bluuebunny/crossref_metadata_2025_split huggingface dataset:
Catecholamine secretion from the adrenal medulla is blunted in high‐altitude deer mice (Peromyscus maniculatus)
Authors: Scott Angela L , Pranckevicius Nicole A , Patal Paras , Nurse Colin A , Scott Graham R 
Published: November 2023

Chronic hypoxia stimulates the sympathetic nervous system and adrenal catecholamine (CAT) secretion, which helps to protect vital organs during low oxygen conditions. However, chronic sympathetic activation has also been associated with systemic and pulmonary dysfunction related to the extended elevation of circulating CATs. In this study, we compared the effects of chronic hypoxia exposure (6–8 weeks, 12 kPa O2) on CAT secretion from adrenomedullary chromaffin cells (AMCs) obtained from low‐versus high‐altitude populations of deer mice. Under normoxic conditions, acetylcholine released from the splanchnic nerve acts on nicotinic acetylcholine receptors (AChR) in the adrenal medulla, and results in CAT secretion into the circulation. Using carbon fiber amperometry, CAT secretion was measured in thin adrenal slices exposed to the AChR agonist, nicotine (10 or 50 uM). CAT secretion in response to low doses of nicotine (10 uM) was blunted in AMCs of lowland mice after chronic hypoxia exposure, but restored in hypoxic lowlanders when higher concentrations of nicotine (50 uM) were applied. In comparison to lowlanders CAT secretion from AMCs of the highland population, acclimated to either normoxic or hypoxic conditions, was significantly lower in response to both high and low doses of nicotine. The prominent reduction of CAT secretion in the adrenal medulla of the highland population across both environmental conditions suggests an alteration in nicotinic AChR function and/or a reduction in CAT secretory function in these mice. Further examination of AMCs in low‐versus high‐altitude deer mice revealed lower expression of key enzymes in catecholamine synthesis (particularly DOPA decarboxylase), as well as lower plasma levels of adrenaline, in the highland population. Our findings suggest that high‐altitude adaption in deer mice suppresses catecholamine secretion from the adrenal gland in hypoxia, which appears to involve a reduction in catecholamine synthesis and storage.Support or Funding InformationFunded by the Natural Sciences and Engineering Research Council (NSERC) of Canada. Angela L Scott is a NSERC Postdoctoral Fellow.
The Effects of Sildenafil, phosphodiesterase 5 inhibitor, on the Expression of α and β Myosin Heavy Chains in Hypoxia induced Right Ventricular Hypertrophy in Mice
Authors: Khatib Said Younes , AlJanabi Mukhallad Mohammed 
Published: November 2023

IntroductionMyosin heavy chains are known to be the main contractile protein in muscles. It is present in the cardiac muscle in two forms alpha (α), and beta (β). The contractile properties of the cardiac muscle are determined by the types of myosin heavy chain (MHC) present in the muscle. The expression of these MHCs can be altered by many physiological and pathological conditions. In this study we investigated the effect of sildenafil on MCHs isoforms in hypoxia induced right ventricular hypertrophy in mice.Method and resultsRight ventricular hypertrophy was induced by exposing the animals to low oxygen tension (11%) in normobaric chamber for 20 days. 32 mice were distributed randomly into: 10 as control (C). 10 were exposed to hypoxia for 20 days without sildenafil treatment (I) and 12 were given sildenafil orally at dose of 30 mg.Kg‐1.day‐1 while they were exposed to hypoxia for 20 days (II). MCHs isoforms were detected using two ELISA kits containing antibodies against α and β MHCs. Compared to control group C, mice exposed to hypoxia (group I) showed a significant increase in right ventricle weight to body weight mg/g ratio, (0.89±0.13 in group C and 1.3± 0.3 in group I, P> 0.001) but significant changes in ratio of group II, (0.91+ 0.15). Expression of β MHC isoform was significantly decreased in mice group I (P>0.001), while mice exposed to hypoxia and treated with sildenafil showed significant shift of MHC towards β isoform (P>0.000). Hypertrophied right ventricle expresses more α myosin heavy chain and this is beneficial to the heart since hearts with more α MHC have more ATPase activity and powerful and fast contraction.Conclusionsildenafil reduced hypoxia induced right ventricular hypertrophy and caused a shift in MCH towards β form which makes the heart contraction more economical (i.e using less ATPase).
Cardiac Hypertrophy and Ventricular Contractility in Rats Exposed to Neonatal Supplemental Oxygen and High Fat Diet
Authors: Chandrasekar Shreya , Vellookunnel Shilpa , Hoover Michael , Sturgeon Madison , Murphy Austin , Bates Melissa 
Published: November 2023

