bluuebunny/crossref_metadata_2025_split huggingface dataset:
Amplification of Endothelium‐Dependent Vasodilatory Signaling in Contracting Skeletal Muscle of Humans: Role of Inwardly Rectifying Potassium Channels
Authors: Hearon Christopher M , Luckasen Gary J , Larson Dennis G , Dinenno Frank A 
Published: November 2023

The local vasodilatory response to muscle contraction is due in part to the activation of inwardly rectifying potassium (KIR) channels and subsequent smooth muscle cell hyperpolarization. In addition to direct activation of KIR channels via elevated extracellular potassium, KIR channels may function as “amplifiers” of electrical signals originating from the endothelium and thus augment vasodilatory responsiveness to endothelium‐derived hyperpolarizing signals. In this study, we tested the hypothesis that exercise will selectively amplify vasomotor responses to the endothelium‐dependent vasodilator acetylcholine (ACh) and that this effect will be mediated in part by activation of KIR channels.MethodsIn a total of 15 young adults, we measured forearm blood flow (Doppler ultrasound) and calculated changes in vascular conductance (FVC) to local intra‐arterial infusion of ACh or sodium nitroprusside (SNP) during: 1) control resting conditions, 2) mild handgrip exercise (5% maximum voluntary contraction [MVC]), or 3) pharmacologically induced vasodilation (either by ACh or SNP infusion) to match the level of hyperemia observed during mild exercise, thus serving as a “high flow” resting condition. In the case of ACh, similar trials were performed before and after blockade of KIR channels via infusion of barium chloride, or pharmacological activation of KIR channels via infusion of potassium chloride (KCl).ResultsMild handgrip exercise significantly augmented the peak vasodilatory response to the endothelium‐dependent vasodilator ACh (Δ FVC: control: 116 ± 13; exercise: 253 ± 19 ml/min/100mmHg; P<0.01; +124 ± 12%) but not the endothelium‐independent vasodilator SNP (Δ FVC: control: 144 ± 33; exercise: 116 ± 21ml/min/100mmHg; P=NS). There was no effect of high flow per se on peak vasodilatory response to ACh or SNP (Δ FVC: ACh: 143 ± 18; SNP: 125 ± 37 ml/min/100mmHg; both P=NS vs. respective control). Blockade of KIR channels attenuated the exercise‐induced augmentation of ACh‐mediated dilation (Δ FVC: control: 189 ± 24; exercise: 198 ± 19 ml/min/100mmHg; +9 ± 12%). In a follow up study, direct pharmacological activation of KIR channels via infusion of KCl amplified peak ACh‐mediated vasodilation relative to control ACh infusion (Δ FVC: control: 97 ± 15 vs. 142 ± 16 ml/min/100mmHg; respectively; +50± 9%). These findings provide evidence that muscle contractions amplify endothelium‐dependent vasodilatory signaling via activation of KIR channels in humans. Further, these studies support the idea that KIR channels may act as “amplifiers” of endothelium‐dependent hyperpolarization and that this may be an important mechanism contributing to the normal vasodilatory response to exercise.Support or Funding InformationHL119337, HL095573
Endothelial Dysfunction following Prolonged Sitting is Mediated by a Reduction in Shear Stress
Authors: Restaino Robert M. , Walsh Lauren K. , Morishima Takuma , Vranish Jennifer R. , Martinez‐Lemus Luis A. , Fadel Paul J. , Padilla Jaume 
Published: November 2023

