bluuebunny/crossref_metadata_2025_split huggingface dataset:
Minimally invasive transverse aortic banding as a model to study heart disease in SD, SS and Mas−/− rat strains
Authors: Anene‐Maidoh Ogugua T. , Greene Andrew S. 
Published: June 2021

Minimally invasive transverse aortic banding (MTAB) is a model for inducing ventricular dysfunction that has been used exclusively in mice. Our objective was to test the efficacy of the MTAB model in rats by using the Sprague Dawley, Dahl salt‐sensitive hypertensive and the recently developed Mas receptor knock out rat. The Mas receptor mediates the physiological effects of the angiotensin peptide ANG1‐7 and thus modulates cardiovascular function. A rat knockout of the Mas1 receptor was generated using zinc‐finger nuclease (ZFN) mediated engineering on the SS genetic background. A 10‐bp deletion in exon1 of the Mas1 gene led to a severely truncated protein and a loss of function. Cardiac function was assessed following MTAB using cardiac ultrasound, PV loop analysis, and histology.Weekly echocardiography showed rat MTAB resulted in significant LV hypertrophy associated with a biphasic change in fractional shortening compared to sham controls. Six weeks after banding, acute measurements of LV pressures and volumes revealed significant changes in systolic and diastolic function associated with decreases in ventricular contractility and compliance. Histology showed increases in fibrosis. Differences in severity of disease between rat strains were observed suggesting MTAB combined with ZFN engineering can reveal functional cardiac effects and supports the role of the Mas1 receptor in cardiac fibrosis.HL082798
The effects of a multiflavonoid supplement on blood pressure and oxidative stress
Authors: Campbell Kristen Joanne , Kappus Rebecca M. , Nieman David C. , McAnulty Steven R. , Cook Carol , Hubner Martin , Collier Scott R. 
Published: June 2021

Antioxidant supplementation has been shown to reduce blood pressure. Moderate intensity aerobic exercise also elicits a reduction in blood pressure immediately following exercise, termed post exercise hypotension (PEH). The purpose of this study was to test the effects of a multi‐flavonoid supplement plus exercise on PEH following a 2‐week dosing period.Methods12 normotensive subjects between the ages of 18–24 were randomized into either a placebo or a multiflavonoid supplement. Each subject was studied pre, immediately before and after exercise and at 30 minutes post‐exercise both prior to and following 2 weeks supplementation. Blood was taken both pre and immediately following the exercise sessions and was assayed for ferric reducing antioxidant power (FRAP) and the oxygen radical absorbance capacity (ORAC).ResultsSignificant decreases in systolic blood pressure in the treatment vs. placebo group (−3 ± 0.44 mmHg vs. −0.3 ± 0.56 mmHg, respectively, interaction p = 0.05,) and significant increases in FRAP (742 ± 41 to 956 ± 46 μmol/L vs. 658 ± 41 to 670 ± 46 μmol/L, interaction p=0.024) were found following supplementation and no differences in the control group. ORAC produced no significant differences with supplementation.ConclusionsThese data suggest that Q‐EGCG supplementation increases FRAP in young normotensives which may be a mechanism for the resting blood pressure reduction.
Impaired ATP release during exercise in older adults: potential mechanism for impaired skeletal muscle blood flow with advancing age
Authors: Kirby Brett S , Crecelius Anne R , Voyles Wyatt F , Dinenno Frank A 
Published: June 2021

