bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 556: ACE2-Independent Effect of XNT in Ang II-Induced Hypertension
Authors: Ye Minghao , Haber Philipp K , Wysocki Jan , Raizada Mohan , Batlle Daniel 
Published: July 2021

Previous studies using XNT have suggested that the molecule has a unique role as a hypotensive and antifibrotic agent within the RAS acting primarily as an activator of the ACE2. In this study, we assessed the hypothesis that XNT attenuates hypertension by an ACE2-independent mechanism.
Studies were performed in C57BL6 WT and ACE2KO mice. BP was monitored continuously for a period of 25 min following a bolus of Ang II infusion after either XNT or recombinant (r)ACE2 was administered.
Ang peptides were examined in plasma ex-vivo using MAS spectrometry analysis (RAS-fingerprint). ACE2 activity in serum was measured after XNT and/or Ang II infusion, in order to investigate a potential effect of XNT on serum ACE2.
With regard to blood pressure, both XNT (n=11) and rACE2 (n=11) were able to markedly attenuate Ang II -induced hypertension in WT mice. However, a similar decline in BP caused by XNT was also seen in ACE2KO mice (n=14), indicating that the BP-lowering effect of XNT was ACE2-independent. This was additionally evidenced by serum ACE2 activity measurements in WT mice performed 5 minutes after Ang II infusion, showing no significant variation between XNT (0.351±0.06 RFU/ul/hr) and control group (0.393±0.04 RFU/ul/hr). Moreover, results from MAS spectrometry analysis showed that the presence of XNT did not alter plasma Ang II, Ang (1-7) or Ang (1-5) levels, whereas rACE2, without XNT addition, significantly increased Ang (1-7) and Ang(1-5) levels as a result of enhanced Ang II degradation.
XNT has a potent BP-lowering effect in AngII-dependent hypertension but this action is ACE2-independent and unrelated to Ang II or Ang (1-7).
Abstract 64: Heart Rate Values and Variability in Controlled versus Resistant Hypertensive Patients and in True versus False Resistant Hypertensives
Authors: De La Sierra Alejandro , Calhoun David A , Vinyoles Ernest , Banegas Jose R , De La Cruz Juan J , Gorotidi Manuel , Segura Julian , Ruilope,, Madrid Luis M 
Published: July 2021

Sympathetic nervous system seems to play an important role in resistant hypertension (RH) as both renal denervation and baroreflex stimulation reduce BP in such patients. Heart rate (HR) is an indirect, but probably the only clinical marker of sympathetic activity which can be measured in every hypertensive. We aimed to evaluate differences in clinical and ambulatory HR, as well as in HR variability between RH and those controlled on therapy. Moreover, we examined differences among RH patients, depending on ABPM normalcy.
We included 14627 RH (uncontrolled with 3 drugs or treated with ≥
4 drugs) versus 11951 controlled patients (on ≤ 3 drugs). Moreover, among 13555 patients uncontrolled with ≥ 3 drugs, we compared those with elevated 24h BP (≥ 130 and/or 80 mmHg; 8730 true-RH) versus those with normal 24-h BP (<130/80 mmHg; 4825 white-coat RH). Variables analyzed were office, 24-h, daytime and nighttime HR, and HR variability (nocturnal HR dip, SD and coefficient of variation of HR).
After adjusting for age, gender and the use of beta blockers, HR values and variability were slightly, but significantly elevated in RH vs controlled patients and in true vs false RH (Table shows adjusted means±sem). In logistic regression models a blunted HR dip and elevated HR-SD increased the risk of having RH, whereas elevated nocturnal HR, HR-SD and a blunted HR dip were associated with true RH. In conclusion, RH present increased HR variability, whereas night HR and increased variability are both associated with true RH. The increase in HR and HR variability may suggest the involvement of the sympathetic nervous system in the development of resistance to antihypertensive treatment.
Abstract 528: Dose- And Salt-dependency Of Angiogenesis Inhibition-induced Blood Pressure Rise And Renal Toxicity
Authors: Lankhorst Stephanie , Kappers Mariëtte H , Sleijfer Stefan , Danser A H , van den Meiracker Anton H 
Published: July 2021

