Atlanta Veterans Administration Medical Center

Decatur, GA, United States

Atlanta Veterans Administration Medical Center

Decatur, GA, United States
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News Article | November 15, 2016

NEW ORLEANS, Nov. 15, 2016 -- Poverty and black race are independently predictive of greater amputation risk among patients with narrowing of the blood vessels, or peripheral artery disease (PAD), according to preliminary research presented at the American Heart Association's Scientific Sessions 2016. PAD is a serious disease that occurs when fat, cholesterol, and other substances accumulate in blood vessels away from the heart, restricting blood flow. In addition to increasing the risk for heart attack and stroke, untreated PAD can cause gangrene, or tissue death, requiring amputation. Usually affecting the legs, PAD can cause symptoms such as pain and cramping during walking or other activity that disappear with rest, although some patients have no symptoms at all. Using data from 208,194 veterans with PAD in the Veterans Affairs database from 2003 to 2014, researchers found: "There may be biological mechanisms still unknown as to why black patients are at a higher risk for amputations in PAD, but access to care is an important independent contributor to the risk," said study lead author Shipra Arya, M.D., S.M., assistant professor of surgery at Emory University School of Medicine in Atlanta, Georgia, and vascular surgeon at the Atlanta Veterans Administration Medical Center in Decatur. "Treatment for PAD is multimodal. It includes optimal medical management of risk factors associated with cardiovascular disease, in addition to supervised exercise, which is not yet covered by insurance." Researchers compared PAD amputations by socioeconomic status across different zip codes nationwide, defining the poorest communities as those with more than 30 percent of inhabitants below the poverty level. Sixteen percent of participants were black, 83 percent were white, and almost all were male. During an average follow-up of just over five years, 14,981 major amputations occurred. Previous evidence indicated that the risk of amputation was greater among blacks than among whites, but whether this difference stemmed from biological factors or access to care and other socioeconomic factors was unclear. Accordingly, investigators examined the risk of PAD amputation by race and socioeconomic status as indicators for access to care. "Patients living in zip codes with a high poverty burden also have incrementally higher risk of amputation, suggesting a role for access to care in determining outcomes for PAD," Arya said. The main risk factors for developing PAD are smoking, diabetes, high blood pressure and high cholesterol. Fortunately, PAD usually is easily treatable with lifestyle changes and medication. The study was observational so could only identify associations, not causes. Researchers also caution that the study included mostly male veterans, so its findings may not apply to other groups. Statements and conclusions of study authors that are presented at American Heart Association scientific meetings are solely those of the study authors and do not necessarily reflect association policy or position. The association makes no representation or warranty as to their accuracy or reliability. The association receives funding primarily from individuals; foundations and corporations (including pharmaceutical, device manufacturers and other companies) also make donations and fund specific association programs and events. The association has strict policies to prevent these relationships from influencing the science content. Revenues from pharmaceutical and device corporations are available at http://www. .

Ishikawa C.,University of Ryukyus | Arbiser J.L.,Emory University | Arbiser J.L.,Atlanta Veterans Administration Medical Center | Mori N.,University of Ryukyus
Biochimica et Biophysica Acta - General Subjects | Year: 2012

Background: Honokiol, a naturally occurring biphenyl, possesses anti-neoplastic properties. We investigated activities of honokiol against adult T-cell leukemia (ATL) associated with human T-cell leukemia virus type 1 (HTLV-1). Methods: Cell viability was assessed using colorimetric assay. Propidium iodide staining was performed to determine cell cycle phase. Apoptotic effects were evaluated by 7A6 detection and caspases activity. Expressions of cell cycle- and apoptosis-associated proteins were analyzed by Western blot. We investigated the efficacy of honokiol in mice harboring tumors of HTLV-1-infected T-cell origin. Results: Honokiol exhibited cytotoxic activity against HTLV-1-infected T-cell lines and ATL cells. We identified two different effects of honokiol on HTLV-1-infected T-cell lines: cell cycle inhibition and induction of apoptosis. Honokiol induced G1 cell cycle arrest by reducing the expression of cyclins D1, D2, E, CDK2, CDK4, CDK6 and c-Myc, while apoptosis was induced via reduced expression of cIAP-2, XIAP and survivin. The induced apoptosis was also associated with activation of caspases-3 and -9. In addition, honokiol suppressed the phosphorylation of IκBα, IKKα, IKKβ, STAT3, STAT5 and Akt, down-regulated JunB and JunD, and inhibited DNA binding of NF-κB, AP-1, STAT3 and STAT5. These effects resulted in the inactivation of survival signals including NF-κB, AP-1, STATs and Akt. Honokiol was highly effective against ATL in mice Conclusions: Our data suggested that honokiol is a systemically available, non-toxic inhibitor of ATL cell growth that should be examined for potential clinical application. General significance: Our findings provide a rationale for clinical evaluation of honokiol for the management of ATL. © 2012 Elsevier B.V. All rights reserved.