Premature birth represents about 13% of live births each year. Since lungs of these infants are underdeveloped, they receive supplemental oxygen right after birth, but little is known about its effects on the development of normal physiological responses and whether it impacts long‐term cardio‐metabolic function. Based on previous studies from our lab that showed increased pulse wave velocity in 12 month old rats exposed to neonatal supplemental oxygen, we hypothesized that neonatal exposure to supplemental oxygen causes cardiac hypertrophy and decreased left ventricular contractility. We also hypothesized that these effects to supplemental oxygen would be enhanced by 10 weeks on a high fat diet. To test the hypothesis, we used our rat model of OXY and CON rats exposed to FlO2=0.80 and 0.21 respectively, for 8 days post‐birth. Two months after birth, these OXY and CON rats were randomly assigned to either a high fat diet (60% of calories from animal fat) or low fat diet for 10 weeks during which their weights and caloric consumptions were monitored. After 10 weeks, a Miller conductance catheter was inserted into the left ventricle to obtain pressure volume loops and end‐systolic pressure volume relationship, which was used to evaluate contractility. OXY rats tended to have larger left ventricles (1.40±0.24 g vs 1.18±0.08g) and OXY rats fed a high fat diet showed greater average weight gain than CON rats on the same diet. There was no difference in contractility. These data suggest that neonatal supplemental oxygen may promote left ventricular hypertrophy and weight gain.Support or Funding InformationThe University of Iowa Start‐Up Fund
Left Ventricular Remodeling and Cardiac Dysfunction in Long‐Term Burn Survivors
Authors: Nasirian Aida , Nelson Michael , Kouda Ken , Romero Steven , Adams Amy , Jaffery Manall , Cramer Matthew , Moralez Gilbert , Kowalske Karen , Phelan Herb , Wolf Steven , Merz Noel Bairey , Crandall Craig 
Published: November 2023

Burn injury is characterized by increased morbidity and mortality and decreased quality of life. Our group has shown that ~75% of burn survivors (beyond 2 years post‐recovery), having 15 to 75% of their body surface area (BSA) grafted, have a maximal oxygen uptake (VO2max) in the lowest 20th percentile rankings, relative to sex and age adjusted non‐burned individuals. The exact mechanism responsible for this impairment remains unclear but may be related to adverse cardiac remodeling and left ventricular dysfunction. To address this knowledge gap, we recruited 16 burn survivors (age: 40 ± 20 years; female/male: 8/8), with burns ≥ 20% BSA. Left ventricular (LV) morphology and global function were assessed by cardiac magnetic resonance imaging (cMRI). Additionally, myocardial strain analysis, a more sensitive indicator of LV function, was assessed by novel MR tissue tracking of conventional CINE images. The major novel findings of this investigation are twofold. First, the burned subjects' LV mass was ≥ 2 standard deviations less than published normative values (105.8 ± 12.4 vs. 147 ± 20, burn vs. published norm, respectively). Second, all three principal strains (radial, circumferential, longitudinal) were impaired in burn survivors compared to a group of healthy reference controls (radial: 40.0 ± 1.5% vs. 52.4 ± 1.8%; circumferential: −19.8 ± 0.6% vs. −23.8 ± 0.5%; longitudinal: −20.2 ± 0.5% vs. −23.1 ± 0.6%, burn vs. control, respectively; all P<0.05). Taken together, these novel and innovative findings suggest that burn‐injuries lead to severe cardiac atrophy and impaired LV systolic function, which persist well beyond the recovery period. More work is needed to define mechanisms contributing to this adverse response, with a goal to attenuate/eliminate these adverse changes.Support or Funding InformationThis work is supported by: NIH – R01GM068865
Environmental Enrichment Alters the Impact of Social Stress on the Cardiovascular System
Authors: Normann Marigny , McNeal Neal , Colburn William , Dagner Ashley , Ihm Elliott , Toghraee Amir , Woodbury Matthew , Grippo Angela J 
Published: November 2023

