bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 4921: Endothelial-targeted Expression of a Conditional Fas-fKBP Chimera in Transgenic Mice Establishes the Role of Lung Microvascular Apoptosis in Pulmonary Hypertension
Authors: Jiang Jin-Yi , Jurasz Paul , Courtman David W , Deng Yupu , Yang Anli , Zhang Qiuwang , Turksen Kursad , Sinclair Tammy , Stewart Duncan J 
Published: April 2024

Introduction: Pulmonary arterial hypertension (PAH) is a lethal disorder characterized by pulmonary arteriolar remodeling and obliteration. Although its pathogenesis is still unclear, endothelial cell (EC) apoptosis has been suggested to be an initiating event in PAH, possibly leading directly to the degeneration of fragile precapillary arterioles. This study was to create a transgenic model of tritrable EC apoptosis to test the hypothesis that this is sufficient to induce the PAH phenotype.

Methods: The Fas-Induced Apoptosis (FIA) construct contains the Fas cytoplasmic death domain fused with 2 copies of the FK506-binding peptide (FKBP) domain. This construct was targeted to ECs (i.e. EFIA) under the control of the Tie2 promoter and apoptosis was induced by a small molecule dimerizing agent, AP20187, which binds tightly to the FKBP domain. After
in vitro
validation of its activity, the EFIA gene construct was microinjected into fertilized oocytes in CD1 mice. Apoptosis was assessed by TUNEL staining and right ventricular systolic pressure (RVSP) and hypertrophy (RV/LV+septal weight) were determined with and without i.p. injection of AP20187.

Results: EFIA transgenic mice appeared normal, however, administration of the AP20187 at 10 mg/kg/day for 2 weeks resulted in an increase in RVSP, which was greater in homozygous vs. heterozygous EFIA mice (37 ± 7 and 31 ± 7 mm Hg, respectively) compared WT mice either with or without AP20187 (26 ± 2 and 23 ± 2, respectively; p = 0.02). As well, there was a significant increase in right ventricular remodeling in homozygous EFIA mice treated with AP20187 compared to WT mice (RV/LV+ septal wt: 0.366 ±0.132 vs. 0.244 ± 0.048, respectively). AP20187 treatment also induced apoptosis in the peripheral lung (0.22 ± 0.05%) as well as in the kidney (9 ± 2%), which was significantly correlated with increases in RVSP. Of noted, increased lung cell proliferation, as evidenced by PCNA staining, was seen only in AP20187-treated EFIA mice.
Conclusions: These results provide the first evidence that EC apoptosis is sufficient to produce PAH. This was characterized in EFIA mice by both increased peripheral lung apoptosis and reactive cellular proliferation, thus representing a new tool to further explore the pathogenesis of the lethal disease.
Abstract 4933: A 17B-estradiol Conjugated Chitosan-phosphorylcholine Polymer Supports Survival and Amplification of Endothelial Progenitor Cells (EPCs)
Authors: Tardif Kim , Cloutier Isabelle , Miao Zheime , Lemieux Caroline , Winnik Françoise , Tanguay Jean-François 
Published: April 2024