Aging is associated with impaired control of skeletal muscle blood flow during exercise. In young adults, circulating adenosine triphosphate (ATP) aids in the control of muscle vascular tone during exercise. We tested the hypothesis that increases in plasma [ATP]v and ATP release during forearm exercise are impaired in aging humans. We measured forearm blood flow (FBF; Doppler ultrasound) and [ATP]v, and calculated ATP release (FBF x [ATP]v) during 5, 15, and 25% MVC rhythmic handgrip exercise in 14 young (22±1) and 12 older (63±2 yrs) adults. Deep venous blood samples were mixed in stop solution to preserve [ATP]v for plasma measurement. FBF tended to be lower during 5% MVC and was lower during 15 and 25% MVC in older adults (P<0.05). At rest, there were no age‐group differences in [ATP]v (Y=214±16; O=183±35 nmol/L; P=0.4) or ATP release. [ATP]v increased above rest during all exercise intensities in young adults (P<0.05); in contrast there was no significant increase in [ATP]v in older adults. ATP release increased in a graded fashion in both age groups, however this increase was blunted ~50–60% at all exercise intensities in older adults (P<0.05 vs young). ATP release was related to FBF during exercise in both groups (r2=0.73). We conclude that the increase in [ATP]v and ATP release during forearm exercise is impaired in healthy older adults and relates to the observed declines in exercise hyperemia.Supported by HL‐087952
Estrogen and sympathetic modulation of hindlimb blood flow variability in rats
Authors: Mattar Louis , Noble Earl , Shoemaker J. Kevin 
Published: June 2021

Recent evidence suggests that males and females rely on different physiologic mechanisms to maintain blood flow and vasculature conductance. To test the hypothesis that sympathetic inputs affect hindlimb flow variability, the coefficient of variation (CV = standard deviation/mean) of hindlimb flow and conductance were measured in male and female animals of various rat strains (Sprague Dawley, Spontaneously Hypertensive and Wistar‐Kyoto). One thousand consecutive heart beats at baseline and during sympathectomy (25mg/kg Hexamethonium; Hex) were used to assess each CV. Female rats (any strain) exhibited greater CV in hindlimb conductance at baseline compared to males (grouped gender averages: 35±19AU vs. 12±11AU, respectively; P<0.05). A subgroup of female hypertensive animals that were ovariectomized (OVX) exhibited lower CV (25±21AU) compared to their intact counterparts (41±14AU; P<0.05), and OVX animals given estrogen (51±22AU; P<0.05). The variability in female animals was driven by changes in hindlimb flow, and was blunted (i.e. not different from males) following Hex (19±13AU vs. 10±6AU, n.s. between female and male animals respectively). Therefore, blood flow variability was greater in the hindlimb of female rats of various strains and this variability was related to both estrogen and sympathetic mechanisms.Supported by CIHR.
Nitrite supplementation reverses vascular endothelial dysfunction in old mice via improved nitric oxide bioavailability
Authors: Sindler Amy L , Calvert John W , Fleenor Bradley S , Zigler Melanie L , Lefer David J , Seals Douglas R 
Published: June 2021

Aging causes vascular endothelial dysfunction as indicated by impaired endothelium‐dependent dilation (EDD), and this is mediated by reduced nitric oxide (NO) bioavailability. Administration of nitrite (NO2−), a product of NO oxidation, is associated with enhanced NO bioavailability. We hypothesized that treatment with NO2− would enhance EDD with aging. Old (27 mo, n = 7) adult C57 male mice had a lower ex vivo carotid artery acetylcholine (ACh)‐induced EDD (70.9 ± 3.7 vs. 94.0 ± 2.9%, P < 0.05) and NO component of EDD (mean dilation to ACh + L‐name minus mean dilation to ACh alone, −26.6 ± 5.9 vs. −50.5 ± 9.5%, P < 0.05) compared with young adult controls (6 mo, n = 6). In old mice (n = 4), 3 weeks of dietary supplementation with sodium NO2− (50 mg/l in drinking water) restored EDD (96.6 ± 1.9%, P < 0.05) and its NO component (−60.2 ± 5.0%, P < 0.001). Sensitivity to ACh and endothelium‐independent dilation were not different in young, old and old NO2− supplemented mice. These preliminary results support the idea that NO2− supplementation may be an effective strategy for reversing vascular endothelial dysfunction with aging by enhancing NO bioavailability.Work supported by NIH R37 AG013038, HL 007822
Age‐ and limb‐related differences in the vascular response to limb dependency in humans
Authors: Monahan Kevin D. , Solaiman Adil Z. , Snyder Katherine A.M. , Sielatycki John A. , Feehan Robert P. , Wilson Thad E. 
Published: June 2021

