bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract P517: Dialysis Vintage Longer Than Sixty Months Contributes to Increased Arterial Stiffness and Impaired Diastolic Function in Patients with End-stage Renal Disease
Authors: Calvez Valentin , Palladino Marco , Montefusco Giulio , Cesario Vincenzo , Fofi Claudia , Ciavarella Giuseppino M , Volpe Massimo , Savoia Carmine 
Published: July 2021

Hemodialysis (HD) may induce vascular stiffness through several mechanisms. We sought to determine the role of dialysis vintage (DV) on the development of cardiovascular alterations. We studied 14 patients in chronic HD and 24 newly diagnosed never treated hypertensive patients and 16 normotensive controls.
The patients in HD were divided in two groups according to DV: <60-months (DV<60,n=7) or >60-months (DV>60,n=7). After HD session, when dry weight was reached, we evaluated peripheral blood pressure (pBP), the parameters derived by tonometric analysis of the pulse waveform (central blood pressure-cBP-, Subendocardial Viability Ratio-SEVR-, carotid-femoral pulse wave velocity-cf-PWV-) and those derived from echocardiography: ejection fraction (EF-for systolic function) and E/e’ (for diastolic function), and the ultrafiltration volume (UV). Calcium/phosphate (Ca/P) levels, serum albumin, and Kt/V were evaluated retrospectively on repeated measurements over the past 5 years.
All the groups were similar for sex and BMI, both DV<60 and DV>60 were older than hypertensives and controls (58.33±3.71 and 59.83±7.98 vs 44.14±1.28 and vs 40.63±2.05 years, respectively, P<0.05). Both DV<60 and DV>60 presented similar levels of Ca/P, serum albumin, Kt/V and UV. pBP was increased and similar to hypertensives in DV>60 vs DV<60 (systolic-pBP: 154.2±4.5 vs 132.5±5.18 mmHg, P<0.01 and diastolic-pBP: 90.4±49 vs 78.5±3.3 mmHg, P<0.01). Likewise cBP was increased and similar to hypertensive patients in DV>60 vs DV<60 (systolic-cBP: 140.8±8.4 vs 111.2±3.36 mmHg, P<0.001 and diastolic-cBP: 88.2±3.73 vs 72.33±7.78 mmHg, respectively, P<0.05). cf-PWV was similar in normotensives, hypertensives and DV<60, and increased only in DV>60 vs DV<60 (9.6±1.4 vs 7.13±1.4 m/s, p<0.05). SEVR and EF were preserved and similar in all the groups. E/e’ was significantly increased only in the groups in HD, however it was higher in DV>60 vs DV<60 (9.16±1.14 vs 6.96±0.72, P<0.01).
In conclusion, only patients with DV>60 presented increased aortic stiffness. This was associated to higher BP and diastolic dysfunction. Hence, chronic HD, particularly after 60 months, may play a putative role in developing cardiovascular alterations in patients with end-stage renal disease.
Abstract P541: Ambulatory Blood Pressure and Endothelial Dysfunction an Hematopoietic Cell Transplant Patients
Authors: Pao Emily , Gove Nancy , Flynn Joseph , Hingorani Sangeeta 
Published: July 2021

Hematopoietic cell transplantation (HCT) is a common treatment for malignancies, metabolic, and genetic disorders. Albuminuria post-HCT, which may represent systemic endothelial injury or inflammation from graft vs host disease, increases the risk of kidney disease and non-relapse mortality at 1 year post-HCT. HCT patients are also known to have abnormal blood pressure (BP) and increased rates of cardiovascular complications. We sought to determine the relationships between albuminuria, endothelial dysfunction and ambulatory BP in HCT patients.
Patients ≥ 12 years of age who had their first allogeneic HCT between 2012-2015 and survived through day 80 were eligible. Peripheral endothelial function was assessed using the EndoPAT2000 device at day 80 post HCT along with a 24 hour ambulatory blood pressure monitor (ABPM) study. Clinical and lab data were collected and a urine sample for an albumin to creatinine ratio (ACR). Both logistic and linear regression analyses were used to identify associations between EndoPAT score and clinical variables including eGFR, 24 hour ABPM study, albuminuria, and serum lipids.
Sixty patients completed the study. The median age was 48 years (range, 14-69). The median EndoPAT score (RHI normal ≥ 1.69) was 2.05 (range, 1.02- 4.45) and 28% (17/60) of the patients had abnormal endothelial function. Forty-two patients (72%) had hypertension based on the 24-hr ABPM results and 63% of the patients (38/60) had abnormal nocturnal dipping. Hypertension on ABPM (p = 0.04), abnormal nocturnal dipping (p=0.04), and elevated serum triglyceride levels (p=0.03) were associated with a lower EndoPAT score. Albuminuria was not associated with EndoPAT score or hypertension based on ABPM. Abnormal nocturnal dipping was associated with lower eGFR (p=0.03). There was a lack of agreement between office BP and use of medications and results on a 24 hour ABPM study (p < 0.001).
We did not find a correlation with lower EndoPAT scores and albuminuria; we did find associations between abnormal nocturnal dip, elevated triglyceride levels and hypertension diagnosed by 24 hour ABPM. Casual office BP readings do not accurately reflect the HCT patient’s true BP suggesting that 24 hour ABPM studies are needed to diagnose and treat hypertension appropriately.
Abstract P544: Osteopontin Deficiency Decreases Autophagy and Exacerbates Tubular Injury in Acute Kidney Injury Induced by Folic Acid
Authors: Nagao Tomoaki , Okura Takafumi , Tanino Akiko , Miyoshi Ken-ichi , Kukida Masayoshi , Higaki Jitsuo 
Published: July 2021