Introduction The mobilization of bone marrow derived cells (BMDC) including endothelial progenitors cells (EPCs) accelerates the reendothelialization process. Therefore, methodologies to favour EPC mobilization and amplification at the lesion site are needed. 17B-estradiol (E2) was shown to favour vascular healing through mechanisms involving EPCs. Chitosan (CH), a biodegradable polymer when combined to phosphorylcholine (PC) groups demonstrates an enhanced biocompatibility within a physiological environment and represents an attractive tool for tissue engineering. Hypothesis E2 conjugated CH-PC polymer improves survival, amplification and functionality of bone marrow derived EPC.
Methods: A system of mixed BMDC isolated from C57BL/6 female mice was cultured on fibronectin (control matrix), CH-PC-E2 or CH-PC alone or with soluble E2. BMDC proliferation, survival and organization were evaluated over 14 days. Proportion of mesenchymal cells (CD44+) and hematopoietic cells (CD117+) was determined by flow cytometry analysis. Cell migration through a CH-PC, CH-PC-E2 or fibronectin microfilm was assessed in a transwell system where E2 was used as the chemoattractant.
Results: BMDC adhesion and organization were comparable on the CH-PC, CH-PC-E2 and fibronectin matrixes over tested times. Soluble E2 or conjugated to CH-PC did not affect cell growth in standard proliferation assay. However, in specific population analysis, CH-PC-E2 markedly increased the proportion of hematopoietic cells (7,7±1,2 % vs CH-PC 2,4±0,65% and fibronectin 0,98±0,2%, p<0.05) and EPCs (2,31±0,3% vs CH-PC 0,2±0,05% and fibronectin 0,03±0,01, p<0.05). At the opposite, it decreased mesenchymal fraction (82,4±5,2% vs CH-PC 94,7±1,2% and fibronectin 89,4±3,0%, p<0.05). Moreover, even if all matrixes preserved the heterogeneous morphology of cell populations, only the CH-PC based polymers triggered spontaneous tubules formation suggesting a proangiogenic potential. Finally, the E2-induced migratory activity of BMDC was reduced by half but not abrogated on CH-based matrixes.
Conclusion: E2 conjugated CH-PC promotes EPC amplification and is a promising vehicle for cell delivery at the vascular lesion to increase healing process.
Abstract 5094: Effect of Celiprolol on Prevention of Cardiovascular Events in Vascular Ehlers-Danlos Syndrome
Authors: Ong Kim-Thanh , Perdu Jérôme , Plauchu Henri , De Backer Julie , De Paepe Anne , Emmerich Joseph , Jeunemaitre Xavier , Germain Dominique , Collignon Patrick , Georgesco Gabriella , Bozec Erwan , Hulot Jean-Sébastien , Laurent Stéphane , Boutouyrie Pierre 
Published: April 2024

Background: Vascular Ehlers-Danlos syndrome (vEDS) is a rare severe genetic disease which results from mutations in the gene encoding type III procollagen (COL3A1), characterized by vascular and/or hollow organic ruptures. No treatment is yet validated. We tested the ability of celiprolol, a beta1-adrenoceptor antagonist with a beta2-adrenoceptor agonist action, for preventing the complications of vEDS in a prospective, randomized, open, blinded endpoints trial.
Methods: Fifty three previously untreated vEDS patients were randomized to a 5-year treatment with either celiprolol (n=25) or no treatment (n=28). The two groups were matched for demographic, medical historic and clinical characteristics. Celiprolol was up-titrated from 100 to 400 mg by steps of 100 mg every 6 months. The primary end-point was an arterial event (rupture or dissection, fatal or not) occurring during follow-up. Secondary endpoints were intestinal or uterine rupture or major clinical events, related to vEDS, judged by the event committee.
Results: Mean duration of follow-up was 47 (±15) months. The study was ended prematurely by the safety monitoring board since significant differences were reached between two groups. The primary endpoint was reached by 5 patients (20%) in the celiprolol group and by 14 patients (50%) in the control group (hazard ratio, 0.36; 95% CI, 0.15 to 0.88; P=0.04). Primary plus secondary endpoints occurred in 6 patients (24%) in the celiprolol group and in 17 patient (61%) in the control group (hazard ratio, 0.31; 95% CI, 0.14 to 0.71; P=0.0097).
Conclusions: Celiprolol effectively reduced both vascular complications and organic ruptures in vEDS patients.
Abstract 5139: Critical Role of CalDAG-GEFI Signaling in Myocardial Ischemia-Reperfusion Injury
Authors: Stolla Moritz , Gao Erhe , Stefanini Lucia , Most Patrick , Force Thomas L , Bergmeier Wolfgang 
Published: April 2024