To determine if age‐ and limb‐related differences exist in the vascular response to limb dependency we studied 9 young (25±1 yrs, mean±SE) and 7 older adults (65±3 yrs). We hypothesized that vasoconstriction (VC) during limb dependency would be greater in the leg than arm and attenuated with age. Supine subject's arms and legs were lowered 30 cm below heart level while measurements of skin blood flow velocity (BFV; laser Doppler flowmetry) and limb BFV (brachial and popliteal arteries) were obtained. Limb dependency induced significant VC (%Δvascular resistance; MAP/MBV) in the arm (Δ27.5±8.2%) and leg (Δ49.8±8.1%) of young adults although the magnitude of this response was greater in the leg (P<0.05 arm vs. leg). In older adults limb dependency induced significant VC in the arm (Δ23.6+6.8%) and leg (Δ22.4±4.3%; P>0.05 arm vs. leg). Leg VC during limb dependency was attenuated with age (Δ49.8±8.1% vs. Δ22.4±4.3% in young and older, respectively; P<0.05). In contrast skin VC during limb dependency was similar in the arm (Δ165±27% and Δ156±29% for young and older, respectively) and leg (Δ167±27% and Δ162±23%; all P<0.05 from baseline) of young and older adults. These findings identify important age‐, limb‐, and possible tissue‐related differences in the vasoconstrictor response to limb dependency, which may be attributable to altered myogenic and or venoarteriolar responses.Support: NIH HL92309 and AG24420
Hyperoxia decreases brain derived neurotrophic factor (BDNF) production in the carotid body and brainstem and catecholaminergic neurons in nucleus tractus solitarii (nTS).
Authors: Mason Ariel Vanessa , Chavez‐Valdez Raul , Johnson Sheree , Gauda Estelle B 
Published: June 2021

BDNF in the carotid body (CB) has trophic effects on the development of primary sensory afferents. Hyperoxic exposure (HYP) during early postnatal development causes hypoplasia of the CB, reduces sensory neurons, and ablates hypoxic chemosensitivity. We hypothesized that HYP would directly affect BDNF production in the CB and brainstem (BS) and tyrosine hydroxylase (TH) expression in the nTS.MethodsTime‐dated SD rats were exposed to HYP (60% O2) or (21% O2) for 48h prior to delivery and for 7 or 14 days after delivery and then returned to 21% O2 until postnatal day 9, 16 or 22 when the CB and BS were harvested and processed for gene (qRT‐PCR) and protein expression.ResultsHYP exposure for 7days reduced BDNF mRNA levels by 80% and 50% in the CB and BS, respectively (p=0.002) along with a 90% reduction in protein expression (p=0.04) in both tissues. HYP also up‐regulated p75 receptor gene expression in BS (1.6‐fold, p=0.002) without significant change in TrkB receptor. BS BDNF mRNA levels decreased from day 9 to 16 (p=0.04) but was not different between HYP and control animals at day 16. At day 22, there was a reduction in TH‐ir+ neurons and in TH protein levels (15%) in the nTS region of animals exposed to HYP, while no change in TH protein levels was observed in the locus coeruleus.ConclusionThe reduction in TH+ neurons in the nTS in hyperoxic exposed animals may be linked to reduced BDNF production in the CB.Supported by NIH R01HL080725
Neurotrophic Factors and the Growth of the Carotid Body
Authors: Kostuk Eric Wildon , Pichard Luis , Shirahata Machiko 
Published: June 2021

