bluuebunny/crossref_metadata_2025_split huggingface dataset:
Characterization of Endothelial Cilia Distribution During Cerebral-Vascular Development in Zebrafish (
Danio rerio
)
Authors: Eisa-Beygi Shahram , Benslimane Fatiha M. , El-Rass Suzan , Prabhudesai Shubhangi , Abdelrasoul Mahmoud Khatib Ali , Simpson Pippa M. , Yalcin Huseyin C. , Burrows Patricia E. , Ramchandran Ramani 
Published: October 2018

Objective—
Endothelial cells (ECs) sense and respond to flow-induced mechanical stress, in part, via microtubule-based projections called primary cilia. However, many critical steps during vascular morphogenesis occur independent of flow. The involvement of cilia in regulating these stages of cranial vascular morphogenesis is poorly understood because cilia have not been visualized in primary head vessels. The objective of this study was to investigate involvement of cilia in regulating the early stages of cranial vascular morphogenesis.

Approach and Results—

Using high-resolution imaging of the
Tg(kdrl:mCherry-CAAX
)

y171

;(bactin::Arl13b:GFP
) zebrafish line, we showed that cilia are enriched in the earliest formed cranial vessels that assemble via vasculogenesis and in angiogenic hindbrain capillaries. Cilia were more prevalent around the boundaries of putative intravascular spaces in primary and angiogenic vessels. Loss of cardiac contractility and blood flow, because of knockdown of cardiac troponin T type 2a (
tnnt2a
) expression, did not affect the distribution of cilia in primary head vasculature. In later stages of development, cilia were detected in retinal vasculature, areas of high curvature, vessel bifurcation points, and during vessel anastomosis. Loss of genes crucial for cilia biogenesis (
ift172
and
ift81
) induced intracerebral hemorrhages in an EC-autonomous manner. Exposure to high shear stress induced premature cilia disassembly in brain ECs and was associated with intracerebral hemorrhages.

Conclusions—
Our study suggests a functional role for cilia in brain ECs, which is associated with the emergence and remodeling of the primary cranial vasculature. This cilia function is flow-independent, and cilia in ECs are required for cerebral-vascular stability.
Time-Dependent Hypotensive Effect of Aspirin in Mice
Authors: Chen Lihong , Yang Guangrui , Zhang Jiayang , Ren Baoyin , Tang Soonyew , Li Xuanwen , FitzGerald Garret A. 
Published: October 2018

Objective—
Evening but not morning administration of low-dose aspirin has been reported to lower blood pressure in hypertensive patients. The present study was designed to determine whether this phenomenon could be replicated in mice, and if so, whether a time-dependent effect of aspirin on blood pressure was because of alteration of circadian clock function.

Approach and Results—
We recapitulated the protective effect of aspirin (50 μg/d for 7 days) at zeitgeber time 0 (active-to-rest transit), but not at zeitgeber time 12, on a high-salt diet–induced increase of blood pressure. However, the time of aspirin administration did not influence expression of canonical clock genes or their acetylation. We used mouse Bmal1 and Per2-luciferase reporters expressed in U2OS cells to determine the real-time effect of aspirin on circadian function but found that the oscillation of bioluminescence was unaltered. Timing of aspirin administration also failed to alter urinary prostaglandin metabolites or catecholamines, or the acetylation of its COX-1 (cyclooxygenase-1) target in platelets.

Conclusions—
The time-dependent hypotensive effect of aspirin in humans has been recapitulated in hypertensive mice. However, this does not seem to reflect a direct impact of aspirin on circadian clocks or on acetylation of platelet COX-1.
Transfusion of Platelets Loaded With Recombinant ADAMTS13 (A Disintegrin and Metalloprotease With Thrombospondin Type 1 Repeats-13) Is Efficacious for Inhibiting Arterial Thrombosis Associated With Thrombotic Thrombocytopenic Purpura
Authors: Abdelgawwad Mohammad S. , Cao Wenjing , Zheng Liang , Kocher Nicole K. , Williams Lance A. , Zheng X. Long 
Published: October 2018

