bluuebunny/crossref_metadata_2025_split huggingface dataset:
Exposure to Doxorubicin Modulates the Cardiac Response to Isoproterenol in a Sex‐Dependent Manner
Authors: Agostinucci Kevin , Grant Marianne K. O. , Melaku Wongel , Abdelgawad Ibrahim Y. , Zordoky Beshay N. 
Published: May 2022

IntroductionSubclinical cardiotoxicity occurs in cancer patients who receive low doses of anthracyclines such as doxorubicin (DOX), which can develop into overt cardiomyopathy when triggered by other cardiovascular stressors. Female rodents are protected from DOX‐induced cardiac dysfunction in experimental studies. However, the sex‐related differences in DOX‐induced increased susceptibility to later‐onset cardiovascular stressors are yet to be determined. Therefore, in the present study, we determined the effects of a low dose of DOX on the cardiac response to catecholamine stress induced by isoproterenol (ISO) in male and female mice. Since sex hormones are believed to mediate the sexually dimorphic response to DOX, we determined whether gonadectomy is able to reverse the observed response.MethodsFive‐week old intact and gonadectomized male and female C57Bl/6 mice were administered saline or DOX (4 mg/kg/week for 5 weeks by intraperitoneal injections). After a 5‐week recovery period, mice were administered daily subcutaneous injections of ISO (10 mg/kg) or saline for 14 days. Cardiac function was measured by echocardiography before, immediately after the first dose of ISO (stress echo), and following 14 days of daily ISO injections. Hearts were harvested and weighed at the end of the experiment.ResultsStress echo shows that the positive chronotropic effect of ISO was blunted in DOX‐treated male and female mice, while the positive inotropic effect is maintained. Following 14 days of daily ISO injections, saline‐treated male mice exhibited a hypertrophic response to ISO, indicated by an increase in the heart weight‐to‐tibia length, while DOX‐treated male mice did not. In addition, ISO caused more reduction of cardiac output in DOX‐treated male mice than that in saline‐treated male mice. On the other hand, both saline‐treated and DOX‐treated female groups exhibited a hypertrophic response to ISO. ISO treatment for 14 days did not cause significant reduction in cardiac output in either saline‐treated or DOX‐treated female mice. Similar experiments were performed in a cohort of gonadectomized male and female mice. Intriguingly, sexually dimorphic responses are observed in gonadectomized mice similar to those observed in intact mice.ConclusionExposure to DOX modulates the cardiac response to isoproterenol in a sex‐dependent manner. DOX treatment abrogates the adaptive hypertrophic response to ISO in male mice, making them more susceptible to declining cardiac output. Deprivation of sex hormones by gonadectomy did not reverse this sexual dimorphism, suggesting that other mechanisms are implicated. Further research is warranted to determine the mechanisms of this sexual dimorphism.
Characterization of molecular basis of anti‐platelet effect of daphnetin
Authors: Chaudhary Preeti K. , Kim Sanggu , Kim Soochong 
Published: May 2022

Coumarin derivates have been known for their antithrombotic, anti‐inflammatory, and antioxidant activities and daphnetin is one of the natural coumarin derivatives isolated from Daphne Korean Nakai. Although the pharmacological value of daphnetin is well documented in diverse biological activities, its antithrombotic effect is not studied till date.We investigated the functional role of daphnetin and its molecular basis on the regulation of platelet activation using murine platelets.In order to check the effect of daphnetin on GPVI‐mediated platelet response, we first measured the effect of daphnetin on collagen‐induced platelet aggregation and secretion. Collagen‐induced platelet aggregation and dense granule secretion were partially inhibited in the presence of daphnetin. Interestingly, 2‐MeSADP‐induced secondary wave of aggregation and secretion were completely inhibited in the presence of daphnetin. It has been known that 2‐MeSADP‐induced secretion and the resultant secondary wave of aggregation are mediated by positive‐feedback effect of thromboxane A2 (TxA2) generation, suggesting the important role of daphnetin on TxA2 generation in platelets. Consistently, daphnetin did not affect the 2‐MeSADP‐induced platelet aggregation in aspirin‐treated platelets where the contribution of TxA2 generation is blocked. Additionally, AYPGKF‐induced platelet aggregation and secretion were inhibited in the presence of daphnetin by blocking the positive‐feedback effect of TxA2 generation. Moreover, 2‐MeSADP‐induced TxA2 generation was completely inhibited in the presence of daphnetin confirming the role of daphnetin on TxA2 generation. Finally, 2‐MeSADP‐induced ERK phosphorylation was inhibited in the presence of daphnetin.We conclude that daphnetin plays a role in platelet function by inhibiting the TxA2 generation through the regulation of ERK phosphorylation.
Epigenetic regulation of Anoctamin1 in pulmonary arterial hypertension
Authors: D'Silva Natalie M. , Wang Eric R. , Fernandez‐Nicolas Ana , Vang Alexander , Yano Naohiro , Zimmer Alexsandra , Fedulov Alexey V. , Zhang Peng , Choudhary Gaurav 
Published: May 2022