Angiogenesis inhibition with the VEGF inhibitor sunitinib is an established anti-cancer therapy, inducing hypertension and nephrotoxicity. We explored the dose- and salt-dependency of these side effects. In male WKY rats, mean arterial pressure (MAP) was monitored telemetrically during oral treatment with a high (27.5 mg/kg.day, n=14), an intermediate (14 mg/kg.day, n=6) and low dose (7 mg/kg.day, n=6) of sunitinib or vehicle (n=8) after normal salt diet for 2 weeks. The low dose-model was also combined with a high salt diet (8% NaCl and saline water). Eight days after administration rats were sacrificed and blood and 24h urine samples collected for biochemical measurements.
With the high dose of sunitinib, MAP increased from 94.7±0.9 mmHg to 125.8±1.5 mmHg (Δ31.1±0.9 mmHg, p<0.001). The intermediate and low doses induced MAP rises of 24.3±2.7 mmHg (p<0.001) and 13.4±3.3 mmHg (p<0.001), respectively. The low dose of sunitinib with high salt, induced a MAP rise of 43.5±2.2 mmHg (p<0.001 compared to normal salt). With the high dose, circulating ET-1 increased from 0.6±0.1 pg/ml to 1.6±0.2 pg/ml (p<0.01) and serum cystatine-C from 4.5±0.1 mg/L to 6.6±0.3 mg/L (p<0.001). Comparable increases in circulating ET-1 were seen with the intermediate and low doses, whereas serum cystatine-C did increase with the intermediate dose (to 6.3±0.1 mg/L, p0.05). Serum cystatine-C levels with low and high salt were identical. With the high dose of sunitinib, proteinuria increased from 7.5±1.3 to 33.3±4.8 mg/day (p<0.05). The rise in proteinuria was attenuated with the intermediate (16.2±2.1 mg/day, p<0.01) and low dose (19.9±3.3 mg/day, p<0.01), but increased to 40.4±30.1 mg/day (p>0.05) with high salt.
Angiogenesis inhibition-induced hypertension and nephrotoxicity are dose-dependent with a lower threshold for the rise in BP than for renal toxicity. The BP rise observed with the low dose of sunitinib observed in normotensive rats is comparable to the sunitinib-induced BP rise observed in patients and clearly is salt-sensitive. Since cystatine-C levels during normal and high salt diet were comparable, the BP rise during high salt seems independent of renal dysfunction.
Abstract 097: Knockout of Matrix Metalloproteinase 9 Protects Against Hypertension-induced Renal Disease in Hypertensive Dahl S Rats
Authors: Zhang Chao , Mims Paige N , Zhu Tongyu , Fan Fan , Roman Richard J 
Published: July 2021

