alpha in tubular Na transport in the remnant kidney (860.7)
Authors: Singh Prabhleen , Ayoyama Koji , Pham Hai , Thomson Scott 
Published: June 2021

Remnant nephrons after subtotal nephrectomy (STN) show significant hyperfiltration. We have also shown increased oxygen consumption for tubular Na reabsorption in STN leading to hypoxia. We hypothesized that this increase may be due to a relative shift in Na transport to nephron segments distal to the proximal tubule, where oxygen costs for Na transport are higher. In STN kidney, activation of HIF‐1α, master regulator of cell response to hypoxia, lowers the elevated oxygen consumption. Hence, we also examined the effect of HIF‐1α on Na transport in different nephron segments.In the STN kidney, when adjusted for SNGFR, proximal reabsorption was lower in STN (p=0.01), and the early distal flow rate was nearly double that in shams. This was accompanied by a reduced expression of Na/H exchanger (NHE3) in the proximal tubule (p<0.05), while the expression of Na‐Cl cotransporter (NCC) in the distal tubule was increased (p<0.05). In micropuncture experiments, SNGFRs were found to be higher in STN treated with DMOG, a pharmacological HIF‐1α activator, compared to untreated STN (67±4 vs. 50±4 nl/min, p=0.01), as were the APRs (25±2 vs. 20±2 nl/min, p=0.09), but the fractional reabsorption was modestly lower (0.37 vs. 0.4). This suggests a mild effect of HIF‐1α induction on proximal reabsorption. Moreover, DMOG lowered the NHE3 expression in controls but did not have a significant effect in the STN, but significantly lowered the NCC expression in both controls and STN kidney (p<0.05). Alteration in Na transport in the thick limbs and distal tubules along with expression of NKCC2 and ENaC are currently being performed.These data suggest that there is relative shift in Na transport to the distal segments of the nephron in early STN, which increases renal oxygen consumption required for Na transport. HIF‐1α activation improves kidney oxygen consumption by lowering Na transport in these segments, thus demonstrating a novel role of HIF‐1α in regulation of the coupling between tubular transport and metabolism.Grant Funding Source: NIH
Influence of late N‐acetylcysteine administration on cardiac remodeling in long‐term follow‐up postinfarction rats (862.3)
Authors: Lopes V , Oliveira Junior S , Cezar M , Damatto R , Bonomo C , Pagan L , Lima A , Gomes M , Zornoff L , Okoshi K , Okoshi M , Martinez P 
Published: June 2021

This study aimed to evaluate the influence of late N‐acetylcysteine (NAC) administration on cardiac remodeling in long‐term follow‐up postinfarction rats. Methods: Myocardial infarction (MI) was induced by left coronary occlusion. Four months later, rats were assigned to three groups: Sham (n=13), MI‐C (MI without treatment, n=16), and MI‐NAC (MI treated with N‐acetylcysteine, 120 mg/kg/day, n=16). Six months after surgery, cardiac structures and function were evaluated by transthoracic Doppler echocardiogram and rats were euthanized the next day. Infarct size was measured by histological analysis, and rats with small MI (< 30%) were excluded. Results: MI size did not differ between MI‐C and MI‐NAC groups (p>0.05; Student’s t test). Right ventricle (RV) and lung weight, RV/body weight (BW) and lung/BW ratios were similar between MI‐C and MI‐NAC and higher than Sham. Left ventricle diastolic diameter, left atrium (LA) diameter, and LA/BW ratio were higher in MI‐C than Sham and similar between MI‐C and MI‐NAC. The systolic function variables fractional area shortening and posterior wall shortening velocity were similar between MI‐C and MI‐NAC and both lower than Sham. Concerning diastolic function, E wave‐to‐A wave ratio was higher in MI‐C than in both Sham and MI‐NAC (Sham: 1.47±0.14; MI‐C: 4.83±2.41; MI‐NAC: 3.25±1.85; p<0.001, ANOVA and Bonferroni). Conclusion: Late N‐acetylcysteine treatment attenuates diastolic dysfunction in long‐term follow‐up postinfarction rats.Grant Funding Source: FAPESP and CNPq
Role of phosphodiesterase‐1 in muscarinic receptor‐induced human urinary bladder smooth muscle excitability and contractility (865.4)
Authors: Xin Wenkuan , Li Ning , Rovner Eric , Cheng Qiuping , Petkov Georgi 
Published: June 2021