Introduction/HypothesisPulmonary arterial hypertension (PAH) is associated with substantial pulmonary vascular remodeling wherein endothelial cells (ECs) within the lumen hyper‐proliferate leading to occlusive plexiform lesions. We previously reported that Anoctamin‐1 (ANO1) expression is increased in lung ECs from patients with PAH and is associated with increased EC proliferation. However, the mechanism of ANO1 expression regulation in PAH remains unclear. DNA methylation has been recognized as an important mechanism in gene regulation. In this study, we test the hypothesis that ANO1 expression in PAH is epigenetically mediated via DNA methylation.Methods/ResultsDNA was extracted from lung ECs of patients with idiopathic PAH (n=7) and controls (n=6), followed by Bisulfite Next‐Generation Sequencing (EpigenDx, MA) to determine DNA methylation profile in human ANO1 gene (Ensembl Gene ID: ENSG00000131620). We used 19 assays to cover 97 CpG sites in the human ANO1 gene, including regions of 5’‐upstream, 5’‐UTR, and different introns. Our data show that the methylation of 29 of 97 (30%) CpG sites in human ANO1 gene is significantly altered in lung ECs from PAH patients than that from control subjects. Among the significantly altered 29 CpG sites, the methylation at 22 CpG sites (76%) is significantly decreased. To determine whether decreased DNA methylation changes human ANO1 gene expression, we then exposed normal human pulmonary artery ECs to RG108, which is a DNA methyltransferase inhibitor that broadly reduces DNA methylation. Our data show that cells treated with RG108 for 72 hours have a significant 2‐fold increase in ANO‐1 mRNA expression in comparison to control cells, suggesting that decreased DNA methylation is sufficient to upregulate human ANO1 expression. We are developing CRISPR‐based approaches to target these identified CpG sites to determine the specific contribution of their methylation in regulation of human ANO1 gene.ConclusionsOur results demonstrate that DNA methylation in human ANO1 gene is significantly altered in PAH and reduction in DNA methylation may serve as a regulatory mechanism for ANO1 upregulation in settings of PAH.
Sex Differences and Cardiovascular Diseases in Down Syndrome
Authors: Flores Laura D. , Pryakhina Yana , Tomasson Michael H. , Bates Melissa L. , DeRuisseau Lara R. 
Published: May 2022

Congenital heart disease and cardiovascular disease are the leading causes of death for individuals with Down Syndrome (Ds) (Zhu, J.L., et al, 2013). A systematic review was conducted in June 2021 to address the research question “Are there reported sex differences for cardiovascular disease and cardiovascular physiological function in Ds”. Since there are significant sex differences in the risk of congenital heart and cerebrovascular disease in the general population, we hypothesized that these differences are present in the Ds population. Four domains were developed: congenital heart disease, baseline physiology and risk factors, heart disease and hypertension, and cerebrovascular disease. Exclusion criteria were applied to identify studies that addressed sex differences. The systematic review shows that women with Ds have a higher rate of congenital heart disease, coronary and cerebrovascular events and Moyamoya. Following the systematic review, a retrospective medical chart review of the University of Iowa Hospitals and Clinics was conducted using the platform TriNetX to identify the incidence of congenital and cardiovascular diseases in males and females. Relative risk was computed comparing Ds to general patient counts as well as men and women within each population. Ds patients did not share most of the sex differences in risk factors observed in the general population, however there are important sex differences in each domain that may contribute to earlier mortality in women with Ds. Several studies report women have an increased probability of developing risk factors for cardiovascular disease, such as obesity. Therefore, future research to understand the mechanism underlying these sex differences is necessary.ReferencesZhu, J.L., et al., Survival among people with Down syndrome: a nationwide population‐basedstudy in Denmark. Genetics in Medicine, 2013. 15(1): p. 64‐69.
Hypoxic Vasodilation is Augmented During the High versus Low Estrogen Phase of the Menstrual and Oral Hormonal Contraceptive Pill Cycle
Authors: Jacob Dain , Harper Jennifer , Ivie Clayton , Limberg Jacqueline 
Published: May 2022