Background: Myocardial infarction (MI) is a national health concern, with an occurrence of over 1 million cases per year. An event central to MI is reperfusion injury, i.e. the damage to tissue caused when blood supply returns to the tissue after the period of ischemia. An important role for both leukocytes and platelets in the development of reperfusion injury has been described. Our recent studies demonstrated that the signaling molecule CalDAG-GEFI (Calcium and diacyglycerol-regulated guanine nucleotide exchange factor I) is predominantly expressed in neutrophils and platelets, where it plays a critical role for integrin activation and cell adhesion. Objective: We evaluated if CalDAG-GEFI is a potential target for intervention with reperfusion injury.
Methods/Results: Myocardial ischemia was induced for 30 minutes in wild-type (WT) and CalDAG-GEFI−/− mice by a minimally invasive operative procedure. After 24 hours of reperfusion, the mice were sacrificed and the hearts were extracted for further analysis. CalDAG-GEFI-deficient mice showed an approximately 40% reduction in infarct size compared to WT mice (48% vs. 30% in WT and CalDAG-GEFI−/− respectively). In order to rule out that CalDAG-GEFI affects mI/R injury due to its role in endothelial cell and/or cardiomyocyte function, we first studied its expression in these cell types. Compared to the strong expression in both platelets and neutrophils, only trace amounts of CalDAG-GEFI expression were observed in cardiomyocytes or endothelial cells. In a next step, mI/R injury was studied in lethally irradiated CalDAG-GEFI−/− mice reconstituted with bone marrow isolated from WT (KO/WT) or CalDAG-GEFI−/− (KO/KO) mice. As expected, the infarct size in KO/WT chimeras was similar to that observed in WT mice and significantly larger than that of KO/KO chimeras, strongly suggesting that CalDAG-GEFI is critical for the development of mI/R injury due to its role in platelet and/or neutrophil function. Interestingly, CalDAG-GEFI−/− mice showed a stronger protection from mI/R injury than neutrophil-depleted WT mice.
Conclusion: Our studies identify CalDAG-GEFI as a novel and promising intracellular therapeutic target for the reduction of myocardial reperfusion injury.
Abstract 5145: Central or Ambulatory Peripheral Blood Pressure: Which Best Relates to Target-organs and Future Mortality?
Authors: Huang Chi-Ming , Wang Kang-Ling , Cheng Hao-Min , Vhuang Shao-Yuan , Ting Chih-Tai , Lakatta Edward G , Yin Frank , Chou Pesus , Chen Chen-Huan 
Published: April 2024

Background: Central blood pressure (CBP) relates more to target organs and future cardiovascular mortality than peripheral blood pressure. It remains unknown whether single measurement of CBP is superior to multiple measurements of peripheral blood pressure from ambulatory blood pressure (AmBP) monitoring in the association with target organs and future mortality.
Methods: CBP by carotid tonometry and 24-hour AmBP from a community-based population of 943 participants were analyzed. Cross-sectional association of the various blood pressure variables with left ventricular mass (LVM), carotid intima-media thickness (IMT), and estimated glomerular filtration rate (eGFR), and longitudinal association with all-cause and cardiovascular mortality over a 14.9-year median follow-up were investigated.
Results: Among the 4 blood pressure variables, including the 24-hour SBP-Am and PP-Am, and SBP-C and PP-C, LVM correlated best with SBP-Am, whereas IMT and eGFR correlated best with PP-C. All 4 blood pressure variables, as well as target-organ indices predicted 14.9-year all-cause and cardiovascular mortality in the univariate analysis. With adjustment for conventional risk factors as well as LVM, IMT, and eGFR, individually entered SBP-Am, PP-Am, SBP-C or PP-C independently predicted cardiovascular mortality but not all-cause mortality. When the blood pressure variables were jointly entered into the multivariate models, only SBP-Am consistently predicted cardiovascular mortality.
Conclusion: SBP-Am and PP-C relate differently to different target-organs. SBP-Am is more powerful than SBP-C or PP-C in the prediction of cardiovascular mortality.
Abstract 5452: Consistency of Detection of Abnormal Late Enhancement in Left Ventricular Myocardium by Multislice CT in Myocardial Disease in Comparison With Cardiac Magnetic Resonance Using Segment by Segment Analysis
Authors: Takaoka Hiroyuki , Funabashi Nobusada , Uehara Masae , Daimon Michiko , Ueda Marehiko , Murayama Taichi , Komuro Issei 
Published: April 2024