Baker M.B.,Emory University | Bao G.,Georgia Institute of Technology | Searles C.D.,Emory University | Searles C.D.,Atlanta Veterans Administration Medical Center
Nucleic Acids Research | Year: 2012

MicroRNAs (miRNAs), a class of non-coding RNAs, have become a major focus of molecular biology research because of their diverse genomic origin and ability to regulate an array of cellular processes. Although the biological functions of miRNA are yet to be fully understood, tissue levels of specific miRNAs have been shown to correlate with pathological development of disease. Here, we demonstrate that molecular beacons can readily distinguish mature- and pre-miRNAs, and reliably quantify miRNA expression. We found that molecular beacons with DNA, RNA and combined locked nucleic acid (LNA)-DNA backbones can all detect miRNAs of low (<1nM) concentrations in vitro, with RNA beacons having the highest detection sensitivity. Furthermore, we found that molecular beacons have the potential to distinguish miRNAs that have slight variations in their nucleotide sequence. These results suggest that the molecular beacon-based approach to assess miRNA expression and distinguish mature and precursor miRNA species is quite robust, and has the promise for assessing miRNA levels in biological samples. non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited. © The Author(s) 2011. Published by Oxford University Press.

Gray W.D.,Georgia Institute of Technology | Gray W.D.,Emory University | French K.M.,Georgia Institute of Technology | Ghosh-Choudhary S.,Georgia Institute of Technology | And 7 more authors.
Circulation Research | Year: 2015

RATIONALE:: Myocardial infarction is a leading cause of death in developed nations, and there remains a need for cardiac therapeutic systems that mitigate tissue damage. Cardiac progenitor cells (CPCs) and other stem cell types are attractive candidates for treatment of myocardial infarction; however, the benefit of these cells may be as a result of paracrine effects. OBJECTIVE:: We tested the hypothesis that CPCs secrete proregenerative exosomes in response to hypoxic conditions. METHODS AND RESULTS:: The angiogenic and antifibrotic potential of secreted exosomes on cardiac endothelial cells and cardiac fibroblasts were assessed. We found that CPC exosomes secreted in response to hypoxia enhanced tube formation of endothelial cells and decreased profibrotic gene expression in TGF-β-stimulated fibroblasts, indicating that these exosomes possess therapeutic potential. Microarray analysis of exosomes secreted by hypoxic CPCs identified 11 miRNAs that were upregulated compared with exosomes secreted by CPCs grown under normoxic conditions. Principle component analysis was performed to identify miRNAs that were coregulated in response to distinct exosome-generating conditions. To investigate the cue-signal-response relationships of these miRNA clusters with a physiological outcome of tube formation or fibrotic gene expression, partial least squares regression analysis was applied. The importance of each up-or downregulated miRNA on physiological outcomes was determined. Finally, to validate the model, we delivered exosomes after ischemia-reperfusion injury. Exosomes from hypoxic CPCs improved cardiac function and reduced fibrosis. CONCLUSIONS:: These data provide a foundation for subsequent research of the use of exosomal miRNA and systems biology as therapeutic strategies for the damaged heart. © 2014 American Heart Association, Inc.

Bonner M.Y.,Emory University | Bonner M.Y.,Atlanta Veterans Administration Medical Center | Arbiser J.L.,Emory University | Arbiser J.L.,Atlanta Veterans Administration Medical Center
Cellular and Molecular Life Sciences | Year: 2012

NADPH oxidases are a family of oxidases that utilize molecular oxygen to generate hydrogen peroxide and superoxide, thus indicating physiological functions of these highly reactive and short-lived species. The regulation of these NADPH oxidases (nox) enzymes is complex, with many members of this family exhibiting complexity in terms of subunit composition, cellular location, and tissuespecific expression. While the complexity of the nox family (Nox1-5, Duox1, 2) is daunting, the complexity also allows for targeting of NADPH oxidases in disease states. In this review, we discuss which inflammatory and malignant disorders can be targeted by nox inhibitors, as well as clinical experience in the use of such inhibitors.

Weber M.,Emory University | Baker M.B.,Emory University | Moore J.P.,Emory University | Searles C.D.,Emory University | Searles C.D.,Atlanta Veterans Administration Medical Center
Biochemical and Biophysical Research Communications | Year: 2010

Mechanical forces associated with blood flow play an important role in regulating vascular signaling and gene expression in endothelial cells (ECs). MicroRNAs (miRNAs) are a class of noncoding RNAs that posttranscriptionally regulate the expression of genes involved in diverse cell functions, including differentiation, growth, proliferation, and apoptosis. miRNAs are known to have an important role in modulating EC biology, but their expression and functions in cells subjected to shear stress conditions are unknown. We sought to determine the miRNA expression profile in human ECs subjected to unidirectional shear stress and define the role of miR-21 in shear stress-induced changes in EC function. TLDA array and qRT-PCR analysis performed on HUVECs exposed to prolonged unidirectional shear stress (USS, 24 h, 15 dynes/cm2) identified 13 miRNAs whose expression was significantly upregulated (p < 0.05). The miRNA with the greatest change was miR-21; it was increased 5.2-fold (p = 0.002) in USS-treated versus control cells. Western analysis demonstrated that PTEN, a known target of miR-21, was downregulated in HUVECs exposed to USS or transfected with pre-miR-21. Importantly, HUVECs overexpressing miR-21 had decreased apoptosis and increased eNOS phosphorylation and nitric oxide (NO{radical dot}) production. These data demonstrate that shear stress forces regulate the expression of miRNAs in ECs, and that miR-21 influences endothelial biology by decreasing apoptosis and activating the NO{radical dot} pathway. These studies advance our understanding of the mechanisms by which shear stress forces modulate vascular homeostasis.

