bluuebunny/crossref_metadata_2025_split huggingface dataset:
Splicing of Histone Deacetylase 7 Modulates Smooth Muscle Cell Proliferation and Neointima Formation Through Nuclear β-Catenin Translocation
Authors: Zhou Boda , Margariti Andriana , Zeng Lingfang , Habi Ouassila , Xiao Qingzhong , Martin Daniel , Wang Gang , Hu Yanhua , Wang Xian , Xu Qingbo 
Published: August 2011

Objective—
Vascular smooth muscle cell (SMC) proliferation has an indispensable role in the pathogenesis of vascular disease, but the mechanism is not fully elucidated. The epigenetic enzyme histone deacetylase 7 (HDAC7) is involved in endothelial homeostasis and SMC differentiation and could have a role in SMC proliferation. In this study, we sought to examine the effect of 2 HDAC7 isoforms on SMC proliferation and neointima formation.

Methods and Results—
We demonstrated that overexpression of unspliced HDAC7 (HDAC7u) could suppress SMC proliferation through downregulation of cyclin D1 and cell cycle arrest, whereas spliced HDAC7 (HDAC7s) could not. Small interfering RNA (siRNA)–mediated knockdown of HDAC7 increased SMC proliferation and induced nuclear translocation of β-catenin. Additional experiments showed that only HDAC7u could bind to β-catenin and retain it in the cytoplasm. Reporter gene assay and reverse transcription polymerase chain reaction revealed a reduction of β-catenin activity in cells overexpressing HDAC7u but not HDAC7s. Deletion studies indicated that the C-terminal region of HDAC7u is responsible for the interaction with β-catenin. However, the addition of amino acids to the N terminus of HDAC7u disrupted the binding, further strengthening our hypothesis that HDAC7s does not interact with β-catenin. The growth factor platelet-derived growth factor-BB increased the splicing of HDAC7 while simultaneously decreasing the expression of HDAC7u. Importantly, in an animal model of femoral artery wire injury, we demonstrated that knockdown of HDAC7 by siRNA aggravates neointima formation in comparison with control siRNA.

Conclusion—
Our findings demonstrate that splicing of HDAC7 modulates SMC proliferation and neointima formation through β-catenin nuclear translocation, which provides a potential therapeutic target in vascular disease.
Endothelial Cells Derived From Human iPSCS Increase Capillary Density and Improve Perfusion in a Mouse Model of Peripheral Arterial Disease
Authors: Rufaihah Abdul Jalil , Huang Ngan F. , Jamé Sina , Lee Jerry C. , Nguyen Ha N. , Byers Blake , De Abhijit , Okogbaa Janet , Rollins Mark , Reijo-Pera Renee , Gambhir Sanjiv S. , Cooke John P. 
Published: August 2011

Objective—
Stem cell therapy for angiogenesis and vascular regeneration has been investigated using adult or embryonic stem cells. In the present study, we investigated the potential of endothelial cells (ECs) derived from human induced pluripotent stem cells (hiPSCs) to promote the perfusion of ischemic tissue in a murine model of peripheral arterial disease.

Methods and Results—

Endothelial differentiation was initiated by culturing hiPSCs for 14 days in differentiation media supplemented with BMP-4 and vascular endothelial growth factor. The hiPSC-ECs exhibited endothelial characteristics by forming capillary-like structures in matrigel and incorporating acetylated-LDL. They stained positively for EC markers such as KDR, CD31, CD144, and eNOS. In vitro exposure of hiPSC-ECs to hypoxia resulted in increased expression of various angiogenic related cytokines and growth factors. hiPSC-ECs were stably transduced with a double fusion construct encoded by the ubiquitin promoter, firefly luciferase for bioluminescence imaging and green fluorescence protein for fluorescent detection. The hiPSC-ECs (5×10
5
) were delivered by intramuscular injection into the ischemic hindlimb of SCID mice at day 0 and again on day 7 after femoral artery ligation (n=8). Bioluminescence imaging showed that hiPSC-ECs survived in the ischemic limb for at least 2 weeks. In addition, laser Doppler imaging showed that the ratio of blood perfusion was increased by hiPSC-EC treatment by comparison to the saline-treated group (0.58±0.12 versus 0.44±0.04;
P
=0.005). The total number of capillaries in the ischemic limb of mice receiving hiPSC-EC injections was greater than those in the saline-treated group (1284±155 versus 797±206 capillaries/mm
2
) (
P
<0.002).