Stress has been linked to negative cardiovascular consequences in both humans and non‐human animals, such as an increased risk of cardiovascular disease (CVD) and mortality, as well as an increase in depressive and anxiety related behaviors. To combat the effects of stress, research has incorporated environmental enrichment (EE) into animal models of stress. EE involves exposure to novel items and other species‐relevant engaging stimuli such as nesting material and toys. EE has cognitive benefits, such as improving recognition, acquisition and retention of information; as well as psychological benefits, such as reducing anxiety‐related behaviors. This study utilized the prairie vole to investigate the potential protective effects of EE on behavior and cardiovascular function. Prairie voles have a social structure similar to humans, including social monogamy and co‐parenting of offspring, which are rare characteristics in rodents. In this study, female prairie voles were surgically implanted with radiotelemetry transmitters to measure continuous heart rate and heart rate variability [using standard deviation of normal‐to‐normal intervals (SDNN Index) and respiratory sinus arrhythmia (RSA)]. Each female was paired with a male partner for five days followed by a period of isolation for an additional five days. The females were subsequently placed into one of three conditions for ten days: (a) isolation in a standard cage, (b) isolation in an EE cage, or (c) re‐paired with their male partner. The females were then tested in the forced swim test (FST) for five minutes as an index of depressive behavior. Cardiovascular measures were recorded during all phases of the experiment. All animals experienced negative cardiovascular effects of isolation. During exposure to the various treatment conditions, heart rate in the EE and re‐paired groups returned to baseline, but remained elevated in the prolonged isolation group. Similar effects were found for RSA. SDNN Index was increased in the EE group (relative to baseline and isolation), but remained similar to the isolation phase under both the prolonged isolation and re‐paired conditions. In the FST, the animals in the prolonged isolation group spent twice as much time immobile than the EE or repaired groups, which were comparable, indicating lower levels of depressive behaviors in the EE and re‐paired groups. These results suggest that EE may be as beneficial for an animal's behavioral and cardiovascular health as being re‐paired with a previously socially‐bonded partner. EE or a similar non‐social experience may attenuate psychological and physiological consequences of social stress in humans.Support or Funding InformationHL112350
Exposure to PM2.5 In Utero Contributes to Early Adult Cardiac Dysfunction
Authors: Tanwar Vineeta , Adelstein Jeremy , Grimmer Jacob , Youtz Dane , Wold Loren 
Published: November 2023

ObjectiveFine particulate matter (PM2.5) exposure during developmental is strongly associated with adverse cardiovascular outcomes at adulthood. The present study was designed to investigate the effects of in utero exposure to PM2.5 on cardiac function in 14 day old pups.MethodsFemale FVB mice were exposed either to filtered air (FA) or PM2.5 at an average concentration of 73.61μg/m3 for 6h/day, 7days/wk (mimicking exposure in a large industrial area) throughout pregnancy. To examine cardiac function, male offspring at 14 days of age underwent baseline echocardiographic assessment. Following sacrifice, cardiomyocytes were isolated to assess in vitro cardiomyocyte sarcomere function using the IonOptix system. LV tissue from a separate group of mice was used to isolate protein for western blot analyses.ResultsMice exposed to PM2.5 during the in utero period demonstrated decreased percentage fractional shortening (%FS). Isolated cardiomyocyte function illustrated reduced peak shortening (%PS), decreased 360/380 ratio of fura 2 fluorescence and increased fluorescence decay time constant (tau). Western Blot analyses showed increased expression of SERCA and p‐PLN and decreased expression of CaV1.2 and NCX in 14 day old in utero PM2.5 exposed mouse hearts compared to FA exposed hearts.ConclusionExposure to PM2.5 during the in utero period caused adverse effects on the developing fetus by modifying expression of Ca2+ signaling proteins leading to cardiac dysfunction, which is evident during the very early stages (14 days) of the postnatal period.Support or Funding InformationFunding for the project was provided by a grant from the National Institutes of Health (RO1ES019923) to LEW.
Specific Afferent Renal Denervation Improves Reduced nNOS in the Paraventricular Nucleus in Rats with Heart Failure
Authors: Zheng Hong , Liu Xuefei , Knuepfer Mark M , Patel Kaushik P 
Published: November 2023