Weber M.,Emory University | Kim S.,Emory University | Patterson N.,Emory University | Rooney K.,Emory University | And 2 more authors.
American Journal of Physiology - Heart and Circulatory Physiology | Year: 2014

Previously, we identified a microRNA (miRNA) signature for endothelial cells (ECs) subjected to unidirectional shear stress (USS). MiR-155, a multifunctional miRNA that has been implicated in atherosclerosis, was among the shear stress-responsive miRNAs. Here, we examined the role of miR-155 in modulating EC phenotype and function. In vitro, increased miR-155 levels in human ECs induced changes in morphology and filamentous (F)-actin organization. In addition, ECs transfected with miR-155 mimic were less migratory and less proliferative and had less apoptosis compared with control ECs. In mouse aorta, miR-155 expression was increased in the intima of thoracic aorta, where blood flow produces steady and unidirectional shear stress, compared with the intima of the lower curvature of the aortic arch, which is associated with oscillatory and low shear stress. These differences in miR-155 expression were associated with distinct changes in EC morphology and F-actin. The effects of miR-155 in vitro were mediated through suppression of two key regulators of the EC cytoskeleton organization: RhoA and myosin light chain kinase (MYLK). A novel direct interaction between miR-155 and the MYLK 3′UTR was verified by luciferase-MYLK 3′UTR reporter assays. Furthermore, the intensity of immunofluorescence staining for RhoA and MYLK in mouse aorta correlated inversely with miR-155 expression. In conclusion, a prominent effect of the multifunctional miR-155 in ECs is modulation of phenotype through alterations in RhoA, MYLK expression, and actin cytoskeleton organization. © 2014 the American Physiological Society.

Brown R.H.,Atlanta Veterans Administration Medical Center | Zhong L.,University of Miami | Lynch M.G.,Emory University
Journal of Cataract and Refractive Surgery | Year: 2014

Cataract surgery has been demonstrated to lower intraocular pressure (IOP) in eyes with glaucoma. The evidence is strong in angle-closure patients that cataract surgery improves IOP and dramatically reduces the future risk for IOP spikes and acute attacks. Randomized controlled trials (RCTs) have shown that cataract surgery may be preferable to laser iridotomy or phacotrabeculectomy. The data are so convincing that an RCT has been undertaken to assess whether clear lens extraction may be appropriate following acute attacks and in cases of uncontrolled IOP. The case favoring cataract surgery in open-angle glaucoma (OAG) is more controversial. Impressive IOP reduction has been shown in OAG patients when the patients are stratified by preoperative IOP. The patients with the highest preoperative IOPs have pressure reductions up to 8.5 mm Hg. However, these findings have been criticized for methodological weaknesses. Combining cataract surgery with microinvasive glaucoma surgery in phaco-plus procedures provides further options for lens-based glaucoma surgery. Financial Disclosure No author has a financial or proprietary interest in any material or method mentioned. © 2014 ASCRS and ESCRS.

Finn N.A.,Emory University | Searles C.D.,Emory University | Searles C.D.,Atlanta Veterans Administration Medical Center
Current Angiogenesis | Year: 2012

Angiogenesis, the process by which new blood vessels are formed, is a critical phenomenon that is activated during various stages of mammalian development. MicroRNAs (miRNAs), a class of short, single stranded, non-coding RNAs, are recognized as important regulators of angiogenesis, and the role of intracellular miRNAs in modulating angiogenesis signaling has been identified. The recent discovery of extracellular and circulating miRNAs has sparked new questions regarding their potential in modulating angiogenesis signaling not only within cells but also between cells. In this review, we discuss the characteristics of intracellular and extracellular miRNAs and decipher the potential functional roles for these molecules in regard to the angiogenic process. We summarize what is currently known about circulating miRNAs in distinct clinical populations and discuss evidence that implicates extracellular miRNAs as novel mediators of angiogenesis-associated intercellular signaling. Lastly, we offer a new perspective on the functional role of vesicleencapsulated circulating miRNA in modulating angiogenesis signaling pathways. © 2012 Bentham Science Publishers.

Arbiser J.L.,Atlanta Veterans Administration Medical Center
Blood | Year: 2011

In this issue of Blood, Lakshmikanthan et al examine the relative roles of the closely related rap1a and rap1bGproteins in angiogenesis.1 Based on previous findings in which angiogenesis was found to be defective in mice with complete knockout of both rap1a and rap1b, they created mice in which rap1 genes were specifically knocked out in endothelium.

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