Conclusion—
This study is a first step toward development of a regenerative strategy for peripheral arterial disease based on the use of ECs derived from hiPSCs.
C1q/TNF-Related Proteins, A Family of Novel Adipokines, Induce Vascular Relaxation Through the Adiponectin Receptor-1/AMPK/eNOS/Nitric Oxide Signaling Pathway
Authors: Zheng Qijun , Yuan Yuexing , Yi Wei , Lau Wayne Bond , Wang Yajing , Wang Xiaoliang , Sun Yang , Lopez Bernard L. , Christopher Theodore A. , Peterson Jonathan M. , Wong G. William , Yu Shiqiang , Yi Dinghua , Ma Xin-Liang 
Published: August 2011

Objective—
Reduced plasma adiponectin (APN) in diabetic patients is associated with endothelial dysfunction. However, APN knockout animals manifest modest systemic dysfunction unless metabolically challenged. The protein family CTRPs (C1q/TNF-related proteins) has recently been identified as APN paralogs and some CTRP members share APN′s metabolic regulatory function. However, the vasoactive properties of CTRPs remain completely unknown.

Methods and Results—
The vasoactivity of currently identified murine CTRP members was assessed in aortic vascular rings and underlying molecular mechanisms was elucidated in human umbilical vein endothelial cells. Of 8 CTRPs, CTRPs 3, 5, and 9 caused significant vasorelaxation. The vasoactive potency of CTRP9 exceeded that of APN (3-fold) and is endothelium-dependent and nitric oxide (NO)-mediated. Mechanistically, CTRP9 increased AMPK/Akt/eNOS phosphorylation and increased NO production. AMPK knockdown completely blocked CTRP9-induced Akt/eNOS phosphorylation and NO production. Akt knockdown had no significant effect on CTRP9-induced AMPK phosphorylation, but blocked eNOS phosphorylation and NO production. Adiponectin receptor 1, but not receptor 2, knockdown blocked CTRP9-induced AMPK/Akt/eNOS phosphorylation and NO production. Finally, preincubating vascular rings with an AMPK-inhibitor abolished CTRP9-induced vasorelaxative effects.

Conclusion—
We have provided the first evidence that CTRP9 is a novel vasorelaxative adipocytokine that may exert vasculoprotective effects via the adiponectin receptor 1/AMPK/eNOS dependent/NO mediated signaling pathway.
Secreted Frizzled-Related Protein-1 Improves Postinfarction Scar Formation Through a Modulation of Inflammatory Response
Authors: Barandon Laurent , Casassus Fréderic , Leroux Lionel , Moreau Catherine , Allières Cécile , Lamazière Jean-Marie Daniel , Dufourcq Pascale , Couffinhal Thierry , Duplàa Cécile 
Published: August 2011

Objective—
The inflammatory response after myocardial infarction plays a crucial role in the healing process. Lately, there is accumulating evidence that the Wnt/Frizzled pathway may play a distinct role in inflammation. We have shown that secreted frizzled-related protein-1 (sFRP-1) overexpression reduced postinfarction scar size, and we noticed a decrease in neutrophil infiltration in the ischemic tissue. We aimed to further elucidate the role of sFRP-1 in the postischemic inflammatory process.

Methods and Results—
We found that in vitro, sFRP-1 was able to block leukocyte activation and cytokine production. We transplanted bone marrow cells (BMCs) from transgenic mice overexpressing sFRP-1 into wild-type recipient mice and compared myocardial healing with that of mice transplanted with wild-type BMCs. These results were compared with those obtained in transgenic mice overexpressing sFRP-1 specifically in endothelial cells or in cardiomyocytes to better understand the spatiotemporal mechanism of the sFRP-1 effect. Our findings indicate that when overexpressed in the BMCs, but not in endothelial cells or cardiomyocytes, sFRP-1 was able to reduce neutrophil infiltration after ischemia, by switching the balance of pro- and antiinflammatory cytokine expression, leading to a reduction in scar formation and better cardiac hemodynamic parameters.