Osteopontin (OPN), a secreted glycosylated phosphoprotein and pro-inflammatory cytokine, has been implicated in the pathology of several renal conditions, especially renal fibrosis in chronic kidney disease. OPN is slightly expressed in renal tubular cells in normal condition, but after acute tubular injury, OPN is highly induced in these cells. However, the role of induced OPN is still unclear.
The aim of this study was to clarify the roles of OPN in acute kidney injury (AKI).
AKI was induced in wild type (WT) and OPN knockout (KO) mice by using folic acid (FA) injection (0.35mg/kg). After 2days of injection, 34% of WT mice died, whereas 54% of KO died from renal failure. Kidneys from survived mice were removed and the renal histological changes, protein expression were examined. BUN and Creatinine levels were markedly elevated in WT-AKI and KO-AKI mice (BUN: WT-sham; 25.7±4.7mg/dl, WT-AKI; 315.0±173.2mg/dl, KO-AKI; 337.7±163.7mg/dl, Creatinine: WT-sham; 0.08±0.03 mg/dl, WT-AKI; 1.60±0.87 mg/dl, KO-AKI; 1.80±0.94 mg/dl). Renal OPN mRNA expression was increased in WT-AKI mice compared to WT-sham mice (p<0.05). High levels of OPN expression in renal tubular cells were induced in WT-AKI mice. TUNEL positive tubular cells were increased in KO-AKI mice compared to WT-AKI mice. In immunohistochemical analysis, Kidney injury molecules 1 (Kim-1) positive tubular cells were also highly
increased in KO-AKI mice compared to WT-AKI mice. In contrast, LC3B (autophagy related protein) positive tubular cells were decreased in KO-AKI mice compared to WT-AKI mice.
These results indicate that OPN deficiency exacerbates tubular injury via through the inhibiting autophagy in folic acid induced AKI mice.
Cardiovascular Biomarkers of Obesity and Overlap With Cardiometabolic Dysfunction
Authors: Lau Emily S. , Paniagua Samantha M. , Zarbafian Shahrooz , Hoffman Udo , Long Michelle T. , Hwang Shih‐Jen , Courchesne Paul , Yao Chen , Ma Jiantao , Larson Martin G. , Levy Daniel , Shah Ravi V. , Ho Jennifer E. 
Published: July 2021

Background
Obesity may be associated with a range of cardiometabolic manifestations. We hypothesized that proteomic profiling may provide insights into the biological pathways that contribute to various obesity‐associated cardiometabolic traits. We sought to identify proteomic signatures of obesity and examine overlap with related cardiometabolic traits, including abdominal adiposity, insulin resistance, and adipose depots.

Methods and Results

We measured 71 circulating cardiovascular disease protein biomarkers in 6981 participants (54% women; mean age, 49 years). We examined the associations of obesity, computed tomography measures of adiposity, cardiometabolic traits, and incident metabolic syndrome with biomarkers using multivariable regression models. Of the 71 biomarkers examined, 45 were significantly associated with obesity, of which 32 were positively associated and 13 were negatively associated with obesity (false discovery rate
q
<0.05 for all). There was significant overlap of biomarker profiles of obesity and cardiometabolic traits, but 23 biomarkers, including melanoma cell adhesion molecule (MCAM), growth differentiation factor‐15 (GDF15), and lipoprotein(a) (LPA) were unique to metabolic traits only. Using hierarchical clustering, we found that the protein biomarkers clustered along 3 main trait axes: adipose, metabolic, and lipid traits. In longitudinal analyses, 6 biomarkers were significantly associated with incident metabolic syndrome: apolipoprotein B (apoB), insulin‐like growth factor‐binding protein 2 (IGFBP2), plasma kallikrein (KLKB1), complement C2 (C2), fibrinogen (FBN), and N‐terminal pro‐B‐type natriuretic peptide (NT‐proBNP); false discovery rate
q
<0.05 for all.