Objective—
ADAMTS13 (a disintegrin and metalloprotease with thrombospondin type 1 repeats-13) cleaves VWF (von Willebrand factor). This process is essential for hemostasis. Severe deficiency of plasma ADAMTS13 activity, most commonly resulting from autoantibodies against ADAMTS13, causes thrombotic thrombocytopenic purpura. Therapeutic plasma exchange is the standard of care to date, which removes autoantibodies and replenishes ADAMTS13. However, such a therapy is often ineffective to raise plasma ADAMTS13 activity, and in-hospital mortality rate remains as high as 20%.

Approach and Results—

To overcome the inhibition by autoantibodies, we developed a novel approach by delivering rADAMTS13 (recombinant ADAMTS13 ) using platelets as vehicles. We show that both human and murine platelets can uptake rADAMTS13 ex vivo. The endocytosed rADAMTS13 within platelets remains intact, active, and is stored in α-granules. Under arterial shear (100 dyne/cm
2
), the rADAMTS13 in platelets is released and effectively inhibits platelet adhesion and aggregation on a collagen-coated surface in a concentration-dependent manner. Transfusion of rADAMTS13-loaded platelets into
Adamts13
−/−
mice dramatically reduces the rate of thrombus formation in the mesenteric arterioles after FeCl
3
injury. An ex vivo transfusion of rADAMTS13-loaded platelets to a reconstituted whole blood containing plasma from a patient with immune-mediated thrombotic thrombocytopenic purpura and the cellular components (eg, erythrocytes and leukocytes) from a healthy individual, as well as a fresh whole blood obtained from a patient with congenital or immune-mediated thrombotic thrombocytopenic purpura also dramatically reduces the rate of thrombus formation under arterial flow.

Conclusions—
Our results demonstrate that transfusion of rADAMTS13-loaded platelets may be a novel and potentially effective therapeutic approach for arterial thrombosis, associated with congenital and immune-mediated thrombotic thrombocytopenic purpura.
Distinct Proteomic Signatures in 16 HDL (High-Density Lipoprotein) Subspecies
Authors: Furtado Jeremy D. , Yamamoto Rain , Melchior John T. , Andraski Allison B. , Gamez-Guerrero Maria , Mulcahy Patrick , He Zeling , Cai Tianxi , Davidson W. Sean , Sacks Frank M. 
Published: October 2018

Objective—
HDL (high-density lipoprotein) in plasma is a heterogeneous group of lipoproteins typically containing apo AI as the principal protein. Most HDLs contain additional proteins from a palate of nearly 100 HDL-associated polypeptides. We hypothesized that some of these proteins define distinct and stable apo AI HDL subspecies with unique proteomes that drive function and associations with disease.

Approach and Results—
We produced 17 plasma pools from 80 normolipidemic human participants (32 men, 48 women; aged 21–66 years). Using immunoaffinity isolation techniques, we isolated apo AI containing species from plasma and then used antibodies to 16 additional HDL protein components to isolate compositional subspecies. We characterized previously described HDL subspecies containing apo AII, apo CIII, and apo E; and 13 novel HDL subspecies defined by presence of apo AIV, apo CI, apo CII, apo J, α-1-antitrypsin, α-2-macroglobulin, plasminogen, fibrinogen, ceruloplasmin, haptoglobin, paraoxonase-1, apo LI, or complement C3. The novel species ranged in abundance from 1% to 18% of total plasma apo AI. Their concentrations were stable over time as demonstrated by intraclass correlations in repeated sampling from the same participants over 3 to 24 months (0.33–0.86; mean 0.62). Some proteomes of the subspecies relative to total HDL were strongly correlated, often among subspecies defined by similar functions: lipid metabolism, hemostasis, antioxidant, or anti-inflammatory. Permutation analysis showed that the proteomes of 12 of the 16 subspecies differed significantly from that of total HDL.