Conclusion—
sFRP-1 impaired the loop of cytokine amplification and decreased neutrophil activation and recruitment into the scar, without altering the neutrophil properties. These data support the notion that sFRP-1 may be a novel antiinflammatory factor protecting the heart from damage after myocardial infarction.
Paraoxonase-2 Modulates Stress Response of Endothelial Cells to Oxidized Phospholipids and a Bacterial Quorum–Sensing Molecule
Authors: Kim Juyong Brian , Xia Yu-Rong , Romanoski Casey E. , Lee Sangderk , Meng YongHong , Shi Yi-Shou , Bourquard Noam , Gong Ke Wei , Port Zachary , Grijalva Victor , Reddy Srinivasa T. , Berliner Judith A. , Lusis Aldons J. , Shih Diana M. 
Published: August 2011

Objective—

Chronic infection has long been postulated as a stimulus for atherogenesis.
Pseudomonas aeruginosa
infection has been associated with increased atherosclerosis in rats, and these bacteria produce a quorum-sensing molecule 3-oxo-dodecynoyl-homoserine lactone (3OC12-HSL) that is critical for colonization and virulence. Paraoxonase 2 (PON2) hydrolyzes 3OC12-HSL and also protects against the effects of oxidized phospholipids thought to contribute to atherosclerosis. We now report the response of human aortic endothelial cells (HAECs) to 3OC12-HSL and oxidized 1-palmitoyl-2-arachidonoyl-sn-glycero-3-phosphocholine (Ox-PAPC) in relation to PON2 expression.

Methods and Results—
Using expression profiling and network modeling, we identified the unfolded protein response (UPR), cell cycle genes, and the mitogen-activated protein kinase signaling pathway to be heavily involved in the HAEC response to 3OC12-HSL. The network also showed striking similarities to a network created based on HAEC response to Ox-PAPC, a major component of minimally modified low-density lipoprotein. HAECs in which PON2 was silenced by small interfering RNA showed increased proinflammatory response and UPR when treated with 3OC12-HSL or Ox-PAPC.

Conclusion—
3OC12-HSL and Ox-PAPC influence similar inflammatory and UPR pathways. Quorum sensing molecules, such as 3OC12-HSL, contribute to the proatherogenic effects of chronic infection. The antiatherogenic effects of PON2 include destruction of quorum sensing molecules.
Expression of Sar1b Enhances Chylomicron Assembly and Key Components of the Coat Protein Complex II System Driving Vesicle Budding
Authors: Levy Emile , Harmel Elodie , Laville Martine , Sanchez Rocio , Emonnot Léa , Sinnett Daniel , Ziv Ehud , Delvin Edgard , Couture Patrick , Marcil Valérie , Sane Alain T. 
Published: August 2011

Objective—

SAR1b plays a significant role in the assembly, organization, and function of the coat protein complex II, a critical complex for the transport of proteins from the endoplasmic reticulum to the Golgi. Recently, mutations in
SARA2
have been associated with lipid absorption disorders. However, functional studies on Sar1b-mediated lipid synthesis pathways and lipoprotein packaging have not been performed.

Methods and Results—
Sar1b was overexpressed in Caco-2/15 cells and resulted in significantly augmented triacylglycerol, cholesteryl ester, and phospholipid esterification and secretion and markedly enhanced chylomicron production. It also stimulated monoacylglycerol acyltransferase/diacylglycerol acyltransferase activity and enhanced apolipoprotein B-48 protein synthesis, as well as elevated microsomal triglyceride transfer protein activity. Along with the enhanced chylomicrons, microsomes were characterized by abundant Sec12, the guanine exchange factor that promotes the localization of Sar1b in the endoplasmic reticulum. Furthermore, coimmunoprecipitation experiments revealed high levels of the complex components Sec23/Sec24 and p125, the Sec23-interacting protein. Finally, a pronounced interaction of Sec23/Sec24 with sterol regulatory element binding protein (SREBP) cleavage-activating protein and SREBP-1c was noted, thereby permitting the transfer of the transcription factor SREBP-1c to the nucleus for the activation of genes involved in lipid metabolism.