Matrix metalloproteinase 9 (MMP9) is a member of gelatinase family of enzymes with potentially opposing actions on tissue fibrosis (i.e. the degradation of extracellular matrix). Our previous study showed that two nonselective MMP inhibitors, XL081 and XL784, which inhibit MMP2, 9, 13 and Adam10 could delay and even reverse the development of renal fibrosis in hypertensive Dahl Salt sensitive (SS) rats. However, the specific role of MMP9 to the development of hypertensive nephropathy in MMP9 knockout (KO) rat models is unknown.
In the present study, MMP9 KO rats were created on the SS genetic background using a CRISPR/Cas 9 system and the effect of KO was verified in this model. The systolic pressure, diastolic pressure and mean blood pressure (MAP) were similar in 12 weeks old MMP9 KO (n=6) and SS rats (n=9) fed a low salt diet (145 ± 3 vs. 148 ± 2mmHg; 111 ± 2 vs. 107 ± 2mmHg; 128 ± 2 vs. 126 ± 2mmHg). MAP increased to 180 ± 4 vs. 154 ± 3mmHg in SS rats versus MMP9 KO rats fed 8% high salt (HS) diet for 3 weeks. Proteinuria increased from 196 ± 18 mg/day to 718 ± 61mg/day in HS treated SS rats (n=9). It was significantly reduced in HS treated MMP9 KO rats (211 ± 30mg/day, n=6). The degree of glomerular injury (2.88 ± 0.08 vs. 3.52 ± 0.02), interstitial fibrosis (4.57 ± 0.35% vs. 10.45 ± 0.55%), vascular wall-to-lumen ratio (0.63 ± 0.04 vs. 1.22 ± 0.08) and protein cast area (6.40 ± 0.07% vs. 20.27 ± 2.65%) were all significantly reduced in MMP9 KO rats (n=6) versus the corresponding values in SS rats (n=6) fed 8% HS diet for 3 weeks. Autoregulation of renal blood flow (RBF) to elevations in perfusion was impaired in SS rats prior to the development of hypertension, for RBF rose by 20.6 ± 3.6% (n=8) when MAP was increased from 110 to 150 mmHg. Autoregulation of RBF was restored in MMP9 KO rats and only increased by 7% when pressure was increased over the same range. In contrast, there was no difference in the fall in RBF in SS versus MMP9 KO rats when pressure was reduced from 110 to 50 mmHg. These findings suggest that knockout of MMP9 in SS rats restores autoregulation of RBF and opposes the development of hypertension, proteinuria, glomerular injury and renal interstitial fibrosis.
Abstract P158: MicroRNA-22 Modulates Cardiac Gene Expression and Controls Compensation to Hemodynamic Stress in Mice
Authors: Gurha Priyatansh , Kelm Robert , Entman Mark , Taffet George , Bradley Allan , Rodriguez Antony 
Published: July 2021

Recent evidence suggests that miRNAs play an important role in cardiac morphogenesis and pathophyiology of heart failure. To explore the role of miR-22 in the mouse heart physiology, we generated miR-22 null (KO) mice. Although, miR-22 KO mice showed normal cardiac structure and function at baseline, these mice are sensitized to maladaptive remodeling (cardiac dilation) and decompensation in response to pressure overload by transverse aortic constrictions (TAC) stimulation. Genome-wide molecular analysis of KO hearts revealed attenuated expression of numerous CarG-dependent genes encoding proteins that reside at the sarcomeric Z-disc (including Myh7, Acta1, Mlp, Melusin, MyoZ2) indicating that miR-22 is required for optimum muscle gene expression. Alterations in sarcomeric gene expression is especially interesting as this suggests a primary role of miR-22 in controlling cardiac contractility and adaptation to stress. Targetomics analysis revealed that mechanistically this effect could be modulated in part by miR-22 target PURB (Purine Rich element binding protein B), a transcriptional/translational repressor.
In conclusion we define a critical role of miR-22 in cardiac adaptation to hemodynamic stress. Furthermore, these data provides a previously unseen essential molecular mechanism that underlies homeostatic control of sarcomeric protein expression in the heart.
Abstract P327: COPa Library: A Proteomic Knowledge Base for Cardiovascular Biology and Medicine
Authors: Zong Nobel , Li Haomin , Deng Ning , Chen Lingxuan , Wang Yueju , Fang Caiyun , Jimenez Rafael , Xu Tao , Hermjakob Henning , Duan Huilong , Yates John , Apweiler Rolf , Ping Peipei 
Published: July 2021