Conclusions
We found that the proteomic architecture of obesity overlaps considerably with associated cardiometabolic traits, implying shared pathways. Despite overlap, hierarchical clustering of proteomic profiles identified 3 distinct clusters of cardiometabolic traits: adipose, metabolic, and lipid. Further exploration of these novel protein targets and associated pathways may provide insight into the mechanisms responsible for the progression from obesity to cardiometabolic disease.
Abstract P277: Cardioprotection Enabled by Proteomic Remodeling of the Mitochondrial Respiratory Chain
Authors: Lotz Christopher , Deng Ning , Zhang Jun , Wang Yueju , Zong Chenggong , Liem David , Youn Ji-Youn , Cai Hua , Wu Christine , Yates John , Weiss James , Ping Peipei 
Published: July 2021

The mitochondrial respiratory chain is a collection of five multi-protein complexes, whose unobstructed functionality represents a pivotal element at the crossroads of cell death or survival. However, its molecular composition and stochiometric information remains elusive and the adaptive abilities of the chain remain largely unknown.
We employed a quantitative proteomic approach to investigate the hypothesis that cardioprotection against ischemic injury is afforded by a salutary proteomic remodeling of the mitochondrial respiratory chain.
The respiratory chain of cardiac mitochondria isolated from wild type (WT) mice and from mice expressing a constitutively active protein kinase Cε (AE-PKCε) were characterized using 15N-stable isotope labeled murine models (SILAM), as well as a label-free method in conjunction with high resolution LC-MS/MS, respectively. Enzymatic function of electron transport chain and the ATP synthase were evaluated (n=7/group); and mitochondrial superoxide production was examined by ESR-spectroscopy (n=3/group).
Three novel and important observations are made: (i) five individual respiratory complexes exhibited a molar ratio of 1:1:1.4:1.2:4.5 in the WT-heart; (ii) subunits within the five complexes encoded by the mitochondrial genome were expressed at much lower abundance (p<0.05) than those encoded by the nuclear genome; and (iii) Genetic cardioprotection by AE-PKCε elicited a proteomic remodeling of complex I and III, mitochondria from AE-PKCε exhibited an increased expression of multiple subunits, including the catalytic complex III subunit Cyc1. This finding was accompanied by a preserved complex III activity (p<0.05), as well as tempered superoxide production (p<0.01) subsequent to Ca2+-induced damage.
This is the first study documenting a salutary proteomic remodeling of the mitochondrial respiratory machinery in cardioprotection. Quantitative proteomics technology enabled novel information and new insights into mitochondrial biology.
Abstract P288: ATP Signaling Stimulates Fibroblast Activation: The Role of Pannexin1 Channels in Fibrosis
Authors: Duffy Heather S , Dolmatova Elena , Baum Jennifer , Keith Kimberly , Boassa Daniella , Sosinsky Gina , Kontaridis Maria I 
Published: July 2021