BackgroundHypoxia elicits peripheral vasodilation to preserve oxygen delivery to metabolically active tissue. Hypoxic vasodilation, predominantly mediated by β‐adrenergic and nitric oxide mechanisms, is greater in adult female participants compared to adult male participants. Greater circulating estrogen in adult females has been purported to contribute to observed sex differences in hypoxic vasodilation. Nearly 80% of adult females in the United States will take oral hormonal contraceptive pills (OCPs) in their lifetime. Adult females taking OCPs exhibit greater β‐adrenergic receptor mediated vasodilation and nitric oxide production relative adult females with natural menstrual cycles (NC). Strategically utilizing the fluctuations of circulating estrogen that occur within a NC and OCP cycle, we aimed to examine the contribution of endogenous and exogenous estrogen on hypoxic vasodilation in female participants. We hypothesized female participants taking OCPs would exhibit greater hypoxic vasodilation relative to female participants with a NC. We further hypothesized hypoxic vasodilation would be greatest during the high estrogen (HE) phase of the menstrual or pill cycle compared to the low estrogen (LE) phase.MethodsTen female participants with a NC (25±1 yrs, 23±1 kg/m2) and ten female participants taking monophasic OCPs (24±1 yrs, 21±1 kg/m2) completed two study visits (IRB #2011312, NCT03606434). Participants were studied once during the LE phase of the menstrual or pill cycle (Cycle day: NC 3±1; OCP 5±1) and once during the HE phase of the menstrual or pill cycle (Cycle day: NC 15±1; OCP: 17±1). Forearm blood flow (venous occlusion plethysmography) and blood pressure (BP, finger plethysmography) were measured during normoxia and hypoxia (80% SpO2). Blood flow was normalized for BP and expressed as forearm vascular conductance (FVC).ResultsHypoxia elicited an increase in FVC (% change from baseline) that was greater during the HE phase (NC: 21±10%, OCP: 41±6%) of the menstrual/pill cycle compared to the LE phase (NC: 5±8%, OCP: 10±8%) in both NC and OCP participants (Main effect of phase, p<0.01; Main effect of group, p=0.16; Interaction of phase and group, p=0.30).ConclusionHypoxic vasodilation is augmented in the HE phase of the menstrual and pill cycle in healthy young female participants, independent of whether the hormone is endogenous (NC) or exogenous (OCP). These data further our understanding of the role of estrogen in hypoxic vasodilation. These findings may have clinical implications for the vascular response to hypoxia in conditions of low estrogen (i.e., postmenopause) and/or estrogen excess, and warrant further investigation.
The Effect of a Family History of Hypertension on Left Ventricular Mass When Controlling for Physical Activity Frequency
Authors: Matthews Evan L. , Callaghan Kerry N. , Hosick Peter A. , Brian Michael S. 
Published: May 2022

A positive family history of hypertension (+FHH) is associated with non‐exercise induced increases in left ventricular mass (LVM) and high‐normal blood pressure (BP). Regular physical activity (PA) can lead to non‐pathological increases in LVM, but evidence shows adults with elevated BP can decrease LVM with PA.PURPOSETo determine if a +FHH is associated with a greater LVM indexed to body surface area (BSA) compared to a negative family history of hypertension (‐FHH) group within a sample of young, mostly active healthy adults.METHODSHealthy young (18‐32yrs) participants self‐reported family history of hypertension (FHH) status and habitual moderate and vigorous PA frequency as days per week with at least 10 minutes of recreational activity. Participants then underwent an echocardiogram. Participants were excluded from this retrospective analysis if there was a prior diagnosis of cardiovascular‐related disease or hypertension. Within‐group normality of each variable was tested using the Shapiro‐Wilk test. Simple bivariate comparisons between groups were made using unpaired t‐tests for normally distributed variables and Mann‐Whitney tests when normality was violated. LVM/BSA was logarithmically transformed prior to ANCOVA testing due to non‐normality.RESULTSOf the 61 participants, 32 (M=11, W=21; non‐active=8) reported ‐FHH and the remaining 29 (M=13, W=16; non‐active=2) reported a +FHH. While still in the normal range, the +FHH group displayed greater systolic BP (‐FHH 112±12, +FHH 117±12 mmHg, p=0.043), but similar values for all other demographic information when compared to the ‐FHH group (age ‐FHH 23±3, +FHH 23±2 yrs, p=0.116; BSA ‐FHH 1.74±0.20, +FHH 1.74±0.21 m2, p=0.903; diastolic BP ‐FHH 68±6, +FHH 69±8 mmHg, p=0.287; resting heart rate ‐FHH 66±13, +FHH 64±9 bpm, p=0.578; moderate exercise frequency ‐FHH 1.8±1.8, +FHH 2.6±2.1 days/week, p=0.117; vigorous exercise frequency ‐FHH 2.5±2.2, +FHH 3.4±2.0 days/week, p=0.105). The +FHH group had greater LVM (‐FHH 129.5±41.8, +FHH 155.2±42.6 g, p=0.015) and LVM/BSA (‐FHH 73.5±17.4, +FHH 88.4±17.3 g/m2, p=0.004). Separate ANCOVA models accounting for moderate and vigorous PA found that FHH status independently predicted LVM/BSA and PA frequencies were a significant modifier (ANCOVA controlling moderate PA: FHH status p=0.004, partial η2=0.133; moderate PA p=0.020, partial η2=0.089), (ANCOVA controlling vigorous PA: FHH status p=0.004, partial η2=0.132; vigorous PA p=0.007, partial η2=0.117).CONCLUSIONThis preliminary analysis suggests that young adults with a family history of hypertension have elevated left ventricular mass compared to their counterparts without a family history of hypertension. This finding is independent of their habitual moderate and vigorous physical activity patterns.
IL‐10 Attenuates ER‐Stress Induced Apoptosis in Doxorubicin Treated Cardiomyocytes
Authors: Malik Akshi , Bagchi Ashim K. , Jassal Davinder S. , Singal Pawan K. 
Published: May 2022