Conclusions—
Taken together, correlation and permutation analyses support speciation of HDL. Functional studies of these novel subspecies and determination of their relation to diseases may provide new avenues to understand the HDL system of lipoproteins.
Myeloid HMG-CoA (3-Hydroxy-3-Methylglutaryl-Coenzyme A) Reductase Determines Atherosclerosis by Modulating Migration of Macrophages
Authors: Sakai Kent , Nagashima Shuichi , Wakabayashi Tetsuji , Tumenbayar Bayasgalan , Hayakawa Hiroko , Hayakawa Morisada , Karasawa Tadayoshi , Ohashi Ken , Yamazaki Hisataka , Takei Akihito , Takei Shoko , Yamamuro Daisuke , Takahashi Manabu , Yagyu Hiroaki , Osuga Jun-ichi , Takahashi Masafumi , Tominaga Shin-ichi , Ishibashi Shun 
Published: October 2018

Objective—
Inhibition of HMGCR (3-hydroxy-3-methylglutaryl-coenzyme A reductase) is atheroprotective primarily by decreasing plasma LDL (low-density lipoprotein)-cholesterol. However, it is unknown whether inhibition of HMGCR in myeloid cells contributes to this atheroprotection. We sought to determine the role of myeloid HMGCR in the development of atherosclerosis.

Approach and Results—

We generated mice with genetically reduced
Hmgcr
in myeloid cells (
Hmgcr

m−

/m

−
) using LysM (Cre) and compared various functions of their macrophages to those of
Hmgcr

fl/fl

control mice. We further compared the extent of atherosclerosis in
Hmgcr

m
−/
m
−

and
Hmgcr

fl/fl

mice in the absence of
Ldlr
(LDL receptor).
Hmgcr

m
−/
m
−

macrophages and granulocytes had significantly lower
Hmgcr
mRNA expression and cholesterol biosynthesis than
Hmgcr

fl/fl

cells. In vitro,
Hmgcr

m
−/
m
−

monocytes/macrophages had reduced ability to migrate, proliferate, and survive compared with
Hmgcr

fl/fl

monocytes/macrophages. However, there was no difference in ability to adhere, phagocytose, store lipids, or polarize to M1 macrophages between the 2 types of macrophages. The amounts of plasma membrane–associated small GTPase proteins, such as RhoA (RAS homolog family member A), were increased in
Hmgcr

m
−/
m
−

macrophages. In the setting of
Ldlr
deficiency,
Hmgcr

m
−/
m
−

mice developed significantly smaller atherosclerotic lesions than
Hmgcr

fl/fl

mice. However, there were no differences between the 2 types of mice either in plasma lipoprotein profiles or in the numbers of proliferating or apoptotic cells in the lesions in vivo. The in vivo migration of
Hmgcr

m
−/
m
−

macrophages to the lesions was reduced compared with
Hmgcr

fl/fl

macrophages.

Conclusions—
Genetic reduction of HMGCR in myeloid cells may exert atheroprotective effects primarily by decreasing the migratory activity of monocytes/macrophages to the lesions.
Endothelial FN (Fibronectin) Deposition by α5β1 Integrins Drives Atherogenic Inflammation
Authors: Al-Yafeai Zaki , Yurdagul Arif , Peretik Jonette M. , Alfaidi Mabruka , Murphy Patrick A. , Orr A. Wayne 
Published: October 2018

Objective—
Alterations in extracellular matrix quantity and composition contribute to atherosclerosis, with remodeling of the subendothelial basement membrane to an FN (fibronectin)-rich matrix preceding lesion development. Endothelial cell interactions with FN prime inflammatory responses to a variety of atherogenic stimuli; however, the mechanisms regulating early atherogenic FN accumulation remain unknown. We previously demonstrated that oxLDL (oxidized low-density lipoprotein) promotes endothelial proinflammatory gene expression by activating the integrin α5β1, a classic mediator of FN fibrillogenesis.