We constructed the Cardiac Organellar Peptide Atlas Library (COPa library) as a targeted and interactive resource to the cardiovascular community. Annotated peptide spectra are hosted using a relational database in a modular fashion based on species (e.g. human, mouse) and organelles (e.g. mitochondria, proteasome). Within this release of COPa library, a total of 108,268 spectra have been disseminated via two avenues. A web portal was established to navigate the library via parallel set of identifiers, such as protein name, accession number, gene symbol, etc. In parallel, a web-service cyber-infrastructure was engineered to aid the annotation of mass spectra submitted via internet. The large raw spectra files are dissected into small data packages at the local PC before submission. This workflow surpasses the limitation of network bandwidth, as well as enables parallel data submission and search. A benchmark test with 897,327 ms/ms spectra showed the library searching covers 93.4% of proteins identified via database searching, as well as additional 23.9% of proteins at the same level of statistical confidence. In addition, a wiki-like web interface was embedded in the library web portal in order to facilitate the synthesis of consensus knowledge among the cardiovascular community on innovations of functional proteomics. Overall, the COPa library search supports targeted proteomic characterization, which complements database search for exploratory survey.
The implementation of the COPa library-based proteomic knowledgebase leverages state-of-the-art technology and annotated datasets among the research community at large. Its application bridges discovery-driven and hypothesis-driven research while fostering translational medicine.
Abstract 188: Atrial Tachyarrhythmia in Rgs5-Null Mice
Authors: Qin Mu , Wang Teng , Hu He , Liu Yu , Huang He , Li Hong L , Huang Cong X 
Published: July 2021

Abstract
Aims
The aim of this study was to elucidate the effects of regulator of G-protein signaling 5 (Rgs5), a negative regulator of G protein-mediated signaling, on atrial repolarization and tachyarrhythmia (ATA) in mice.

Methods and Results
In present study, the incidence of ATA were increased in isolated mouse Rgs5
-/-
hearts during program electrical stimulation (PES) (46.7%, 7 of 15) and burst pacing (26.7%, 4 of 15) compared with wild-type (WT) mice (PES: 7.1%,1 of 14; burst:7.1%,1 of 14) (P<0.05). And the duration of ATA also shown longer in Rgs5

[[Unable to Display Character:
+
]]/-

heart than that in WT, 2 out of 15 hearts exhibited sustained ATA (>30s) but none of them observed in WT mice. Atrial prolonged repolarization was observed in Rgs5
-/-
hearts including widened P wave in surface ECG recording, increased action potential duration (APD) and atrial effective refractory periods (AERP), all of them showed significant difference with WT mice (P<0.05). At the cellular level, whole-cell patch clamp recorded markedly increased densities of repolarizing K
+
currents including I
Kur
(at + 60mV: 14.0 ± 2.2 pF/pA) and I
to
(at + 60mV: 16.7±1.3 pA/pF) in Rgs5
-/-
atrial cardiomyocytes, compared to those of WT mice (at +	60mV I
to
: 20.4 ± 2.0 pA/pF; I
kur
: 17.9 ± 2.0 pF/pA) (P<0.05).

Conclusion
These results suggest that Rgs5 is an important regulator of arrhythmogenesis in the mouse atrium and that the enhanced susceptibility to atrial tachyarrhythmias in Rgs5
-/-
mice may contribute to abnormalities of atrial repolarization.
Abstract 215: Systemic Inflammation Exacerbates Electrophysiological Remodeling and Arrhythmia Following Myocardial Infarction
Authors: De Jesus Nicole , Wang Lianguo , Ripplinger Crystal M 
Published: July 2021