We and others recently reported that prolonged sitting impairs endothelial function in the leg vasculature; however, the mechanisms remain unknown. Herein, we tested the hypothesis that a sustained reduction in flow induced shear stress is the underlying mechanism by which sitting induces leg endothelial dysfunction. Specifically, we examined whether preventing the reduction in shear stress during sitting would abolish the detrimental effects of sitting on popliteal artery endothelial function. In 9 young healthy men, bilateral measurements of popliteal artery flow‐mediated dilation (FMD) were performed before and after a 3‐hour sitting period during which one foot was submerged in 42°C water (i.e. WETFOOT), while the contralateral leg remained dry and served as internal control (i.e., DRYFOOT). Local heating is an effective stimulus for dilating the skin circulation and increasing limb vascular conductance and thus, shear stress without producing systemic cardiovascular effects. During sitting, popliteal artery mean shear rate was significantly (P<0.05) reduced in the leg of the DRYFOOT (pre sit: 44.1±4.9s−1, post sit: 25.4±3.8s−1) and sustained in the leg of the WETFOOT (pre sit: 39.6±3.7s−1, post sit: 40.7±5.5s−1). Popliteal artery FMD was impaired after 3 hours of sitting in the leg of the DRYFOOT (pre sit: 5.9±0.9% vs. post sit: 2.9±1.0%) but not WETFOOT (pre sit: 7.3±1.7% vs. post sit: 10.6±2.0%). Collectively, these data demonstrate that preventing the reduction of flow induced shear stress during sitting with local heating abolishes the impairment in popliteal artery endothelial function. Thus, a reduction in shear stress mediates sitting‐induced leg endothelial dysfunction.Support or Funding InformationSupport: NIH K01 HL‐125503 and R21 DK‐105368 (JP)
Vascular Responses to Hypovolemic Pressure Challenge in Individuals with Down Syndrome
Authors: Wee Sang Ouk , Rosenberg Alexander J. , Kanokwan Bunsawat , Griffith Garett , Baynard Tracy , Fernhall Bo 
Published: November 2023

Aging is associated with altered vascular and autonomic function. Individuals with Down Syndrome (DS), experience premature aging, and exhibit autonomic dysfunction. Moreover, limited evidence suggests a link between autonomic dysfunction, arterial stiffness and vascular responsiveness to sympathoexcitation in individuals with DS, but this still remains unclear.PurposeTo examine the differences in vascular responsiveness, specifically changes in arterial elastic properties, during sympathoexcitation using lower body negative pressure (LBNP) in individuals with and without DS.MethodsTwenty four volunteers (DS=12, 24 yrs; Control=12, 23 yrs) participated in this study. Changes in vascular indices (β‐stiffness and elastic modulus (Ep) by carotid ultrasonography) were measured before, during and after LBNP (−20 mmHg).ResultsIndividuals with DS showed lower VO2peak (25.0 ± 1.7 vs. 42.5 ± 1.7 ml/kg/min for DS and controls, respectively) and higher BMI (23.1± 1.7 vs. 31.9 ± 1.8 kg/m2 for controls and DS, respectively) (p<0.05). However, there was no group differences and no changes with LBNP in vascular or hemodynamics indices.ConclusionsOur results demonstrated a lack of vascular responsiveness to sympathoexcitation in both individuals with and without DS. These findings may have been influenced by a lack of statistical power.

Hemodynamics and Arterial Stiffness

DS (N = 12)
Control (N = 12)

Baseline
LBNP (‐20mm Hg)
Recovery
Baseline
LBNP (‐20mm Hg)
Recovery

Carotid SBP (mmHg)
132 ± 6
129 ± 5
131 ± 5
125 ± 6
119 ± 5
124 ± 4

Carotid DBP (mmHg)
73 ± 3
74 ± 3
71 ± 3
75±3
74 ± 2
76 ± 3

Carotid MAP (mmHg)
94 ± 4
94 ± 3
93 ± 3
96 ± 3
93 ± 3
97 ± 3

β‐stiffness
5.44 ± 0.59
5.48 ± 0.37
5.78 ± 0.60
6.02 ± 0.56
6.59 ± 0.35
5.99 ± 0.57

Ep
71.22 ± 7.65
71.72 ± 4.57
72.94 ± 6.88
78.70 ± 7.26
82.80 ± 4.34
77.75 ± 6.52

Mean ± SEM, Significance level, p <0.05
Exercise Training Induced Regulation of Muscle Mitochondrial Dynamics
Authors: Fix Dennis K. , Hardee Justin P. , Gao Song , Hetzler Kimbell L. , Carson James A. 
Published: November 2023