Conclusion—
Our data suggest that Sar1b expression may promote intestinal lipid transport with the involvement of the coat protein complex II network and the processing of SREBP-1c.
Deficiency of Scavenger Receptor BI Leads to Impaired Lymphocyte Homeostasis and Autoimmune Disorders in Mice
Authors: Feng Hong , Guo Ling , Wang Dan , Gao Haiqing , Hou Guihua , Zheng Zhong , Ai Junting , Foreman Oded , Daugherty Alan , Li Xiang-An 
Published: August 2011

Objective—
Scavenger receptor BI (SR-BI) is a high-density lipoprotein (HDL) receptor. Recent studies revealed that SR-BI protects against sepsis via modulating innate immunity. However, its role in adaptive immunity is unclear.

Methods and Results—
SR-BI-null mice exhibited impaired lymphocyte homeostasis as shown by splenomegaly and imbalanced expansion of T and B lymphocytes in the spleens. Importantly, the activated T and B lymphocytes were increased 3- to 4-fold, indicating a heightened active status of T and B lymphocytes. More importantly, in line with the accumulation of the activated T and B lymphocytes, SR-BI-null mice developed systemic autoimmune disorders characterized by the presence of autoantibodies in circulation, the deposition of immune complexes in glomeruli, and the leukocyte infiltration in kidney. Further analyses revealed that SR-BI deficiency enhanced lymphocyte proliferation, caused imbalanced interferon-γ and interleukin-4 production in lymphocytes, and caused elevated inflammatory cytokine production in macrophages. Furthermore, HDL from SR-BI-null mice exhibited less capability of suppressing lymphocyte proliferation.

Conclusion—
SR-BI regulates lymphocyte homeostasis, likely through its roles in modulating the proliferation of lymphocytes, the cytokine production by lymphocytes and macrophages, and the function of HDL. Its deficiency leads to impaired lymphocyte homeostasis and autoimmune disorders. Our findings reveal a previously unrecognized role of SR-BI in adaptive immunity.
Activation of the Annexin A1 Pathway Underlies the Protective Effects Exerted by Estrogen in Polymorphonuclear Leukocytes
Authors: Nadkarni Suchita , Cooper Dianne , Brancaleone Vincenzo , Bena Stefania , Perretti Mauro 
Published: August 2011

Objective—
The anti-inflammatory properties of the female sex hormone estrogen have been linked to a reduced incidence of cardiovascular disease. In the present study, we addressed whether estrogen could activate vasculoprotective mechanisms via annexin A1 (AnxA1) mobilization in human polymorphonuclear cells (PMNs).

Methods and Results—

Using whole-blood flow cytometry, we demonstrated that premenopausal women expressed higher levels of surface AnxA1 on circulating PMNs compared with males. This correlated with high plasma estrogen during the menstrual cycle. The addition of estrogen in vitro to male PMNs induced rapid mobilization of AnxA1, optimal at 5 ng/mL and a 30-minute incubation period; this effect was abolished in the presence of the estrogen receptor antagonist ICI182780. Estrogen addition to human PMNs induced a distinct AnxA1
hi
CD62L
lo
CD11b
lo
phenotype, and this was associated with lower cell activation as measured by microparticle formation. Treatment of human PMNs with E
2
inhibited cell adhesion to an endothelial cell monolayer under shear, which was absent when endogenous AnxA1 was neutralized. Of interest, addition of estrogen to PMNs flowed over the endothelial monolayer amplified its upregulation of AnxA1 localization on the cell surface. Finally, in a model of intravital microscopy, estrogen inhibition of white blood cell adhesion to the postcapillary venule was absent in mice nullified for AnxA1.