Hypoxia is potentially a life‐threatening event for humans and animals. In the mammal, the carotid body is a major sensory organ detecting hypoxia. The carotid body function in developing animals differs from that of adult animals. The response of the carotid body to hypoxia is minimal at birth, and then gradually reaches the adult level. Environmental factors as well as genetic factors appear to play a role in the development of the carotid body function and morphology. Our previous studies have shown the vast morphological and genetic differences of the carotid body between the DBA/2J and A/J mice (4‐week old). Interestingly, the morphological differences of the carotid body are not apparent in 1‐day and 1‐week old mice. We hypothesize that neurotrophic factors contribute to the differential growth of the carotid bodies in these strains of mice. Thus, we examine the expression levels of glial cell line‐derived neurotrophic factor (Gdnf) and its family ligand (neurturin: Nrtn) and their receptors (Gdnf family receptor‐α1 and α2: GFR‐α1, GFR‐α2; Ret receptor) in the carotid body during postnatal development. Carotid bodies were harvested from deeply anesthetized mice (2‐day, 1‐week, 2‐week and 4‐week old), and real‐time PCR were performed. At 2‐day and 1‐week old, expression of all these genes was not significantly different between the strains. Gdnf expression was significantly higher in DBA/2J mice than A/J mice at 2‐week and 4‐week old. The results suggest that GDNF may be important for the growth of the carotid body and that 2‐week age may be a critical window for the growth of the carotid body in mice.Supported by HL81345.
Physical inactivity rapidly alters glycemic control in young, lean, previously active volunteers
Authors: Mikus Catherine Renee , Thyfault John P 
Published: June 2021

Postprandial hyperglycemia is a better predictor of cardiovascular disease (CVD) and all cause mortality than fasting blood glucose (FBG) or hemoglobin A1c, regardless of diabetes status. Further, physical inactivity (PIA) is strongly associated with insulin resistance (IR) and CVD. To determine whether transitioning from a high to low level of physical activity (PA) adversely affects glycemic control (GC), we equipped young (30 ± 1 y), lean (24 ± 1 kg·m−2), healthy, physically active (>10,000 steps·d−1) volunteers (N=10) with continuous BG monitors for 3 d during separate ACTIVE (habitual PA) and INACTIVE (≤ 5,000 steps·d−1) phases (diet replicated across phases). During the INACTIVE phase, PA decreased from 15,758 ± 1,103 to 4,334 ± 294 steps·d−1, FBG did not change (84 ± 3 to 87 ± 1 mg·dL−1), fasting insulin increased (4 ± 1 to 6 ± 1 μIU·mL−1; p = 0.02), and, when BG responses to all meals were pooled, the amplitude of glycemic excursions (post‐ minus pre‐meal BG; an index of GC) increased at 30 (16 ± 4 to 30 ± 4 mg·dL−1; p = 0.02) and 60 min (8 ± 2 to 22 ± 5; p = 0.04) post‐meal. We conclude that brief, modest reductions in PA rapidly diminish GC in young, lean individuals, suggesting PIA may: 1) play a key role in the development of IR by impairing GC, 2) cause aberrations in GC prior to changes in fitness and adiposity, and 3) be a useful tool to study early events in the etiology of IR.Support: MU iCATS, T32 AR048523 (CRM), VHA CDA (JPT).
Oxidative stress leads to reduced coupling of oxidative phosphorylation in in vivo resting mouse skeletal muscle
Authors: Siegel Michael , Knowles Gary , Harper Mary‐Ellen , Marcinek David 
Published: June 2021

The “Uncoupling to Survive” Hypothesis suggests that oxidative stress induces reduced coupling of oxidative phosphorylation (P/O), which then reduces reactive oxygen species production by the mitochondria. This study sought to test whether oxidative stress leads to mitochondrial uncoupling in skeletal muscle in vivo. We subjected mice to two different doses of Paraquat (PARA), a redox cycling agent known to stimulate production of reactive oxygen species (ROS) in mitochondria. After two weeks of treatment, we used magnetic resonance spectroscopy to measure ATP flux and optical spectroscopy to measure oxygen uptake to determine the P/O value in the distal hind limb. PARA treatment led to a significant dose dependent decrease in mitochondrial P/O values in vivo (P<0.05), supporting the hypothesis that oxidative stress leads to mitochondrial uncoupling. We are currently investigating the mechanism of this reduced coupling using a UCP3 knockout mouse. Early results indicate no change in the coupling of resting skeletal muscle in the absence of UCP3. Studies are currently underway to determine if the presence of UCP3 is necessary for oxidative stress‐induced uncoupling in vivo.This work was supported by NIH grants AG022385 and AG028455 and the Ellison Medical Foundation.
Low RIP140 Expression Partially Restores Metabolic Flexibility in L6 Muscle Cells Treated with High FA
Authors: Constantinescu Silvana , Turcotte Lorraine P. 
Published: June 2021