Approach and Results—
We now show that oxLDL drives robust endothelial FN deposition and inhibiting α5β1 (blocking antibodies, α5 knockout cells) completely inhibits oxLDL-induced FN deposition. Consistent with this, inducible endothelial-specific α5 integrin deletion in ApoE knockout mice significantly reduces atherosclerotic plaque formation, associated with reduced early atherogenic inflammation. Unlike TGFβ (transforming growth factor β)-induced FN deposition, oxLDL does not induce FN expression (mRNA, protein) or the endothelial-to-mesenchymal transition phenotype. In addition, we show that cell-derived and plasma-derived FN differentially affect endothelial function, with only cell-derived FN capable of supporting oxLDL-induced VCAM-1 (vascular cell adhesion molecule 1) expression, despite plasma FN deposition by oxLDL. The inclusion of alternative exon EIIIA (EDA) of FN (EIIIA) and alternative exon EIIIB (EDB) of FN (EIIIB) domains in cell-derived FN mediates this effect, as EIIIA/EIIIB knockout endothelial cells show diminished oxLDL-induced inflammation. Furthermore, our data suggest that EIIIA/EIIIB-positive cellular FN is required for maximal α5β1 recruitment to focal adhesions and FN fibrillogenesis.

Conclusions—
Taken together, our data demonstrate that endothelial α5 integrins drive oxLDL-induced FN deposition and early atherogenic inflammation. Additionally, we show that α5β1-dependent endothelial FN deposition mediates oxLDL-dependent endothelial inflammation and FN fibrillogenesis.
V-ATPase (Vacuolar ATPase) Activity Required for ABCA1 (ATP-Binding Cassette Protein A1)-Mediated Cholesterol Efflux
Authors: Lorkowski Shuhui Wang , Brubaker Gregory , Gulshan Kailash , Smith Jonathan D. 
Published: October 2018

Objective—
We have shown that ABCA1 (ATP-binding cassette protein A1) mediates unfolding of the apoA1 (apolipoprotein A1) N-terminal helical hairpin during apoA1 lipidation. Others have shown that an acidic pH exposes the hydrophobic surface of apoA1. We postulated that the V-ATPase (vacuolar ATPase) proton pump facilitates apoA1 unfolding and promotes ABCA1-mediated cholesterol efflux.

Approach and Results—

We found that V-ATPase inhibitors dose-dependently decreased ABCA1-mediated cholesterol efflux to apoA1 in baby hamster kidney cells and RAW264.7 cells; and similarly, siRNA knockdown of ATP6V
0
C inhibited ABCA1-mediated cholesterol efflux to apoA1 in RAW264.7 cells. Although ABCA1 expression did not alter total cellular levels of V-ATPase, ABCA1 increased the cell surface levels of the V
0
A1 and V
1
E1 subunits of V-ATPase. We generated a fluorescein isothiocyanate/Alexa647 double-labeled fluorescent ratiometric apoA1 pH indicator whose fluorescein isothiocyanate/Alexa647 emission ratio decreased as the pH drops. We found that ABCA1 induction in baby hamster kidney cells led to acidification of the cell-associated apoA1 pH indicator, compared with control cells without ABCA1 expression. The V-ATPase inhibitor bafilomycin A1 dose-dependently inhibited the apoA1 pH shift in ABCA1-expressing cells, without affecting the levels of cell-associated apoA1. However, we were not able to detect ABCA1-mediated extracellular proton release. We showed that acidic pH facilitated apoA1 unfolding, apoA1 solubilization of phosphatidycholine:phosphatidyserine liposomes, and increased lipid fluidity of these liposomes.

Conclusions—
Our results support a model that ABCA1 recruits V-ATPase to the plasma membrane where V-ATPase mediates apoA1 acidification and membrane remodeling that promote apoA1 unfolding and ABCA1-mediated HDL (high-density lipoprotein) biogenesis and lipid efflux.
Sin1 (Stress-Activated Protein Kinase-Interacting Protein) Regulates Ischemia-Induced Microthrombosis Through Integrin αIIbβ3-Mediated Outside-In Signaling and Hypoxia Responses in Platelets
Authors: Xu Yanyan , Ouyang Xinxing , Yan Lichong , Zhang Mingliang , Hu Zhenlei , Gu Jianmin , Fan Xuemei , Zhang Lin , Zhang Junfeng , Xue Song , Chen Guoqiang , Su Bing , Liu Junling 
Published: October 2018