Purpose: To evaluate the capability of multislice CT (MSCT) to detect abnormal late enhancement (LE) in the left ventricular (LV) myocardium in myocardial disease, we compared MSCT with cardiac magnetic resonance (CMR) using segment by segment analysis and summarized the merit of performing late phase acquisition of MSCT. Materials and
Methods: 79 subjects (61 male, 56.9±15.6 years) with suspected LV myocardial abnormalities (24 hypertrophic cardiomyopathy, 13 dilated cardiomyopathy, 5 cardiac sarcoidosis, 4 cardiac amyloidosis, 3 arrhythmogenic right ventricular cardiomyopathy, and 1 Fabry disease, et al) underwent enhanced MSCT (Aquilion One, or Light Speed Ultra 16) and CMR (Intera Achieva). Images were divided into 8 segments: 6 in the LV and each one in the right ventricle and either right or left atrium for each subject.
Results: Among the 632 segments, LE was detected in 127 segments in MSCT, 137 segments in CMR, and 100 segments in both MSCT and CMR. LE was detected in 27 segments in only MSCT, and in 37 segments in only CMR. LE was not detected in 468 segments in either MSCT or CMR. In comparing CT with CMR for detecting LE, the sensitivity, specificity, positive and negative predictive values, and consistency were 73.0, 94.5, 78.7, 92.7 and 89.9%, respectively.
Conclusions: The consistency of detection of LE in LV myocardium by MSCT in myocardial disease compared with CMR was 89.9% in spite of poor contrast resolution of CT. MSCT should be used to evaluate LV myocardium in subjects with suspected LV myocardial abnormalities by adding late phase acquisition despite increments of radiation exposure, and even though late phase acquisition is more desirable than pre enhanced scanning.
Abstract 5531: The Impacts of Thin-Slice Contrast-Enhanced Computed Tomography and Rapid Cortisol Measurement During Adrenal Venous Sampling
Authors: Nishioka Kenji , Teragawa Hiroki , Oki Kenji , Fujii Yuichi , Mitsuba Naoya , Fujimura Takenori , Mikami Shinsuke , Noma Kensuke , Ishida Takafumi , Higashi Yukihito , Kihara Yasuki 
Published: April 2024

Background: It has been considered that Adrenal venous sampling (AVS) is the golden standard to identify primary aldosteronism (PA). However, there have been technical difficulties in AVS, especially in right AVS. Therefore, we investigated whether the anatomical examination of adrenal vein using thin-slice contrast-enhanced computed tomography (CT) and the monitoring cortisol concentrations during catheterization affect the success rate of AVS in patients with suspected of having PA.
Methods: Forty-eight patients who were suspected of having PA, were enrolled. Thin-slice contrast-enhanced CT with 1.2mm-slice and rapid cortisol assay using electro chemiluminescent Immunoassay (ECLIA) were performed in 18 patients (Group I). Contrast-enhanced CT with 5mm-slice were performed in 20 patients (Group II). Samples were collected from the vena cava as well as from right and left adrenal veins. We evaluated the procedure success rate and the total radiation time in two groups.
Results: Date are expressed as the mean±SEM. The patients characteristics were similar in the two groups. On contrast-enhanced CT, right adrenal vein was detected in all patients in Group I (100%) although it was detected only 11 patients (55%) in Group II (p<0.05). The success rate of AVS was significant higher in Group I (96%), than in Group II (30%, p<0.0001) while the success rate of left AVS was not different in the two groups. The total radiation time was shorter in Group I (22±8 min) than Group II (32±9 min, p<0.05).
Conclusions: Anatomical examination using thin-slice contrast-enhanced CT and intraoperative cortisol assays increase the procedure success rate, and decrease the duration time of radiation. The rapid cortisol assay kit might be valuable and timely information for improving the success rate of adrenal venous sampling.
This research has received full or partial funding support from the American Heart Association, National Center.
Abstract 5532: Apoptosis, Interstitial Collagen and Diastolic Function in Essential Hypertension
Authors: Rivera Miguel , Cortes Raquel , Morillas Pedro , Rosello Esther , Grigorian Lilian , Martinez Luis , Lauwers Catheline , de Burgos Fernando Garcia , Soria Federico , Juanatey Jose Ramon Gonzalez , Paya Rafael , Lozano Teresa , Orosa Placido , Miro Vicente , Antorrena Isabel , de Rivas Beatriz , Mainar Luis , Bosca Jose Leandro Perez , Baron Gonzalo , Climent Vicente , Calabuig Jose Ramon , Jordan Alejandro , Salvador Antonio , Portoles Manuel , Bertomeu Vicente 
Published: April 2024