To elucidate the role of RIP140 in the regulation of fatty acid uptake (FAU) and oxidation (FAO) and glucose uptake (GU) in insulin‐resistant muscle cells, L6 myotubes were transfected with RNAi to genetically silence a control sequence (CS) or RIP140 (RIP). Cells were then incubated ± palmitic acid (FA: 400μM, 12h) to induce insulin resistance followed by incubation ± insulin (I: 1000 nM) before measurement of glucose and FA kinetics. In line with the presence of insulin resistance, FA treatment raised basal GU (122.2±5.2% vs 230.0±18.8%; P<0.05) and obliterated the I‐induced increase in GU (P<0.05). FA treatment decreased basal FAU (107.1±3.7% vs 45.4±10.5%; P<0.05) and FAO (176.8±19.6 vs 82.7±13.9%; P<0.05). I‐induced FAU and FAO was reduced by 24% (P<0.05) and 44% (P<0.05) with FA treatment. Silencing of RIP140 in FA‐treated cells did not affect basal GU or FAO but it was associated with higher FAU (45.4±10.5% vs 75.0±12.1%; P<0.05). With I stimulation, silencing of RIP140 in FA‐treated cells was associated with higher GU (29%; P<0.05), lower FAU (35%; P<0.05) and no change in FAO (P<0.05). Our data show that reduced RIP140 expression in FA‐treated muscle cells rescues insulin‐mediated GU and basal FAU but does not affect basal or I‐mediated FAO. Together, our results indicate that low RIP140 expression may partially restore insulin sensitivity when insulin resistance is induced by high FA treatment.USC Women in Science and Engineering, USC Integrative and Evolutionary Biology and USC Zumberge Research Innovation Fund
ATM plays a role in insulin‐stimulated phosphorylation of AS160 independent of Akt in mouse soleus muscle
Authors: Ching James Kain , Armon Jennifer L. , Renth Allyson , Collins Roy L. , Fisher Jonathan S. 
Published: June 2021

Recent data have emerged suggesting that ataxia telangiectasia mutated (ATM) is a factor that modulates insulin signaling. However, the manner in which ATM impacts the insulin signaling pathway has not been addressed in skeletal muscle. The aim of this study was to determine how ATM impacts proximal insulin signaling in mouse soleus muscle. Isolated soleus muscles from wild type (ATM+/+) mice, ATM deficient (ATM−/−) mice, and mice lacking one functional ATM allele (ATM+/−), were incubated with or without insulin (100 nM). Western blot analysis showed that insulin‐stimulated phosphorylation of Akt S473 and Akt T308 was normal in ATM−/− and ATM +/− mice. Interestingly, however, insulin‐stimulated phosphorylation of Akt substrate of 160 kDa (AS160) was prevented in muscles from ATM−/− mice. Similarly, soleus muscles from ATM+/− mice showed a significant decrease in insulin‐stimulated phosphorylation of AS160, indicating that even partial loss of ATM is sufficient to impair insulin signaling at AS160. Our data suggest that ATM modulates insulin signaling leading to phosphorylation of AS160, independent of Akt.This work is supported by NIH grant R15DKO80437
Myosin loss and muscle wasting in an experimental ICU model: Underlying mechanisms
Authors: Larsson Lars , Ochala Julien , Diaz Monica Llano , Gustafson Ann‐Marie , Dworkin Barry R , Nair Sreekumaran K , Gautel Mathias 
Published: June 2021