Objective—
Microthrombosis as a serious consequence of myocardial infarction, impairs the microvascular environment and increases the occurrences of heart failure, arrhythmia, and death. Sin1 (stress-activated protein kinase-interacting protein) as an essential component of mTORC2 (mammalian target of rapamycin complex 2) is required for cell proliferation and metabolism in response to nutrients, stress, and reactive oxygen species and activates Akt and PKC (protein kinase C). However, the activation and function of Sin1/mTORC2 in ischemia-induced microthrombosis remain poorly understood.

Approach and Results—

The phosphorylation of the mTORC2 target Akt at S473 (serine 473) was significantly elevated in platelets from the distal end of left anterior descending obstructions from patients who underwent off-pump coronary artery bypass grafting compared with platelets from healthy subjects. Consistent with this finding, phosphorylation of T86 in Sin1 was also dramatically increased. Importantly, the augmented levels of phosphorylated Sin1 and Akt in platelets from 61 preoperative patients with ST-segment—elevation myocardial infarction correlated well with the no-reflow phenomena observed after revascularization. Platelet-specific Sin1 deficiency mice and Sin1 T86 phosphorylation deficiency mice were established to explore the underlying mechanisms in platelet activation. Mechanistically, Sin1 T86 phosphorylation amplifies mTORC2-mediated downstream signals; it is also required for αIIbβ3-mediated outside-in signaling and plays a role in generating hypoxia/reactive oxygen species through NAD
+
/Sirt3 (sirtuin 3)/SOD2 (superoxide dismutase 2) pathway. Importantly, Sin1 deletion in platelets protected mice from ischemia-induced microvascular embolization and subsequent heart dysfunction in a mouse model of myocardial infarction.

Conclusions—
Together, the results of our study reveal a novel role for Sin1 in platelet activation. Thus, Sin1 may be a valuable therapeutic target for interventions for ischemia-induced myocardial infarction deterioration.
Collagen Biomarkers and Incidence of New Onset of Atrial Fibrillation in Subjects With No Overt Cardiovascular Disease at Baseline
Authors: Duprez Daniel A. , Heckbert Susan R. , Alonso Alvaro , Gross Myron D. , Ix Joachim H. , Kizer Jorge R. , Tracy Russell P. , Kronmal Richard , Jacobs David R. 
Published: October 2018

Background:
Atrial fibrosis is a hallmark of structural remodeling in atrial fibrillation (AF). Plasma procollagen type III N-terminal propeptide (PIIINP) reflects collagen synthesis and degradation while collagen type I carboxy-terminal telopeptide (ICTP) reflects collagen degradation. We aimed to study baseline plasma PIIINP and ICTP and their associations with incident AF in participants initially free of overt cardiovascular disease.

Methods:

In a stratified sample of the Multi-Ethnic Study of Atherosclerosis, initially aged 45–84 years, 3071 participants had both PIIINP and ICTP measured at baseline. Incident AF in 10-year follow-up was based on a hospital
International Classification of Diseases
code for AF or atrial flutter, in- or outpatient Medicare claims through 2011 (primarily in those aged 65–84 years), or ECG 10 years after baseline (n=357). The associations of PIIINP and ICTP with incident AF were estimated using Poisson regression with follow-up time offset.

Results:

Baseline PIIINP (5.50±1.55 µg/L) and ICTP (mean±SD, 3.41±1.37 µg/L) were positively related (both
P
<0.0001) to incident AF in a model adjusting for age, race/ethnicity, and sex, with an apparent threshold (relative incidence density 2.81 [1.94–4.08] for PIIINP ≥8.5 µg/L [3.5% of the sample] and 3.46 [2.36–5.07] for ICTP ≥7 µg/L [1.7% of the sample]). Findings were attenuated but remained statistically significant after further adjustment for systolic blood pressure, height, body mass index, smoking, and renal function. Additional adjustment for other risk factors and biomarkers of inflammation did not alter conclusions.