IntroductionExercise training is a potent stimulator of muscle oxidative metabolism, which is tightly coupled to mitochondrial biogenesis, dynamics, and mitophagy. Mitochondrial dynamics involves the coordinated processes of fission and fusion. The IL‐6 family of cytokines can activate intracellular signaling pathways, such as STAT3, through the binding of their receptor complexes involving glycoprotein 130 (gp130). While systemic IL‐6 signaling can alter the expression of proteins related to mitochondrial dynamics, gp130 regulation of mitochondrial dynamic protein expression by exercise requires further investigation. The purpose of this study is to examine exercise training induced regulation of skeletal muscle mitochondrial dynamics.MethodsMale, C57BL/6 (B6; N=18) and skeletal muscle‐specific gp130 knockout (skm‐gp130 KO; N=12) mice were assigned to either cage control (CC) or treadmill exercise training (EX) beginning at 6 weeks of age. EX mice performed 6 weeks of treadmill exercise (5% incline, 18 m/min, 55 min/d, 6 d/wk) and were sacrificed 48 hours after the last training session. Gastrocnemius protein expression of mitochondrial dynamics and mitophagy by Western blot.ResultsExercise‐induced improvements in oxidative capacity were accompanied by increased muscle gp130 protein expression regardless of genotype. In B6 mice, EX training increased Fis1 protein expression and decreased Mfn‐1 protein expression. Interestingly, skm‐gp130 KO increased Fis‐1 protein expression and decreased Mfn‐1 protein expression. There were no further effects of EX on Fis1 or Mfn‐1 protein expression in skm‐gp130 KO mice. EX and and skm‐gp130 KO increased Beclin‐1 protein expression, and was further increased by exercise in skm‐gp130 KO.ConclusionsOur results demonstrate that skeletal muscle gp130 knockout did not block the induction of muscle oxidative capacity by treadmill exercise training. We found that the deletion of skeletal muscle gp130 altered protein expression related to mitochondrial fission, fusion, and mitophagy. These findings indicate that the gp130 receptor may be involved in the regulation of mitochondrial dynamics. Future studies are required to establish a mechanistic role of gp130 in the regulation of mitochondrial dynamics.
Evidence for a novel role for eNOS in the regulation of hepatocellular mitophagy
Authors: Sheldon Ryan , Morris E. Matthew , Linden Melissa A. , Meers Grace M. , Thyfault John P. , Laughlin M. Harold , Rector R. Scott 
Published: November 2023

INTRODUCTIONConsistent with the well characterized role for endothelial nitric oxide synthase (eNOS) to stimulate mitochondrial biogenesis, we have previously demonstrated that eNOS knockout (eNOS−/−) mice have reduced hepatic expression of PGC1α and TFAM in association with reduced mitochondrial respiratory capacity in western diet‐induced nonalcoholic steatohepatitis (NASH). Interestingly, hepatic mitochondrial content was preserved in eNOS−/−relative to wild‐type (WT) mice. This led us to hypothesize that eNOS concurrently regulates mitophagy (mitochondrial autophagy).METHODSWT and eNOS−/−mice were fed either a control or western‐style diet (WD; 45% fat, 1% cholesterol, 17% sucrose) for 18‐weeks. Whole liver homogenate and isolated hepatic mitochondria were assessed for markers of autophagy (cleaved microtubule‐associated protein 1A/1B‐light chain 3 [LC3‐II]) and mitophagy (BCL2/Adenovirus E1B 19kDa Interacting Protein 3 [Bnip3]). In a separate cohort of chow‐fed mice, primary hepatocytes from WT and eNOS−/− were isolated and cultured for 5‐days in a collagen matrix. Mitophagic flux was assessed via LC3‐II and Bnip3 accumulation following treatment for 16‐hours with 10 μM chloroquine (CQ; an inhibitor of lysosomal acidification) and 1 μM carbonyl cyanide 3‐chlorophenylhydrazone (CCCP) to induce mitochondrial depolarization in the presence or absence of 500 μM free fatty acids (FFA; 250 μM oleate + 250 μM palmitate).RESULTSWD increased the mitochondrial localization of LC3‐II and Bnip3 in both genotypes (p < 0.05, diet main effect), suggesting that WD increased hepatic mitophagic activity. However, eNOS−/−mice had reduced LC3‐II in liver homogenate (−45%) and isolated mitochondria (−28%) and lower Bnip3 (−25%) content in liver homogenate (genotype main effect; p < 0.05). eNOS−/−primary hepatocytes exhibited a blunted accumulation of LC3‐II (−31%) and Bnip3 (−22%) following 16‐hours of CQ+CCCP treatment compared to WT cells, and failed to further respond to FFA exposure (+32% in Bnip3 in WT vs. eNOS−/− hepatocytes).CONCLUSIONSCollectively these data identify a hepatocellular autonomous function of eNOS in the regulation of mitophagy in response to metabolic insult. This suggests that dysregulation of hepatocellular eNOS may contribute to the accumulation of damaged mitochondria and to the etiology of NASH.Support or Funding InformationSupport: MU Life Sciences Pre‐doctoral Fellowship (RDS), AHA 14POST20110034 (EMM), NIH R01DK088940 (JPT), NIH HL‐36088 (MHL), VHA‐CDA2 IK2BX001299 (RSR).
RESISTIN ENHANCES THE CENTRAL EFFECTS OF LEPTIN ON RENAL SYMPATHETIC NERVE ACTIVITY
Authors: Habeeballah Hamza , Alsuhaymi Naif , Stebbing Martin , Jenkins Trisha , Badoer Emilio 
Published: November 2023