Conclusion—
We unveil a novel AnxA1-dependent mechanism behind the inhibitory properties of estrogen on PMN activation, describing a novel phenotype with a conceivable impact on the vasculoprotective effects of this hormone.
Heritability of Tpeak-Tend Interval and T-Wave Amplitude
Authors: Haarmark Christian , Kyvik Kirsten O. , Vedel-Larsen Esben , Budtz-Jørgensen Esben , Kanters Jørgen K. 
Published: August 2011

Background—
Tpeak-Tend interval (TpTe) and T-wave amplitude (Tamp) carry diagnostic and prognostic information regarding cardiac morbidity and mortality. Heart rate and QT interval are known to be heritable traits. The heritability of T-wave morphology parameters such as TpTe and Tamp is unknown. TpTe and Tamp were evaluated in a large sample of twins.

Methods and Results—
Twins from the GEMINAKAR study (611 pairs, 246 monozygotic, 365 dizygotic; mean age, 38±11 years; 49% men) who had an ECG performed during 1997 to 2000 were included. Tamp was measured in leads V1 and V5. Duration variables (RR interval, QTpeak and QTend interval) were measured and averaged over 3 consecutive beats in lead V5. TpTe was calculated as the QTend- and QTpeak-interval difference. Heritability was assessed using structural equation models adjusting for age, sex, and body mass index. All models were reducible to a model of additive genetics and unique environment. All variables had considerable genetic components. Adjusted heritability estimates were as follows: TpTe, 46%; Tamp lead V1, 34%; Tamp lead V5, 47%; RR interval, 55%; QT interval, 67%; and Bazett-corrected QT interval, 42%.

Conclusions—
RR interval, QT interval, Tamp, and TpTe interval are heritable ECG parameters.
Loss-of-Function Mutations in the
KCNJ8
-Encoded Kir6.1 K
ATP
Channel and Sudden Infant Death Syndrome
Authors: Tester David J. , Tan Bi-Hua , Medeiros-Domingo Argelia , Song Chunhua , Makielski Jonathan C. , Ackerman Michael J. 
Published: August 2011

Background—

Approximately 10% of sudden infant death syndrome (SIDS) may stem from cardiac channelopathies. The
KCNJ8
-encoded Kir6.1 (K
ATP
) channel critically regulates vascular tone and cardiac adaptive response to systemic metabolic stressors, including sepsis.
KCNJ8
-deficient mice are prone to premature sudden death, particularly with infection. We determined the spectrum, prevalence, and function of KCNJ8 mutations in a large SIDS cohort.

Methods and Results—

Using polymerase chain reaction, denaturing high-performance liquid chromatography, and DNA sequencing, comprehensive open reading frame/splice-site mutational analysis of KCNJ8 was performed on genomic DNA isolated from necropsy tissue on 292 unrelated SIDS cases (178 males, 204 white; age, 2.9±1.9 months). KCNJ8 mutations were coexpressed heterologously with SUR2A in COS-1 cells and characterized using whole-cell patch-clamp. Two novel KCNJ8 mutations were identified. A 5-month-old white male had an in-frame deletion (E332del) and a 2-month-old black female had a missense mutation (V346I). Both mutations localized to Kir6.1's C-terminus, involved conserved residues and were absent in 400 and 200 ethnic-matched reference alleles respectively. Both cases were negative for mutations in established channelopathic genes. Compared with WT, the pinacidil-activated K
ATP
current was decreased 45% to 68% for Kir6.1-E332del and 40% to 57% for V346I between −20 mV and 40 mV.