Despite its antitumor efficacy, use of Doxorubicin (Dox) is limited by its cardiotoxic side effects. In Dox‐induced cardiomyopathy (DIC), a causal role of oxidative stress (OS) has gained a lot of traction. Among other subcellular changes, Dox causes vacuolization of the cytoplasm and dilation of endoplasmic reticulum (ER). Dox also causes an excessive production of reactive oxygen species as well as imbalance in redox state both of which can affect ER homeostasis and protein folding. An accumulation of unfolded/misfolded proteins triggers the unfolded protein response (UPR) in the ER, which activates transcriptional and translation pathways involving: a) Protein‐kinase like endoplasmic reticulum kinase (PERK); b) activating transcription factor 6α (ATF6α); and c) inositol requiring kinase1α (IRE1α) (Fig.1). Thus leading to the activation of ER chaperons, protein foldases and induce the expression of various genes, including X‐box binding protein 1 (XBP1). UPR plays an important role in the attenuation of protein translation, upregulation of chaperones and antioxidant expression, and thus maintains ER homeostasis. However, if UPR fails to restore ER homeostasis, ER stress‐initiated apoptotic signaling pathways are activated via CCAAT/enhancer homologous protein (CHOP), caspase‐12 activation, phosphorylation of c‐JUN NH2‐terminal kinase (JNK) and pro‐apoptotic gene expression. Understanding the role of these pathways of the ER under Dox treatment will highlight potential targets for new interventions as an adjunct therapy to restore ER functioning.In this study on isolated rat cardiomyocytes, we analyzed ER‐stress markers, spliced XBP1 mRNA, and ER‐apoptotic proteins. We also assessed protective effects of Interleukin‐10 (IL‐10) against Dox initiated ER‐induced apoptosis and overall ER‐stress. Dox significantly decreased the viability of cardiomyocytes and upregulated ER stress markers (GRP78, GRP94, and PDI). Interestingly, the exogenous administration of IL‐10, one hour prior to the exposure of cardiomyocytes to Dox for 24hrs, was found to be effective in suppressing the expressions of ER‐stress markers as well as ER‐related apoptotic proteins and preserved cell viability. Additionally, significant changes in downstream targets of IRE1α, XBP1 in IL‐10 treatment were recorded. IL‐10 significantly increased the expression of unspliced XBP1 (U), an inhibitor of spliced XBP1(S) particularly in Dox‐treated cells. This was followed by a reduction in the UPR mediated cell death in cardiomyocytes confirmed by a decrease in expression of GRP78, GRP94, and spliced XBP1 (S). IRE1 α arm of UPR initiates phosphorylation of JNK, which was reduced by IL‐10 in Dox treated cells. Dox also initiated activation of procaspase‐12, which is known to activate caspase‐3 and apoptosis. IL‐10 significantly reduced the activation of procaspase‐12 and cell death. These data suggest that IL‐10 provides protection against Dox‐induced cardiotoxicity by restoring ER homeostasis.
Alterations in hepatic albumin phosphorylation in patients with alcohol‐associated hepatitis and cirrhosis
Authors: Hardesty Josiah , Day Le , Warner Jeffrey , Zirnheld Kara , Warner Dennis , Jacobs Jon , McClain Craig , Kirpich Irina 
Published: May 2022