BACKGROUND-We have shown that Pannexin1 (Panx1), a novel ATP channel, is found in ventricular cardiac myocytes and upregulated on myocyte sarcolemmal membranes during acute ischemia. We hypothesize that the channel is part of a protein complex that plays a role in downstream cell signaling post myocardial infarction (MI).
METHODS-Using a canine model of MI, where the left anterior descending coronary artery is occluded (CO) we examined epicardial tissue from hearts subjected to 0–3 hrs of CO. Immunoprecipitation (IP) with subsequent silver stain studies revealed novel binding partners for Panx1. Co-immunoprecipitation studies (Co-IP) were performed to confirm Panx1 binding partners. In vitro dye uptake studies and ATP assays were used to determine the function of Panx1 channels under hypoxic conditions.
RESULTS-IP followed by silver staining revealed multiple potential binding partners for Panx1 in the heart. Following 3 hrs CO some interactions increased while others decreased. Co-immunoprecipitation identified one of these partners for Panx1 as the MAGUK scaffolding protein SAP97, an interaction that is significantly increased following 3 hr CO (n=3, p<0.05). Immunostaining showed that CO increased trafficking and stabilization of Panx1 channels at the cell membranes. In vitro dye uptake studies show that cells increase dye uptake following hypoxia, an event that is blocked by the Panx1 channel blocker, Probenecid. Hypoxia also causes increased ATP release likely due to opening of Panx1 channels. ATP release activated fibroblasts and stimulated early fibrosis signaling.
CONCLUSIONS-Our data show the presence of a Panx1 protein complex in cardiac myocytes that is scaffolded at the cell membranes by SAP97. Under cellular stress Panx1 channels release ATP to induce early fibrotic events. We We conclude that Panx1 plays a key functional role in ATP signaling and formation of fibrosis in the post-MI heart.
Abstract 142: Role of CK2α in Heart Tube Proliferation
Authors: Dominguez Isabel , Roman Degano Irene , Macias Alvarez Laura , Revuelta-Cervantes Jesus 
Published: July 2021

Congenital heart disease (CHD) groups a number of structural malformations of the heart and associated blood vessels present at birth. CHD is the most common birth defect, arise from defective cardiogenesis, and can be due to genetic and/or environmental factors that affect cellular processes such as proliferation during heart formation. The highly conserved serine-threonine kinase, CK2α, has been implicated in proliferative processes, including cancer, and it is a target of environmental toxins. To test whether CK2α plays a role in cardiogenesis, we used a CK2α deficient mouse. CK2α-/- mice die around embryonic day (E)11 and showed dysmorphic outflow tracts (OFT), hypoplastic right ventricles (RV) and poorly developed ventricular trabeculations. These defects, the probable cause of the lethality, could be due to deficient proliferation. Thus, we tested whether reduced CK2α expression leads to proliferative signal defects during cardiogenesis.
We used three or more pairs of somite-matched wild-type and CK2α-/- embryos for the analysis of proteins by immunofluorescence and immunoblot, and of transcript expression by RT-qPCR and in situ hybridization. At E9.5 and E10.5, the number of Isl1+ cells in the OFT and the levels of Isl1 transcript in the heart of CK2α-/- embryos was no different from wild-type. These data suggest that the mechanism underlying the OFT and RV defects is different from progenitor incorporation defects. CK2α deficient hearts expressed pan-cardiac gene and protein markers normally at E9.5 and E10.5; and apoptosis was not affected, indicating that the heart malformations may be due to proliferative defects. Indeed, mitotic rates were decreased throughout the heart in CK2α mutants compared to wild-type embryos at E9.5 and E10.5; but a mitotic defect was not apparent at E8.5. The observed decrease in proliferation correlated with decreased expression of cardiac proliferative markers such as n-myc and decrease in proliferative signal pathways in the heart tube.
In conclusion, these data show that, from E9.5 on, CK2α is necessary for proliferation and proliferative signal pathway activation in the heart tube; and that cellular mechanisms other than progenitor incorporation may play a key role in OFT and RV defects.
Abstract 16: Genomewide Association Study of Isoproterenol-Induced Heart Failure in a Large Mouse Panel
Authors: Rau Christoph D , Wang Jessica J , Ren Shuxun , Wang Yibin , Lusis Aldons J 
Published: July 2021

Heart failure is highly heterogeneous and association studies in humans have yielded few insights into its genetic basis. We have developed a resource, the Hybrid Mouse Diversity Panel, to efficiently perform association studies on complex diseases in a mouse model. Each strain within the panel has been densely genotyped and the panel displays significant baseline inter-strain variation. We used the panel to explore isoproterenol (a β-adrenergic agonist) induced heart failure.
Eight week old females from 105 unique inbred strains (average N = 6.7) were divided into control (average N = 2.5) and treated (average N = 4.1) cohorts. Treated mice received 20 μg/g/day of drug through an abdominally implanted Alzet micropump. All mice underwent echocardiography to assess left ventricular function both before and at weekly timepoints after treatment. At three weeks, all mice were sacrificed. Hearts (sectioned by chamber) lungs, liver and adrenal glands were weighed before storage for further analysis. Phenotypes were analyzed using the Efficient Mixed-Model Association (EMMA) algorithm to correct for population substructure. Promising gene candidates were tested on zebrafish morpholino models to assess any phenotypic effects.
Here we report initial findings from the panel. Chronic β-adrenergic stimulation results in marked variations in both weight and echocardiographic measurements. EMMA analysis of the data revealed several dozen putative peaks, including several repeated peaks in correlated phenotypes as well as replication of previously reported loci in both human and mouse studies. Further analysis of these peaks will shed light on the genetics underlying heart failure.
Abstract 164: MicroRNA-29c Reduces Serca2 Expression During Myocardial Hypoxia
Authors: MacCannell Keith A , Shohet Ralph V , Walton Chad B 
Published: July 2021