Conclusions:
Plasma collagen biomarkers, particularly at elevated levels, were associated with excess risk for AF.
Covered CP Stent for Treatment of Right Ventricular Conduit Injury During Melody Transcatheter Pulmonary Valve Replacement
Authors: Delaney Jeffrey W. , Goldstein Bryan H. , Bishnoi Ram N. , Bisselou Karl S.M. , McEnaney Kerry , Minahan Matthew , Ringel Richard E. ,   for the PARCS Investigators
Published: October 2018

Background:
High-pressure balloon and stent angioplasty are frequently necessary to prepare the dysfunctional right ventricular outflow tract conduit before transcatheter pulmonary valve replacement (TPVR). Conduit injury can result, which may be catastrophic to the patient or prevent successful TPVR.

Methods and Results:
The PARCS trial (Pulmonary Artery Repair With Covered Stent) was a pivotal, prospective multicenter trial to evaluate the safety and efficacy of the NuMED Covered CP Stent (CCPS) for treatment of conduit injury occurring during TPVR. The study also evaluated immediate and short-term TPVR function in patients receiving covered stents. A total of 616 patients were consented; 120 (19.5%) had a wall injury identified and were treated with CCPS. Severe conduit injuries were uncommon (5%), but predictors for severe injury were not identified. Stenotic homografts had the highest incidence of injury (29%), compared with other conduit substrates. Among patients receiving CCPS implant, 96% required no further therapy for conduit injury, and 94% underwent TPVR at that procedure. Only 2 patients (1.6%) required urgent surgery for conduit injury, despite CCPS implant. There were few CCPS-related complications. TPVR function was similar between CCPS and non-CCPS groups at follow-up.

Conclusions:
Conduit injury during TPVR is common, although severe injury is rare. The CCPS was a safe and effective treatment for right ventricular outflow tract conduit injury during preparation for TPVR, allowing nearly all patients to complete the procedure without identifiable impact on valve performance.

Clinical Trial Registration:

URL:
https://www.clinicaltrials.gov
. Unique identifier: NCT01824160.
Clinical Model to Predict 90-Day Risk of Readmission After Acute Myocardial Infarction
Authors: Kini Vinay , Peterson Pamela N. , Spertus John A. , Kennedy Kevin F. , Arnold Suzanne V. , Wasfy Jason H. , Curtis Jeptha P. , Bradley Steven M. , Amin Amit P. , Ho P. Michael , Masoudi Frederick A. 
Published: October 2018

Background:
Readmissions within 30 days after acute myocardial infarction have been used as a performance metric for hospitals. However, evolving concepts of value-based reimbursement have shifted the focus to 90 days after hospital discharge. Tools are needed to determine risk for 90-day readmission to identify patients who might benefit from enhanced transitional healthcare resources.

Methods and Results:
In this cohort study, we identified all Medicare beneficiaries with a primary diagnosis of acute myocardial infarction who were discharged from hospitals participating in National Cardiovascular Data Registry ACTION registry between 2008 and 2014. Among a random 70% sample (derivation cohort), we performed hierarchical proportional hazards regression, accounting for death as a competing risk, to assess predictors of all-cause readmission within 90 days. Models were validated in the remaining 30%. Among 86 849 unique patients, 23 912 (27.5%) were readmitted within 90 days. Of the readmissions, 55% occurred within 30 days and 81% occurred within 60 days. Predictors of readmission included older age and a history of diabetes mellitus or heart failure. Coronary revascularization was associated with a lower risk of readmission. A simple risk score incorporating patient demographic and clinical characteristics known before discharge identified groups of patients with readmission risks ranging from 13.1% to 42.9%. Model discrimination was moderate (C statistic=0.662), and calibration was excellent (slope=0.97, intercept=−0.04).

Conclusions:
Readmission within 90 days of hospitalization for acute myocardial infarction can be predicted by variables known before discharge and offers the potential to prospectively design transitional care to the risks of individual patients.