Conclusions—
Molecular and functional evidence implicated loss-of-function KCNJ8 mutations as a novel pathogenic mechanism in SIDS, possibly by predisposition of a maladaptive cardiac response to systemic metabolic stressors akin to the mouse models of KCNJ8 deficiency.
Cardiorenal Actions of TRV120027, a Novel ß-Arrestin–Biased Ligand at the Angiotensin II Type I Receptor, in Healthy and Heart Failure Canines
Authors: Boerrigter Guido , Lark Michael W. , Whalen Erin J. , Soergel David G. , Violin Jonathan D. , Burnett John C. 
Published: August 2011

Background—

The angiotensin II type 1 receptor (AT1R) plays a key role in regulating cardiorenal function. Classic “unbiased” AT1R antagonists block receptor coupling to both G
αq
and ß-arrestin–mediated signals, which desensitize G-protein signaling as well as transduce G-protein–independent signals. TRV120027 is a novel ß-arrestin–biased AT1R ligand, which engages ß-arrestins while blocking G-protein signaling. At the AT1R, TRV120027 can inhibit angiotensin II–mediated vasoconstriction, whereas, through ß-arrestin coupling, increase cardiomyocyte contractility. We defined for the first time the acute cardiorenal actions of TRV120027 in healthy and heart failure (HF) canines.

Methods and Results—
Healthy and HF canines (induced by tachypacing) were anesthetized. After instrumentation and equilibration, a 30-minute baseline clearance was performed, followed by further clearance with escalating doses of intravenous TRV120027 (0.01, 0.1, 1, 10, and 100 μg/kg per minute) and a 30-minute washout. In healthy canines, TRV120027 decreased pulmonary capillary wedge pressure and systemic and renal vascular resistances, while increasing cardiac output, renal blood flow, glomerular filtration rate, and urinary sodium excretion. In HF canines, TRV120027 decreased mean arterial pressure, right atrial pressure, and pulmonary capillary wedge pressure, systemic and renal vascular resistances and increased cardiac output and renal blood flow. Glomerular filtration rate and urinary sodium excretion were maintained.

Conclusions—
We report for the first time the cardiorenal actions of the novel ß-arrestin–biased AT1R ligand TRV120027. In both normal and HF canines, TRV120027 demonstrated cardiac unloading actions while preserving renal function. With this beneficial pharmacological profile, TRV120027 represents a novel strategy for the treatment of HF.
Incidence of Transient Ischemic Attack and Early Stroke Risk
Authors: Cancelli Iacopo , Janes Francesco , Gigli Gian Luigi , Perelli Anna , Zanchettin Barbara , Canal Giessica , D'Anna Lucio , Russo Valentina , Barbone Fabio , Valente Mariarosaria 
Published: August 2011

Background and Purpose—
The importance of transient ischemic attack (TIA) lies on the short-term risk of stroke, and the ABCD2 score may improve early stroke risk prediction. However, population-based studies are still needed. We aimed to provide data on TIA incidence and to evaluate the ABCD2 predictive ability for early recurrent stroke in a population-based study.

Methods—
This study is part of a 2-year prospective community-based registry of all cerebrovascular events in the district of Udine (153 312 inhabitants), Friuli Venezia Giulia region, northeast of Italy, between April 1, 2007 and March 31, 2009. Multiple overlapping sources for finding cases were used, combining hot and cold pursuit.

Results—
We identified 178 TIA, 161 (90.4%) of which were incident. The crude overall annual TIA incidence rate per 1000 residents was 0.52 (95% confidence interval [CI], 0.45–0.61). Incidence rate was 0.45 (95% CI, 0.31–0.65) when standardized to the 2007 Italian population and 0.25 (95% CI, 0.16–0.39) when standardized to the European standard population. Estimates of stroke risk after the index TIA within 2, 7, 30, and 90 days were, respectively, 2.5% (95% CI, 0.7–6.2), 5.6% (95% CI, 2.6–10.3), 6.2% (95% CI, 3.0–11.1), and 11.2% (95% CI, 6.8–17.1). ABCD2 score was strongly associated with stroke occurrence after index TIA: the areas under the receiver operating characteristic curve at 2, 7, 30, and 90 days were, respectively, 0.85 (95% CI, 0.72–0.97), 0.69 (95% CI, 0.56–0.82), 0.69 (95% CI, 0.56–0.85), and 0.76 (95% CI, 0.67–0.86). No patients with an ABCD2 score <4 had a stroke within the 90-day follow-up period.

Conclusions—
This study adds new data on TIA incidence and prognosis and it further validates the ability of the ABCD2 score to identify patients at early risk for stroke.