BackgroundAlcohol‐associated liver disease (ALD) encompasses a range of disease states including alcohol‐associated hepatitis (AH) and cirrhosis (AC), two severe clinical manifestations with high mortality due to compromised liver function. One key function of the liver is to synthesize and secrete albumin (ALBU), which plays a critical role in maintaining overall homeostasis. Hypoalbuminemia is a common feature of AH and AC; however, the contributing mechanisms are not established. Recently, S82‐ALBU phosphorylation via FA20A/C was shown to be required for hepatocellular release of ALBU. In this study, we hypothesized that hypoalbuminemia in AH and AC may occur in part due to hepatocellular retention secondary to compromised ALBU phosphorylation.MethodsProteomic and phosphoproteomic analyses were conducted using LC/MS/MS on liver biopsy samples from AH patients (n=34), AC patients (n=10), and non‐ALD controls (n=10). Further, AH patients were stratified by MELD score (Model for End‐stage Liver Disease) as follows: AH1 (MELD 17‐20), AH2 (21‐25), AH3 (26‐29), and AH4 (30‐37). Significantly changed proteins were correlated with MELD and compared between non‐surviving and surviving AH patients. One‐way ANOVA was used for comparisons between three groups (parametric), unpaired Student’s t‐test was used for two groups (parametric), and Pearson’s correlation was used for regression analysis. A p<0.05 was considered statistically significant.ResultsExpression of hepatic ALBU was elevated in AH and AC patients relative to non‐ALD controls and was positively associated with MELD in AH patients. Among AH severity groups, liver ALBU was further elevated from AH3 to AH4. We further observed that pS82‐ALBU, and its allosteric regulator FA20A (molecules involved in ALBU release), were reduced in AH and AC relative to non‐ALD controls. This would suggest that one mechanism of increased expression of hepatic ALBU may be due to inhibition of its release. These results for AH were confirmed in an independent cohort.ConclusionThis study demonstrated that hepatic ALBU levels are elevated in AH and AC, likely due to the loss of pS82 phosphorylation by FA20A/C, compromising hepatocellular ALBU release. Altered ALBU phosphorylation and subsequent release could be a key pathogenic mechanism of hypoalbuminemia in AH and AC. Further studies are warranted to test this hypothesis.
Glucocorticoid Hormones Regulate Pendrin Abundance and Subcellular Distribution
Authors: Abood Delaney , Pham Truyen Derek , Mullins Linda , Mullins John , Wall Susan 
Published: May 2022

IntroductionFollowing a low salt diet or aldosterone administration, total and apical plasma membrane pendrin abundance increase through a mechanism thought to involve aldosterone binding to the mineralocorticoid receptor (MR). However, in other cells, aldosterone binding to the MR depends on 11 b Hydroxysteroid Dehydrogenase 2 (11 b HSD2) to oxidize and inactivate glucocorticoids, which are also MR ligands. Although 11 b HSD2 abundance is low or possibly absent in intercalated cells (ICs), it’s abundance might be sufficient to inactivate glucocorticoids, making aldosterone the preferred ligand. If so, 11 b HSD2 gene ablation should reduce pendrin expression. Alternatively, the IC MR might preferentially bind another ligand such as glucocorticoids. To test these possibilities, we examined the effect of 11 b HSD2 gene ablation as well as glucocorticoid administration on pendrin abundance and subcellular distribution.Methods11 b HSD2 KO rats and age‐, and sex matched wild type rats on the same background (controls) were given either a diet with a low or high NaCl content for 10 days. Wild type mice were adrenalectomized and given a diet with either zero, normal, or high (i.e. stress level) doses of corticosterone or dexamethasone for 10 days. Pendrin total protein abundance and subcellular distribution were determined in rats and mice from each group by immunoblot and immunohistochemistry.ResultsBoth pendrin total protein abundance and pendrin’s relative abundance in the most apical region of the cell were greater in the 11 b HSD2 null than in control rats following either a NaCl‐replete or ‐restricted diet. Moreover, we observed a dose‐dependent increase in both total pendrin abundance and pendrin abundance in the most apical region of the cell following either dexamethasone or corticosterone administration, although the increase appeared greater in mice given corticosterone than dexamethasone.ConclusionsGlucocorticoids increase pendrin total protein abundance and its relative abundance in the most apical region of the cell. These results might explain, in part, why pendrin is upregulated in the known absence of 11 b HSD2.