Introduction: Inflammatory macrophages infiltrate the heart following myocardial infarction (MI) and secrete proteases and cytokines that may contribute to adverse electrophysiological remodeling. Atherosclerosis, the leading cause of MI, is associated with elevated systemic inflammation. Using a novel combination of optical mapping and molecular imaging, we sought to determine if systemic inflammation exacerbates electrophysiological remodeling and arrhythmogenesis.
Methods: A protease activatable fluorescent sensor (Prosense680) was injected I.V. 4 days post MI in mice. Optical mapping of transmembrane potential was performed 5 days post MI on Langendorff-perfused hearts to assess electrophysiology. Fluorescence reflectance imaging of Prosense680 was then performed to visualize and quantify inflammatory protease activity. Lipopolysaccharide (LPS:10 μ g/day, n=6) was injected I.P. to promote systemic inflammation or saline as control (SAL, n=7).
Results: Inflammation levels were greater in MI+LPS vs MI+SAL hearts (5.626±1.5 vs 1.73±0.25 A.U., p<0.02) and negligible in sham-operated hearts (SH, n=4). MI+LPS hearts had prolonged action potential (AP) duration vs MI+SAL vs SH (62±4.5 vs 56±1.8 vs 45±3.7 ms, p<0.05) and increased AP rise time (5.5±0.5 vs 4.2±0.2 vs 2.9±0.3 ms, p<0.05). A single premature pacing stimulus induced ventricular tachycardia in 67%(4 of 6) of MI+LPS vs 15%(1 of 7) MI+SAL vs 0% (0 of 4) SH, p<0.02.
Conclusions: Elevated post-MI inflammation may contribute to electrophysiological remodeling and arrhythmias. These findings have important implications for the etiology of post-MI arrhythmias in humans with systemic inflammation.
Abstract 238: Role of Erythropoietin Signaling in the Biology of Mouse Cardiac Progenitor Cells
Authors: Zafiriou Maria P , Noack Claudia , Didie Michael , Unsoeld Bernhard , El-Armouche Ali , Bergmann Martin W , Zimmermann Wolfram H , Zelarayan Laura C 
Published: July 2021

Erythropoietin (Epo) was shown to improve cardiac function following ischemia reperfusion mainly via neo-angiogenesis and anti-apoptotic mechanisms. We found EpoR expression to be particularly high in adult cardiac progenitor cells (CPCs). Thus, we reasoned that Epo may play a role in the biology of these cells.
We isolated CPCs from adult C57BL/6 hearts by enzymatic digestion and filtration (pore size: 30 µm). By means of immunofluorescence microscopy (IF) and flow cytometry (FC) we analyzed EpoR expression in the CPCs. 24±3% of the investigated cardiac cells were positive for EpoR with 3±2% of these being c-kit+ and 28%±2% Sca-1+. 52% of the EpoR+ cells expressed endothelial cell markers (40±2% CD34+, 9±2% FLK1+). 42±4% expressed myocyte markers (αMHC+, cTNT+). IF revealed a progenitor-like population with immature cell morphology and proliferation potential (ki67+). Cell cycle analysis showed an enrichment of αMHC+ EpoR+ cells in S and G2 phase (49±7%, n=3) as compared to the αMHC- EpoR- population (13±3%, n=3). Moreover, we tested the effect of Epo in the biology of these CPCs in vitro. At d14 we observed a two-fold increase of GATA4+ and cTnT+ cardiac cells in the co-cultures treated with Epo (n=3). CPC cycle arrest abrogated the aforementioned effects, suggesting that Epo influences mainly CPC proliferation. Finally, we tested the potential of Epo to protect against ischemia by inducing the proliferation of these αMHC+ CPCs in vivo in a myocardial infarction (MI) model. 4 weeks post MI, echocardiography did not reveal a significant functional improvement of the Epo receiving mice (2x, 2U/g Epo i.p). Nevertheless, FC analysis of the progenitor pool showed a significant augmentation of αMHC+ and cTnT+ cells (Sham: 19±3% vs Epo 35±3%, n=5; MI: 10.6±2.3%, n=6 vs Epo 20.3±1.9%, n=8). These data suggest an activation of myogenic progenitors by Epo, despite the lack of apparent regeneration under the investigated conditions.
In conclusion, we found that EpoR is expressed in a putative cardiomyogenic progenitor cell pool in the adult heart. Epo drives their proliferation in vitro and in vivo even upon acute cardiac injury. We are currently investigating the long-term consequences of the observed progenitor cell activation in models of chronic ischemic injury.
Abstract 286: Long Noncoding RNAs Are Differentially Expressed in Heart Failure
Authors: Robinson Emma L , Haider Syed , Hei Hillary , Lee Richard T , Foo Roger S 
Published: July 2021