BackgroundLeptin is a well known hormone released from fat tissue and acts centrally to influence metabolic and cardiovascular functions. It increases renal sympathetic nerve activity (RSNA) and could be an important contributor to the abnormally elevated RSNA observed in obesity or overweight conditions. Resistin is also a hormone released from fat tissue and acts centrally to elicit effects on RSNA similar to those of leptin. The question arises as to whether resistin can enhance leptin's actions on RSNA. Although the brain nuclei activated by leptin are well known, there has not been a systematic investigation of those activated by resistin. We investigated the effects of acute central administration of leptin and resistin on RSNA. We also used Fos protein to quantify the number of activated neurons in the brain following each treatment.AimTo measure RSNA in response to leptin and resistin alone and in combination, and determine the effect on the distribution of Fos in autonomic brain nucleiMethodsRSNA, mean arterial pressure (MAP) and heart rate (HR) in anaesthetised Sprague‐Dawley male rats were recorded before and for 3 hours after intracerebroventricular saline (control, n=5), leptin (7 μg; n=5), resistin (7 μg; n=4) and the combination of both resistin and leptin (administered 15 minutes after resistin,n=6). At the end of the experiment the animals were perfused with 4% paraformaldehyde and immunohistochemistry was performed on brain sections.ResultsLeptin alone and resistin alone significantly increased RSNA (74±17%, 50±14% respectively) (P<0.0001 from saline). When resistin and leptin were combined there was a significantly greater increase in RSNA (163±23%; P<0.0001, compared to either drug alone). Changes in MAP and HR from pre‐drug levels were not significantly different between groups. The distribution of Fos‐positive cell nuclei elicited by resistin was similar to leptin. When leptin and resistin were combined, the increase in the number of Fos‐positive neurons in the arcuate nucleus, and in the lamina terminalis, was significantly greater than control.ConclusionThe findings show that leptin and resistin, combined, enhance RSNA as well as Fos production in the arcuate nucleus and lamina terminalis. Since leptin makes an important contribution to the elevated RSNA observed in obese / overweight conditions, the increased leptin and resistin levels may mean the contribution of leptin to the elevated RSNA in those conditions is enhanced.
Effects of Mirabegron, a β‐Adrenergic Receptor Agonist, on Metabolic and Cardiovascular Parameters in Obese Mice
Authors: Zanesco Angelina , da silva Carmem P Valga , Calmasini Fabiano B , Alexandre Eduardo C , Candido Tuany , Monica Fabiola T , Delbin Maria A 
Published: November 2023