Introduction: Sustained hypertension (HT) leads to left ventricular hypertrophy (LVH) and left ventricular dilatation, processes associated with loss of cardiac myocytes through apoptosis. Nevertheless, the relationship of apoptosis, myocardial fibrosis and diastolic function remains unknown. Therefore, the aims of the present study were to analyze the relationship between aminoterminal propeptide levels of type III procollagen (PIIINP), sFas, soluble TNF receptor 1 (sTNF-R1) and diastolic function in essential HT. Hypothesis: We assessed the hypothesis that increased cardiac collagen turnover would be associated with LVH, diastolic dysfunction and apoptosis even in asymptomatic HT.
Methods: The asymptomatic hypertensive group consisted of 253 Caucasian patients (mean age 60±13 years, 139 males) from 11 hospitals. A routine physical examination, laboratory analyses, and echo-Doppler study were performed.

Results: Serum concentrations of PIIINP were higher in hypertensive patients compared to control group [4.18 (3.55 – 5.04
μ
g/L) vs. 3.54 (2.98 – 4.54
μ
g/L), p=0.006] and also plasma levels of sFas and sTNF-R1 [1.40 (1.13 – 1.69 ng/mL) vs. 1.00 (0.84 – 1.27 ng/mL), p<0.0001; 385 (291 – 545 pg/mL) vs. 236 (194 – 302 pg/mL), p<0.0001]. Log-transformed concentrations of anti-apoptotic cytokines were correlated between them (r=0.404, p<0.0001). Moreover, serum PIIINP concentrations were associated with log-transformed sFas (r=0.386, p<0.0001) and sTNF-R1 (r=0.298, p<0.001). Then, multivariate analyses included sFas (p<0.0001) and sTNF-R1 (p<0.0001) as independent factors of serum procollagen levels. Finally, marker concentrations were significantly correlated with diastolic parameters.

Conclusions: This study showed increased circulating levels of PIIINP, sFas and sTNF-R1 in our group of asymptomatic hypertensive patients. Furthermore, sFas and sTNF-R1 are independent factors of serum type III procollagen, and diastolic parameters showed a highly significant relationship with myocardial fibrosis and anti-apoptotic cytokines.
Abstract 5751: High Glucose Induces Apoptosis in Endolthelial Cells via Epigenetic Regulation of Insulin-Like Growth Factor Receptor Expression
Authors: Li Yangxin , Song Yao-Hua , Diez Jose G , Elaydar MacArthur A , Wu Hanjing , Geng Yong-Jian 
Published: April 2024