Heart failure comprises of clinically distinct inciting causes but a consistent pattern of change in myocardial gene expression supports the hypothesis that unifying biochemical mechanisms underlie disease progression. The recent RNA-seq revolution has enabled whole transcriptome profiling, using deep-sequencing technologies. Up to 70% of the genome is now known to be transcribed into RNA, a significant proportion of which is long non-coding RNAs (lncRNAs), defined as polyribonucleotides of ≥200 nucleotides. This project aims to discover whether the myocardium expression of lncRNAs changes in the failing heart.
Paired end RNA-seq from a 300-400bp library of ‘stretched’ mouse myocyte total RNA was carried out to generate 76-mer sequence reads. Mechanically stretching myocytes with equibiaxial stretch apparatus mimics pathological hypertrophy in the heart. Transcripts were assembled and aligned to reference genome mm9 (UCSC), abundance determined and differential expression of novel transcripts and alternative splice variants were compared with that of control (non-stretched) mouse myocytes. Five novel transcripts have been identified in our RNA-seq that are differentially expressed in stretched myocytes compared with non-stretched. These are regions of the genome that are currently unannotated and potentially are transcribed into non-coding RNAs. Roles of known lncRNAs include control of gene expression, either by direct interaction with complementary regions of the genome or association with chromatin remodelling complexes which act on the epigenome.Changes in expression of genes which contribute to the deterioration of the failing heart could be due to the actions of these novel lncRNAs, immediately suggesting a target for new pharmaceuticals.

Changes in the expression of these novel transcripts will be validated in a larger sample size of stretched myocytes vs non-stretched myocytes as well as in the hearts of transverse aortic constriction (TAC) mice vs Sham (surgical procedure without the aortic banding).
In vivo
investigations will then be carried out, using siLNA antisense technology to silence novel lncRNAs in mice.
Abstract 119: PRMT5 Is A New Epigenetic Regulator In Cardiovascular Disease
Authors: Merkel Tobias S , Hassel David , Krüger Marcus , Weichenhan Dieter , Plass Christoph , Backs Johannes 
Published: July 2021

Protein arginine methylation is an abundant posttranslational modification involved in various cellular events such as DNA repair, splicing, and transcription. Protein arginine methyltransferases (PRMTs) catalyze the symmetric and asymmetric dimethylation of arginines and can be subdivided into two distinct families: type I enzymes catalyze the formation of asymmetric dimethylation whereas type II enzymes enhance the addition of symmetric methyl groups.
Here, we report evidence that PRMT5 a type II enzyme serves as an important epigenetic regulator in myocardial disease.

We identified PRMT5 via mass spectrometry as an interactant of class IIa histone deacetylases (HDACs). Additional cardiac interaction partners of PRMT5 were identified by a human cDNA library based yeast-two-hybrid screen. Thereby we elucidated Interleukin enhancer binding factor 3 (ILF3) as a putative interacting protein. ILF3 is a member of the NFAT family. NFAT signalling is known to be a potent driver of cardiomyocyte hypertrophy. Accordingly, we detected a 40% decrease in the size of neonatal rat ventricular myocytes in response to siRNA mediated knockdown of
prmt5
. A dominant-negative version of PRMT5 is capable of interfering with the Calcineurin-NFAT axis and blocks NFAT activation.
In vivo
knockdown of endogenous
prmt5
in the zebrafish led to a distinct cardiac phenotype with altered morphology and impaired function. To further elucidate
prmt5
function
in vivo
we use mice with floxed
prmt5
alleles. As a loss of
prmt5
is lethal in the ES cell stadium we use an inducible α myosin heavy chain Mer-Cre-Mer system. Knockout mice display a complete loss of PRMT5 in cardiomyocytes. In line with our
in vitro
studies these mice are viable and show no phenotype under baseline conditions.

Our work in progress investigates the hypothesis that class IIa HDACs serve as a scaffold to recruit PRMT5 to the DNA, forming a complex with ILF3 to block NFAT activity and the pro-hypertrophic gene program.