BackgroundMirabegron, a selective β‐adrenergic receptor (β‐AR) agonist, has been approved for the treatment of overactive bladder. Given the pharmacological properties in activating β‐AR, studies of this compound on metabolism and adipose tissues could open new possibilities for obesity management.AimsThe objective of this study was to examine the effect of Mirabegron on adipose tissue, metabolic parameters and cardiovascular system in obese mice.MethodsC57BL/6J mice were divided into four groups: vehicle control group (CTR); control group treated with mirabegron (CTR‐Mira), obese fed with high‐fat diet (HFD) and obese fed with high‐fat diet treated with mirabegron (HFD‐Mira). High fat diet was given for 12 weeks. A 2‐week treatment of mirabegron (10 mg/kg) initiated at 11th‐week of the protocol design. The study lasted 12 weeks. Body weight, epididymal fat mass, energy intake, lipid profile, blood glucose, blood pressure and heart rate were evaluated. Concentration‐response curves to acetylcholine (ACh) and serotonin (5‐HT) were obtained in aorta with perivascular adipose tissue (PVAT+) or without (PVAT‐).ResultsA 2‐week treatment of mirabegron was effective in reducing epididymal fat in obese mice comparing with HFD group, approximately 25% (CTR: 0.2±01; CTR‐Mira: 0.1±0.01; HFD: 1.6±0.1; HFD‐Mira: 1.2±0.1 g) and body weight, approximately 9% % (CTR: 30.9 ± 0.5; CTR‐Mira: 29.8 ± 0.5; HFD: 41.8 ± 0.5; HFD‐Mira: 38.01 ± 0.2 g) even though energy intake was not affected by mirabegron in HFD‐Mira group. Atherogenic index based on lipid profile was reduced in HFD‐Mira group comparing with HFD group, approximately 122% (CTR: 0.33±0.02; CTR‐Mira: 0.31±0.04; HFD: 0.8±0.1; HFD‐Mira: 0.36±0.08). Mirabegron treatment failed to revert the increased blood glucose in HFD group. In addition, blood pressure and heart rate were not affected by any treatment (diet or mirabegron). As expected, HFD provokes an impairment of endothelium‐dependent relaxing responses in aorta with PVAT, at pEC50 level (CTR: 7.2±0.08; CTR‐Mira: 7.1±0.08; HFD: 6.7±0.1; HFD‐Mira: 6.4±0.3) that was not modified by mirabegron. In contrast, mirabegron increased the maximal responses to 5‐HT in aorta from HFD‐Mira group with PVAT (CTR: 69±8; CTR‐Mira: 77±11; HFD: 66±9; HFD‐Mira: 109±10 %). We found no alterations in the concentration‐responses curves to both agonists in aorta without PVAT in all groups.ConclusionsA 2‐week treatment of mirabegron was effective in reducing the body weight and epididymal adipose tissue in obese mice without interfering with blood pressure, heart rate and endothelium‐dependent relaxing responses to ACh. In addition, atherogenic index was also improved in obese mice treated with β‐AR agonist. Therefore, mirabegron would be an interesting compound to be examined in the management of obesity in clinical trial.Support or Funding InformationSao Paulo Research Foundation and CAPES
The Inwardly Rectifying Potassium Channel GIRK4 Plays a Role in Aldosterone Production in The Mouse Adrenal Cortex
Authors: Hardege Iris , O'Shaughnessy Kevin M 
Published: November 2023