Role of phosphodiesterase‐1 in muscarinic receptor‐induced human urinary bladder smooth muscle excitability and contractility Wenkuan Xin1, Ning Li1, Eric S. Rovner2, Qiuping Cheng1, and Georgi V. Petkov1,2
1Drug Discovery & Biomedical Sciences, South Carolina College of Pharmacy, University of South Carolina, Columbia, SC 29208 and 2Medical University of South Carolina, Charleston, SC 29425 Activation of muscarinic M3 receptors (M3Rs) leads to an inhibition of the large conductance Ca2+‐activated K+ (BK) channels and an increase in human urinary bladder smooth muscle (UBSM) excitability. M3R‐mediated Ca2+ influx activates phosphodiesterase‐1 (PDE1) and reduces cellular cAMP levels. We investigated the mechanism by which the integrated PDE1 and MR signaling pathways stimulate human UBSM excitability and contractility. Pharmacological activation of M3Rs with carbachol (1 µM) decreased the frequency and amplitude of transient BK currents (TBKCs) in UBSM cells and subsequent inhibition of PDE1 with 8MM‐IBMX (10 µM) recovered TBKC activity. In the absence of M3R stimulation, inhibition of PDE1 increased TBKCs frequency, and subsequent inhibition of protein kinase A (PKA) with H‐89 (10 µM) reduced TBKCs frequency. 8MM‐IBMX (10 µM) hyperpolarized UBSM membrane potential, an effect which was blocked upon PKA inhibition. 8MM‐IBMX suppressed spontaneous phasic contractions and nerve‐evoked contractions of UBSM isolated strips. In conclusion, PDE1 enhances the M3R‐mediated inhibition of BK channels. Inhibition of PDE1 attenuates UBSM excitability by increasing BK channel activity via a PKA‐dependent mechanism. A combination of a PDE1 inhibitor and a MR antagonist can be an effective novel approach for the treatment of bladder overactivity.Key words: phosphodiesterase, muscarinic receptor, detrusorGrant Funding Source: NIH R01 DK084284 to Georgi V. Petkov
Prostaglandin E2 inhibits the large‐conductance voltage‐ and Ca2+‐activated K+ channels in guinea pig urinary bladder smooth muscle (865.7)
Authors: Parajuli Shankar , Provence Aaron , Petkov Georgi 
Published: June 2021

Prostaglandin E2 (PGE2) is an important signaling molecule that has been shown to be involved in the regulation of urinary bladder smooth muscle (UBSM) contractility in both rodents and humans. However, the underlying mechanism by which PGE2 evokes UBSM contractions is not well understood. Here, we investigated whether large conductance voltage‐ and Ca2+‐activated K+ (BK) channels mediate the stimulatory effects induced by PGE2 on guinea pig UBSM contractility. We used a combined experimental approach including patch‐clamp electrophysiology, live‐cell Ca2+ imaging, and isometric UBSM tension recordings to investigate BK channel regulation by PGE2 at both cellular and tissue levels. PGE2 increased the spontaneous phasic contractions of UBSM isolated strips in a concentration‐dependent manner (10 nM‐10 µM). BK channel inhibition with paxilline attenuated the PGE2‐induced UBSM phasic contractions, suggesting that BK channels are among the targets of PGE2. Our data also indicate that PGE2 (10 µM) caused an inhibition of the amplitude and frequency of spontaneous transient BK currents and increased the intracellular Ca2+ levels in freshly‐isolated UBSM cells. Thus, for the first time we have revealed a novel mechanism by which BK channels mediate the PGE2 stimulatory effects on guinea pig UBSM contractions.Grant Funding Source: Supported by NIH R01 DK084284 grant to Georgi V. Petkov.
Associations of plasma osteocalcin and fetuin‐A with bone mineral density in post‐menopausal women (867.16)
Authors: Hunter Larry , Farr Joshua , Miller Virginia 
Published: June 2021