The cardiac response to a hypoxic challenge is coordinated by the transcription factor Hypoxia Inducible Factor-1 (HIF-1), which drives the transcription of a large number of genes pertinent to angiogenesis, metabolism, and calcium cycling. Expression of HIF-1alpha that has been mutated to remove oxygen regulation recapitulates many of the changes in gene expression seen in hypoxia. It also results in reversible cardiac dysfunction associated with marked decrease of Sarco-Endoplasmic Reticulum Calcium-Dependent ATP-ase (SERCA2). This decrease in SERCA was more rapid and more substantial than a moderate decrease seen in the mRNA for this protein.
In this study, we tested the hypothesis that the decrease in SERCA2 is mediated by the up-regulation of microRNA (miRNA) in the heart. We identified 30 miRNAs that are dysregulated upon induction of oxygen stable HIF1 expression. Three of these have evident binding sites in the 3’ untranslated region of the SERCA2 gene. Transient co-transfection of a mimic molecule for these three miRs with a luciferase reporter construct that includes the 3’ UTR of SERCA2 showed that mi-29c produced a substantial decrease in reporter expression. This effect is abolished by the mutagenesis of the predicted target site within the 3’UTR. Similarly, transfection of this mimic molecule into a cell line that expresses SERCA2 results in a reduction in SERCA2 protein levels. An antagomir to this miR rescues the reduction in SERCA seen with HIF expression. We conclude that miR-29c, is responsible for an important portion of the down-regulation of SERCA2, and thus the contractile dysfunction, seen in hypoxia.
Abstract 178: Volume Overload Induced by Mitral Regurgitation Alters Spatial Regulation of Nitric Oxide/Reactive Nitrogen Species Signaling
Authors: Liu Yuchuan , Sabri Abdelkarim , Dell'Italia Louis , Rizzo Victor , Tsai Emily J 
Published: July 2021

Volume-overload (VO), as seen in regurgitant valvular disease, large myocardial infarction, and severe cardiac systolic dysfunction, triggers eccentric hypertrophy. Given that nitric oxide (NO) and cyclic guanosine monophosphate (cGMP) modulate cardiomyocyte hypertrophy, apoptosis, and cardioprotection, differential regulation of these signals may distinguish eccentric from the more commonly studied concentric hypertrophy. We recently showed that pressure-overload (PO) induces relocalization and oxidation of the NO receptor soluble guanylyl cyclase (sGC), thereby diminishing cyclase activity and cGMP cardioprotection. The effects of volume-overload on NO and cGMP signaling are unknown. We tested the hypothesis that VO induces relocalization but not oxidation of sGC, thereby disrupting spatial regulation of NO-cGMP signaling without depressing cyclase activity.
Volume-overload was established by chordal rupture-induced mitral regurgitation in dogs. We compared intracellular localization and activity of sGC in VO and control LVs (N=5 per group). Both sGC subunits were detected within and outside of caveolae-enriched lipid raft microdomains (Cav3+LR). In VO hearts, sGCβ1 fell in expression by nearly 50% and relocalized away from Cav3+LR to non-lipid raft microdomains (NLR). Despite VO-induced sGCβ1 changes, overall NO-stimulated sGC activity was preserved. An enhanced response to heme/NO-independent sGC activator BAY 60-2770 suggested that a subset of sGC was heme-oxidized in VO hearts, though to a much lesser degree than in PO hearts. As in PO hearts, Cav3+LR appear to protect sGC from heme-oxidation in VO hearts. Initial study of downstream reactive nitrogen species (RNS) and cGMP signaling supported our theory that VO altered spatial regulation of NO-cGMP signaling. Also, a trend towards increased overall tyrosine-nitration, predominantly within NLR, was observed in VO hearts.
Volume-overload shifted cardiac NO-cGMP signaling from Cav3+LR to NLR microdomains without depressing NO/heme-dependent sGC activation. These findings suggest that differential spatial regulation of NO/RNS signaling, rather than simply increased RNS signaling, might drive the distinct molecular pathophysiology of eccentric hypertrophy.