ObjectiveDetermine the role of wild‐type GIRK4 in the mouse adrenal in relation to Aldosterone regulation.Aldosterone plays a key role in salt homeostasis and blood pressure, its dysregulation accounts for up to 10% of hypertension. Significant portions of these cases are caused by aldosterone producing adenomas (APAs) of the adrenal cortex, and have been shown to harbour mutations in the inwardly rectifying potassium channel GIRK4. Expression of GIRK4 has since been shown in the aldosterone producing zona glomerulosa (ZG) cells of the adrenal cortex. Although the role of these mutant GIRK4 channels have been well studied in vitro, little is known about the role of wild‐type GIRK4 in vivo. Here we utilize the GIRK4 −/− mouse to investigate the role of GIRK4 in aldosterone regulation and blood pressure.Typically aldosterone secretion from the ZG cells of the adrenal cortex is mediated by depolarization upon stimulation with angiotensin II. The presence of GIRK4 in ZG cells is thought to help maintain a hyperpolarized membrane potential post stimulation, and reduce spontaneous depolarization, thereby preventing autonomous aldosterone production.Paradoxically our pilot data has shown a decrease in CYP11B2 gene expression (1.82 fold, P<0.05) and plasma aldosterone levels (1.63 fold, P<0.05) in GIRK4 −/− mice compared to wild‐type animals (Figure). This suggests cells lacking GIRK4 maintain a hyperpolarized membrane potential, and hence GIRK4 is not solely responsible for hyperpolarization of the ZG cells of the adrenal cortex.In order to elucidate the molecular basis for this observation, we are conducting RNAseq analysis of adrenals from wild‐type and GIRK4 −/− mice. This will reveal transcriptomic changes that may explain the observed decrease in aldosterone production, as well as other potential pathways involved in aldosterone regulation in the adrenal cortex.Support or Funding InformationThis work was supported by the British Heart Foundation (PhD studentship to IH FS 12/78/29875)
Ventricular disfunction induces morphofunctional changes in adrenal glands
Authors: de Andrade Thúlio Ramos , Silva Juliane , Souza Leandro , Jordão Camila , Ferreira Tatiane , Negrao Carlos , Brum Patricia , Irigoyen Maria Claudia , Lacchini Silvia , Alves Maria Janieire 
Published: November 2023

ObjectivesTo assess whether ventricular dysfunction (VD) can influence the weight and morphology of adrenal gland in rats with and without deprivation of ovarian hormones.MethodsFemale rats of the Sprague Dawley strain (60 days old) randomly divided into 4 groups: intact ovaries + IM SHAM surgery (INT+SHAM, n = 9); Intact ovaries + VD after MI (INT+DV, n = 5); Ovariectomized + MI SHAM surgery (OVX+SHAM, n = 5), and Ovariectomized + VD after MI (OVX+VD, n = 5). The ejection fraction (EF) was assessed by echocardiography, it was considered VD when EF≤55%. The surgical procedure for myocardial infarction (MI) or SHAM was performed 30 days after OVX. Eight weeks after MI the EF was measured and after 12 weeks the animals were weighed and euthanized. The adrenals, were weighed (and this value corrected by body weight), were then processed histologically and the slices stained with H‐E. The photomicrographs were analyzed by Axion Vision® software, and the thickness of each zone of the adrenal cortex, the area of medulla and gland were measured. The results were expressed as mean±standard deviation, passed through 1 way ANOVA and considered significant if p≤0.05.ResultsBody weight (g) in groups INT+SHAM (318±18.5) and INT+VD (292±16.7) were similar and smaller than OVX+SHAM (368±30.7) and OVX+VD (372±44.3). The relative weight of the adrenal gland (%) was similar between groups INT+SHAM (0.017±0) and INT+VD (0.019±0) and higher, when compared to groups OVX+SHAM (0.013±0) and OVX+VD (0.011±0) ‐ there was no difference between the relative weight of adrenal glands of OVX+VD and OVX+SHAM groups. The thickness of glomerular zone (mm) was similar in OVX +SHAM (68.68±2.9) and OVX+VD (63.1±2.9) and higher than INT+SHAM (55.35±3.5); the OVX SHAM group (68.68±2.9) was higher than INT+VD (61.02±6.3). The thickness of the reticulated area was higher in INT+SHAM (311.1±49.5) when compared to groups INT+VD (234.8±23.7), OVX+SHAM (240.2±32.3) and OVX+DV (233.1±44.09) and similar between these. The medulla/total area ratio (%) was similar between INT+SHAM (0.090±0.01) and OVX+SHAM (0.091±0.01), and lower than INT+VD group (0.120±0.02) and OVX+VD (0.124±0.02) groups.ConclusionThe results show that the VD was efficient to induce morphological changes in adrenal gland.