High glucose-induced endothelial cell dysfunction is considered to be the main cause of the development of vascular complications in patients with diabetes. In this study, we examined the effect of high glucose (HG) on apoptosis of human umbilical vein endothelial cells (HUVEC) and investigated the molecular mechanisms involved. HUVEC was exposed to HG and apoptosis was assessed by Death ELISA. Our data showed that HG induced significant apoptosis in HUVEC cells after exposing to HG for 5 days (O.D. value = 0.36±0.07 in HG group vs. 0.13±0.05 in control, p<0.05). HG induced apoptosis in HUVEC is associated with decreased of insulin-like growth factor receptor (IGF-1R) mRNA (4.1±0.6 fold at 72 h, p<0.05) as assessed by real-time PCR and IGF-1R protein (3. 1±0.5 fold at 96 h, p<0.05) as assessed by western blot, which were dose- and time-dependent effects (25 mM of glucose rather than 5 mM at 72 h and 96 h). The effects of HG on reduced expression of IGF-1R and apoptosis were blocked by silencing histone deacetylase 1 (HDAC1) with small interference RNA (siRNA-HDAC1) compared to non-targeting scrambled siRNA. Moreover, HG negatively regulated IGF-1R promoter activity as determined by ChIP (chromatin immunoprecipitation) analysis, which was dependent on HDAC1 since siRNA-HDAC1 attenuated the effects of HG on IGF-1R promoter activity. HG also increased the association of IGF-1R promoter with HDAC1, and decreased the association of IGF-1R promoter with acetylated histone-4. Furthermore, trichostatin A, a specific HDAC inhibitor, relieved the repression of IGF-1R and prevented apoptosis of HUVEC following HG state. These results suggest that HG-induced repression of IGF-1R is mediated by the association of HDAC1 with the IGF-1R promoter, and by the subsequent reduced recruitment of chromatin-modifying proteins, such as histone 4 to the IGF-1R promoter. In conclusion, our data demonstrate that high glucose exposure decreases expression of IGF-1R and decreases the association of acetylated histone-4 with the IGF-1R promoter, and suggest that enhancing acetylation of histone 4 and IGF-1R expression may be a useful strategy to prevent diabetic-induced apoptosis of endothelial cells.
This research has received full or partial funding support from the American Heart Association, South Central Affiliate (Arkansas, New Mexico, Oklahoma & Texas).
Abstract 5754: Rescue of Diabetes-Related Impairment of Angiogenesis by Gene Silencing of Thioredoxin-Interacting Protein
Authors: Dunn Louise L , Buckle Andrew , Simpson Philippa , Sieveking Daniel , Chow Renee , Lim Patrick , Ng Martin 
Published: April 2024

Objectives: Vascular complications of diabetes mellitus (DM) are associated with impaired angiogenesis, the mechanisms of which are poorly understood. The thioredoxin (TRX) system has been implicated in angiogenesis. Interestingly, thioredoxin-interacting protein (TXNIP), antagonist to TRX, is induced by glucose. We hypothesized that hyperglycemic-modulation of TXNIP/TRX plays a role in DM-impairment of angiogenesis.
Methods:

Endothelial cells (ECs) were cultured in 5–25 mM glucose and siRNA used to modulate the TXNIP/TRX system. EC migration, proliferation, tubulogenesis, TRX activity, VEGF, qPCR and protein were examined.

Unilateral hindlimb ischemia was induced in a murine model of Type 1 DM. Txnip siRNA was delivered i.m. and limb perfusion assessed by laser Doppler, with ischemia, foot movement and capillary density also measured.

Results: Hyperglycemia induced a dose-dependent inhibition of key angiogenic events including EC migration, proliferation and tubulogenesis (62.1Â±2.8%, 72.9Â±7.0% and 48.3Â±4.7% at 25 mM vs. control; P < 0.05), with increased TXNIP expression (5.1Â±1.8-fold mRNA; 2.0Â±0.1-fold protein), enhanced TXNIP/TRX interaction and inhibition of TRX activity (59.8Â±4.8%; P<0.001). TXNIP siRNA reversed the inhibitory effects of hyperglycemia on migration, proliferation, tubulogenesis and TRX activity to levels of control. DM was associated with a profound impairment of blood flow recovery following hindlimb ischemia (0.284Â±0.038 vs. 0.582Â±0.021; P<0.001). However, i.m. delivery of Txnip siRNA dramatically increased limb perfusion in DM mice to levels not statistically different from control (0.443Â±0.047). Txnip siRNA also increased capillary density (2.0Â±0.4-fold), while ischemia and foot movement scores significantly improved in DM mice receiving Txnip siRNA (vs. DM control; P<0.05). In both models, hyperglycemia/DM reduced VEGF expression and interfered with VEGF action, while TXNIP siRNA rescued VEGF levels to that of control.
Conclusions: TXNIP plays a key role in angiogenesis and impaired neovascularization in DM, in part via modulation of VEGF. Our findings demonstrate that inhibition of TXNIP can abrogate the deleterious effects of hyperglycemia in angiogenesis.