Renal denervation (RDN) has been shown to restore endogenous neuronal nitric oxide synthase (nNOS) in the paraventricular nucleus (PVN), and at the same time reduce sympathetic drive during heart failure (HF), however the role of afferent versus efferent renal nerves in this response remains to be determined. The purpose of the present study was to assess the contribution of afferent renal nerves (ARN) in the nNOS within the PVN mediated sympathetic outflow in rats with HF. HF was induced in rats by ligation of the left coronary artery. Four weeks after surgery, selective afferent RDN (A‐RDN) was performed by bilateral perivascular application of capsaicin on the renal arteries. Seven days after intervention, A‐RDN was verified by lack of calcitonin gene‐related peptide in renal pelvic wall. A‐RDN reduced basal lumbar sympathetic nerve activity (LSNA) in rats with HF (8.5 ± 0.5 vs 17.0 ± 1.2 % of Max). nNOS‐positive cells immunostaining and ‐diaphorase staining were significantly decreased in the PVN of HF rats, findings that were ameliorated by A‐RDN. Microinjection of nNOS inhibitor L‐NMMA into the PVN resulted in a blunted increase in LSNA in HF, this response was improved after A‐RDN (ΔLSNA: 25.7 ± 2.4 vs 11.2 ± 0.9%). Resting ARN activity, expressed as a percent of peak ARN activity, was substantially increased in HF compared to sham rats (60.9 ± 2.2 vs 27.7 ± 4.4 %Amax). These results suggest that intact ARN contribute to the reduction of nNOS in the PVN, resulting in activation of the neurons in the PVN of rats with HF. Specific A‐RDN restores nNOS and thus attenuates the sympathoexcitation. Also, resting ARN activity is elevated in HF rats, which may highlight a crucial neural mechanism initiated from the kidney in the maintenance of enhanced sympathetic drive in HF.Support or Funding InformationThis work was supported by NIH grant P01 HL62222.
Insulin‐Like Growth Factor 1 Preserves Cardiac Function after Myocardial Infarction without Affecting Initial Ischemia and Reperfusion Injury
Authors: Heinen Andre , Nederlof Rianne , Raupach Annika , Reffelt Heiko , Gödecke Stefanie , Gödecke Axel 
Published: November 2023

Insulin‐like growth factor 1 (IGF1) preserves cardiac function after myocardial infarction (MI). The remodeling process after myocardial infarction is influenced by the extend of the initial infarction and regulated by multiple cardiac and non‐cardiac cell types. It is unknown whether the beneficial effect of IGF1 on cardiac function is the consequence of a reduction in early myocardial necrosis due to IGF1 receptor (IGF1R) signalling in cardiomyocytes.Inducible cardiomyocyte specific IGF1R KO and wild type mice (WT) underwent 45 min regional myocardial ischemia followed by 4 weeks of reperfusion. At reperfusion, mice received vehicle (Con) or IGF1 as bolus (40 ng/g, ip) followed by continuous infusion over 3 days using osmotic mini pumps (1 μg/g/d, sc). At baseline, there were no differences between WT and KO animals in left ventricular function (end diastolic (EDV), end systolic volume (ESV), and ejection fraction (EF)). IGF1 treatment improved cardiac function not only in WT mice (EF, week 4: 49±4% (IGF1) vs 36±8% (Con)), but also in KO mice (48±5% (IGF1) vs 35±5% (Con)). To investigate the effect of IGF1 on early ischemia and reperfusion injury, C57Bl6 mice underwent 45 min regional myocardial ischemia followed by 2 hours of reperfusion with and without IGF1 treatment. Infarct size staining showed no effect of IGF1 on infarct size (38±10% (IGF1) vs. 39±11% (Con)). In addition, IGF1 did not affect left ventricular function and myocardial damage in isolated perfused mouse hearts after global ischemia.Exogenous IGF1 treatment preserves cardiac function after myocardial infarction independent of cardiomyocyte specific signaling. The preserved function after IGF1 treatment is not caused by an effect on early ischemia and reperfusion injury indicating that IGF1 modulates the cardiac remodeling process in the subacute phase after MI.Support or Funding InformationFunded by the German Research Foundation (SFB1116/A06)
Impact of Methamphetamine on the Ischemic Hearts of Three Generations of Rats
Authors: Rorabaugh Boyd R. , Seeley Sarah L. , Stoops Thorne , Sprague Lisanne , Bui Albert D. , D'Souza Manoranjan 
Published: November 2023