The muscle wasting and impaired muscle function associated with critical llness in ICU patients have negative consequences for recovery from primary disease, but are also the most persistent and debilitating of problems for ICU survivors years after hospital discharge. This study aims at improving our understanding of the mechanisms underlying the muscle wasting in ICU patients by conducting time‐resolved analyses of skeletal muscle structure and function together with measurements of protein synthesis rate, myofibrillar protein and gene expression and intracellular signaling in response to post‐synaptic block of neuromuscular transmission (NMB), sedation, mechanical ventilation and muscle unloading at durations varying from hours to two wks by using a unique experimental rat ICU model. Skeletal muscle structure and function were well maintained during the first four days, followed by a dramatic and progressive decline in muscle size and function. The preferential loss of the molecular motor protein myosin and impaired forcegenerating capacity (specif force) are the major causes underlying the impaired skeletal muscle function in the ICU model. Muscle unloading due to lack of weightbearing (external unloading) and muscle membrane depolarization (internal unloading) are forwarded as very important underlying factors.Supported by the Sweish Research Council and AFM
Phenol increases twitch tension by increasing Ca2+ transients in intact single Xenopus myofibers
Authors: Nogueira Leonardo , Knapp Amy E. , Hogan Michael C. 
Published: June 2021

Phenol is a neurolytic agent used for management of spasticity in patients with neuron injury. The effects of phenol on skeletal muscle function are unknown. We investigated the effects of phenol on force production and Ca2+ release in intact single Xenopus skeletal muscle fibers. To determine the relationship between force production and Ca2+ release in the absence and presence of phenol (0.005% – 0.05% w/v), intact single muscle fibers were dissected and microinjected with FURA‐2 followed by electrically stimulated single‐twitches and tetanic contractions (1–150Hz, 250 ms train, 2 ms stimulus, 8–10V). During single‐twitches at activation frequencies that elicited far less force than maximal, phenol reversibly increased the force and peak Ca2+ ratios compared to the untreated condition in a concentration‐dependent manner (from 10 ± 4% to 57 ± 10% of maximum tetanic force and from 47 ± 11% to 68 ± 10% of the maximum FURA‐2 ratio, both at 0.05% phenol, P<0.01). At higher concentrations (>0.05%), phenol completely blocked force production. These results suggest that phenol increases twitch force by increasing Ca2+ release from the sarcoplasmic reticulum in skeletal muscle fibers. This mechanism remains to be elucidated; however, phenol may prove to be a new agent used to study skeletal muscle function.Supported by NIH grant 1P01HL091830‐01A18101
Pravastatin normalizes peripheral sympathetic hyperactivity in the Spontaneously Hypertensive Rat by reducing cardiac angiotensin 2 levels
Authors: Herring Neil , Lee Chee Wan , Sunderland Nicholas , Wright Kathryn , Paterson David J 
Published: June 2021

Hypertension is associated with heightened sympathetic tone and increased renin‐angiotensin system activity. Recent evidence suggests statins can reduce angiotensin 2 (AT2) signalling independent of cholesterol lowering. We therefore investigated whether 2 weeks treatment with pravastatin (100mg/L in drinking water, n=41 v's n=32 control) could alter the heart rate (HR) response to sympathetic nerve stimulation (SNS) via an AT2 dependent pathway in the spontaneously hypertensive rat (SHR). Pravastatin significantly (p<0.05) lowered resting HR in‐vivo despite unaltered LDL cholesterol levels. In right atrial preparations pravastatin significantly reduced release of 3H labelled norepinephrine (NE) during field stimulation to levels observed in WKY rats. In atria/right stellate ganglion preparations, the HR response to SNS was also significantly reduced by pravastatin whilst the HR response to NE remained similar. Pravastatin significantly reduced left ventricular AT2 levels whilst levels of the AT2 receptor (ATR1) assessed by Western blotting remained similar. The ATR1 antagonist losartan (5μM) equalised release of 3H‐NE to comparable levels in treated and untreated SHRs. This suggests that pravastatin reduces levels of local cardiac AT2 in SHRs and prevents its facilitatory effect on NE release thereby normalizing sympathetic hyper‐responsiveness.Supported by the British Heart Foundation