In postmenopausal women, decreases in estrogen disrupt the normal balance of bone turnover, increasing bone resorption relative to bone formation. This study investigated the effects of menopausal hormone treatment (MHT) on volumetric bone mineral density (vBMD) and markers of bone turnover in plasma of healthy, recently‐menopausal women. Women (age 52.3±2.3 yrs; n=115) enrolled in the Kronos Early Estrogen Prevention Study (KEEPS) were randomized to either: oral conjugated equine estrogen (oCEE), transdermal 17β estradiol (tE2) each with intermittent oral micronized progesterone or placebo (Pl), for 48 months. vBMD was assessed by quantitative computed tomography of the wrist, and plasma levels of osteocalcin (OCN; a bone turnover marker), and of Fetuin‐A, a hepatocyte‐derived modulator of osteogenesis, were quantified by ELISA. At 48 months, cortical vBMD at the distal radius had decreased by 2.9% in the Pl group, correspondent with an increase above initial plasma OCN (15.0 ng/ml) of 38.5%. MHT attenuated the vBMD decrease (0.9% in both treatment groups combined; P=0.015), and the OCN increase (8.8 and 4.3% in oCEE and tE2, respectively). Plasma Fetuin‐A levels did not differ significantly among groups at 48 mo. Unexpectedly, Fetuin‐A was negatively associated (r=‐0.50 to ‐0.62; P <0.05) with changes in trabecular bone microarchitectural parameters at the distal radius in the Pl group, whereas both oCEE and tE2 attenuated this effect (all P‐values >0.05). As expected, MHT attenuated bone turnover in postmenopausal women. However, the relationship between processes regulated by OCN and Fetuin‐A require further evaluation.Grant Funding Source: Supported by Aurora Foundation, HL90639 and AG44170
Nitric oxide inhibits vascular remodeling by decreasing angiotensin II‐induced RhoA translocation to caveolae and ROS formation (867.6)
Authors: Hajj Hussein Inaya , Nourddine Ward , Soudani Nadia , Zeidan Asad 
Published: June 2021

Decreased production of nitric oxide (NO) leads to induce vascular smooth muscle cell (VSMC) hypertrophy via angiotensin II (AngII) receptors. However, the regulatory mechanism of NO activity on Ang II‐mediated VSMC remodeling remains fully unclear. Here we hypothesized that caveolin‐1 (cav1) and NO production are involved in the regulation of AngII‐induced VSMC remodeling via inhibition of the RhoA translocation to caveolae. Rat aortic rings were cultured in the presence of AngII (1 nM) with or without the NO donor S‐nitroso‐nacetylpenicillamine (100 μM; SNAP), the ROCK inhibitor (10 μM; Y‐27632), the RhoA inhibitor C3 exoenzyme (3 ng/ml; C3), or methyl‐B‐cyclodextrin (10 mM; MBCD). AngII‐induced VSMC hypertrophy and protein synthesis were inhibited by pre‐treatment with SNAP, Y‐27632, C3 or MBCD. AngII‐induced protein synthesis was associated with increased in ROS formation and expression of cav‐1 (2 folds), NADPH oxidase1 (NOX1; 4 folds) and NOX3 (5 folds) and decreased NOX2 (2 folds) expression and NO activity (3 folds).Treatment of the aortic ring with AngII for 20 min increased caveolae‐bound RhoA (4‐folds), cofilin‐2 phosphorylation (3 folds), and F‐ to G‐actin ratio (2 folds), which were prevented by increased of NO production. These results will allow for the creation of pharmacological agents for the treatment of vascular hypertrophy due to AngII.
miR‐133a alleviates cardiac autophagy by targeting AMPK in Ins2+/‐ diabetic mice (868.3)
Authors: Nandi Shyam , Mishra Paras 
Published: June 2021