Approximately 5 % of the United States population has used methamphetamine at some point in their lifetime. Methamphetamine is known to increase the risk of a myocardial infarction, but it is unclear whether methamphetamine alters the extent of myocardial injury. The first goal of this study was to determine whether repeated methamphetamine exposure alters the extent of injury in the ischemic heart. Adult rats received daily subcutaneous injections of methamphetamine (5 mg/kg) or saline for 10 days, and their hearts were subjected to an ischemic insult on day 11 using a Langendorff isolated heart apparatus. Hearts from methamphetamine‐treated female rats exhibited significantly larger infarcts and significantly suppressed postischemic recovery of contractile function compared to hearts from saline‐treated females. In contrast, infarct size and postischemic recovery of contractile function were unaffected by methamphetamine in males. The second goal was to determine whether prenatal methamphetamine exposure alters myocardial sensitivity to ischemic injury during adulthood. Pregnant rats (F0 generation) received daily injections of methamphetamine (5 mg/kg) or saline throughout the duration of their pregnancy. When the F1 pups reached 8 weeks of age, their hearts were subjected to an ischemic insult. Infarcts were significantly larger in adult female hearts that had been prenatally exposed to methamphetamine compared to control females that were prenatally exposed to saline. In addition, protein kinase C‐ɛ expression and Akt phosphorylation were decreased in hearts from methamphetamine‐exposed females. In contrast, methamphetamine had no impact on infarct size, PKC‐ɛ, or Akt phosphorylation in their male littermates. Others have reported that rat pups (F2) born to parents (F1) that were prenatally exposed to methamphetamine exhibit deficits in sensory‐motor coordination. Thus, F1 rats that had been prenatally exposed to methamphetamine were used as breeders to produce the F2 generation of rats. Hearts from F2 rats were subjected to an ischemic insult when they reached 8 weeks of age. We found no evidence for myocardial hypersensitivity to ischemic injury in the F2 generation that was not directly exposed to methamphetamine. These data provide evidence that a history of adult or prenatal exposure to methamphetamine worsens ischemic injury in the adult heart. This could have significant implications for people who have both ischemic heart disease and a history of adult or prenatal exposure to methamphetamine.Support or Funding InformationThis work was supported by an Ohio Northern University Bower and Bennet Endowment Award to BRR.
Deficiency of Ataxia‐telangiectasia Mutated Kinase Induces Autophagic Impairment Following Myocardial Infarction
Authors: Thrasher Patsy R. , Scofield Stephanie L.C. , Dalal Suman , Singh Mahipal , Singh Krishna 
Published: November 2023

Autophagy, a conserved physiological process, is typically triggered by nutritional stress and/or growth factor deprivation and ultimately results in the packaging of cellular components into autophagosomes. These autophagosomes then fuse to lysosomes to be degraded. Although often associated with nutrient deprivation, autophagy is suggested to play a significant role in cardiac remodeling, particularly following myocardial infarction (MI). Ataxia‐telangiectasia mutated kinase (ATM) is a 370 kDa threonine/serine kinase. Mutations in ATM cause a multisystemic disease known as Ataxia‐telangiectasia (AT). Although the role of ATM in cell cycle progression is well known, its role in autophagy is not yet completely understood. The present study tested the hypothesis that deficiency of ATM impairs autophagic response in the heart post‐MI. MI was induced in ~4 month old wild‐type (WT) and ATM heterozygous knockout (hKO) mice by ligation of the left anterior descending artery. The mice were sacrificed 4 hours following MI. Levels of microtubule‐associated protein light chain 3 (LC3), sequestosome 1 (p62), cathepsin D, and phosphorylation of Akt and glycogen synthase kinase 3β (GSK3‐β) were analyzed in the heart lysates using western blots. Ratio of LC3II/LC3I, marker of autophagy induction and autophagosome formation, was significantly lower in hKO‐sham when compared to WT‐sham group (P<0.05 vs WT‐sham; n=7). MI decreased LC3II/LC3I ratio in both groups with no significant difference between the two genotypes. Expression of p62, a marker of autophagic clearance, was significantly higher in hKO‐MI group when compared to hKO‐sham and WT‐MI groups (P<0.05 vs hKO‐sham and WT‐MI; n=6–7). Expression of mature cathepsin D, a lysosomal endopeptidase involved in autophagic clearance, was lower in hKO‐MI group when compared to hKO‐sham. Activation of Akt was lower, while activation of GSK3β was higher in hKO‐MI group when compared to hKO‐sham (P<0.05 vs hKO‐sham; n=6–7). These data suggest that 1) ATM deficiency down‐regulates autophagy in the heart at basal levels; 2) MI down‐regulates autophagy in both genotypes 4 h post‐injury as assessed by the ratio of LCII/LC3I; 3) ATM deficiency impairs autophagic response as indicated by the accumulation of p62 and decreased cathepsin D levels in ATM deficient hearts post‐MI; and 4) autophagic impairment during ATM deficiency involves Akt/GSK3β pathway. Thus, ATM deficiency results in impaired autophagic activity in the heart post‐MI via the involvement of Akt/GSK3β signaling.Support or Funding InformationSupported by Department of Veterans Affairs (BX002332), NIH R15HL129140 (NHLBI) and Institutional Research and Improvement account.