Optimum level of autophagy is indispensable for survival and cellular function, and miRNA tightly regulates biological functions. In diabetic hearts, miR‐133a (anti‐hypertrophy and anti‐fibrosis) is attenuated and autophagy is induced. Based on these observations, we hypothesize that inhibition of miR‐133a induces autophagy in diabetic hearts. To test the hypothesis, HL1 cardiomyocytes were treated with low (LG‐5mM) and high (HG‐25mM) dose of D‐glucose, and miR‐133a and scrambled control. To determine whether miR‐133a mitigates autophagy in diabetic hearts, we measured the levels of monodansylcadaverin intensity (marker of autophagolysosome) and then the upstream targets ATG3, LC3B (autophagophore formation) and Beclin‐1 (initiator of autophagy signaling). We also determined the activity and expression of mTOR (upstream inhibitor of Beclin‐1) and AMPK (upstream inhibitor of mTOR) by RT‐qPCR, immunoblotting and immunofluorescence. The specific role of miR‐133a in mitigation of high glucose mediated autophagophore formation is determined by transfecting HL1 cardiomyocytes with LC3‐RFP plasmid. In hyperglycemic cardiomyocytes, miR‐133a decreases the protein levels of AMPK (4.1±0.38 fold), that in turn increases mTOR (3.2±0.4 fold), which suppresses Beclin1 (2.5± 0.33 fold) and the downstream targets LC3B (3.5±0.4 fold) and ATG3 (2.5±0.18 fold), and fluorescent intensity of monodansylcadaverin (2.5±0.47 fold). The in vivo studies were performed on C57BL/6J and Ins2+/‐ (spontaneous, chronic T1D) mice. Both groups of mice were treated with miR‐133a mimic (10^5lentivirus, iv,/day for 5 days) and hearts were extracted after 10 days. The in vivo results corroborate that miR‐133a mitigates cardiac autophagy in diabetes. Further investigation revealed that AMPK 3’UTR is a direct target of miR‐133a. These findings demonstrate a novel mechanism of miR‐133a mediated mitigation of autophagy in diabetic hearts.Grant Funding Source: NIH grants: HL113281 and HL116205.
Unilateral diaphragm muscle paralysis minimally impacts ventilation in rodents (871.5)
Authors: Sieck Gary , Gransee Heather , Gill Luther , Jorgenson Amy , Medina Juan , Alvarez‐Argote Juliana , Mantilla Carlos 
Published: June 2021

Ventilatory behaviors across a range of species including humans require less than 50% of maximal force‐generating capacity by the diaphragm muscle, the main inspiratory muscle in mammals. Near maximal forces are only generated during expulsive behaviors usually associated with airway clearance. There is ongoing controversy regarding the impact of unilateral lesions (e.g., spinal cord injury, denervation) on ventilatory outcomes. We hypothesized that unilateral denervation of the diaphragm muscle in rats and mice would minimally impact ventilation. Transdiaphragmatic pressure (Pdi) measurements were used to estimate diaphragm muscle force in adult male rats and mice. Following acute, unilateral phrenic nerve transection in the neck, there was no change in Pdi during eupnea or hypoxia‐hypercapnia in rats or mice. Reduced Pdi was evident during deep breaths and tracheal occlusion (behaviors associated with ~70% of maximal Pdi elicited by bilateral phrenic nerve stimulation) in both species. These results are also consistent with the lack of changes in tidal volume or respiratory pattern during eupnea measured by whole body plethysmography in unrestrained, spontaneously breathing rats after mid‐cervical contusion or hemisection injuries. These results highlight the large reserve capacity for force generation by the diaphragm muscle in rodents and the importance of measuring multiple motor behaviors.Grant Funding Source: Supported by HL096750, AG044615, HL105355 and Mayo Center for Regenerative Medicine
Peripheral chemoreceptors determine the respiratory sensitivity of central chemoreceptors to CO2: role of carotid body CO2 (872.3)
Authors: Smith Curtis , Henderson Kathleen , Dempsey Jerome 
Published: June 2021

We have shown previously that inhibition of the isolated carotid body (CB) chemoreceptor (via CB‐specific hyperoxia &amp; hypocapnia) markedly reduced the ventilatory response sensitivity of the central chemoreceptors to increased PaCO2 whereas stimulation (via CB‐specific hypoxia &amp; normocapnia) markedly increased it (Blain et al., J. Physiol. 588: 2455‐2471, 2010). These findings were consistent with ventilatory hyperaddition of the CB and central chemoreceptors. We questioned whether changes in CB CO2 alone would result in similar interaction. To date, we have tested this in 4 unanesthetized and chronically instrumented dogs in which the CBs were isolated &amp; perfused independently of the systemic circulation. CB hypocapnia (PcbCO2 ~ 20 mmHg < eupnea; PcbO2 normal) and CB hypercapnia (PcbCO2 ~ 20‐30 mmHg > eupnea; PcbO2 normal) were used to inhibit/stimulate the CB while systemic (and therefore central chemoreceptor) PCO2 was increased with 3 different levels of FICO2 in a normoxic background. We found that CB hypocapnia decreased (mean slope 34% of control), and CB hypercapnia increased (mean slope 125% of control), the ventilatory response of the central chemoreceptors to CO2. Our preliminary conclusion is that the hyperadditive CB/central interaction reported previously is independent of the stimuli used to inhibit/stimulate the CB.Grant Funding Source: Supported by NIH, NHLBI HL50531