Time filter

Source Type

East Northport, NY, United States

Streeter J.,University of Iowa | Schickling B.M.,University of Iowa | Jiang S.,University of Iowa | Stanic B.,University of Iowa | And 5 more authors.
Circulation Research | Year: 2014

Rationale: Activation of Nox1 initiates redox-dependent signaling events crucial in the pathogenesis of vascular disease. Selective targeting of Nox1 is an attractive potential therapy, but requires a better understanding of the molecular modifications controlling its activation. Objective: To determine whether posttranslational modifications of Nox1 regulate its activity in vascular cells. Methods and Results: We first found evidence that Nox1 is phosphorylated in multiple models of vascular disease. Next, studies using mass spectroscopy and a pharmacological inhibitor demonstrated that protein kinase C-beta1 mediates phosphorylation of Nox1 in response to tumor necrosis factor-α. siRNA-mediated silencing of protein kinase C-beta1 abolished tumor necrosis factor-α-mediated reactive oxygen species production and vascular smooth muscle cell migration. Site-directed mutagenesis and isothermal titration calorimetry indicated that protein kinase C-beta1 phosphorylates Nox1 at threonine 429. Moreover, Nox1 threonine 429 phosphorylation facilitated the association of Nox1 with the NoxA1 activation domain and was necessary for NADPH oxidase complex assembly, reactive oxygen species production, and vascular smooth muscle cell migration. Conclusions: We conclude that protein kinase C-beta1 phosphorylation of threonine 429 regulates activation of Nox1 NADPH oxidase. (Circ Res. 2014;115:911-918.) © 2014 American Heart Association, Inc.

Steyers III C.M.,University of Iowa | Miller Jr. F.J.,University of Iowa | Miller Jr. F.J.,Veterans Affair Medical Center
International Journal of Molecular Sciences | Year: 2014

Chronic inflammatory diseases are associated with accelerated atherosclerosis and increased risk of cardiovascular diseases (CVD). As the pathogenesis of atherosclerosis is increasingly recognized as an inflammatory process, similarities between atherosclerosis and systemic inflammatory diseases such as rheumatoid arthritis, inflammatory bowel diseases, lupus, psoriasis, spondyloarthritis and others have become a topic of interest. Endothelial dysfunction represents a key step in the initiation and maintenance of atherosclerosis and may serve as a marker for future risk of cardiovascular events. Patients with chronic inflammatory diseases manifest endothelial dysfunction, often early in the course of the disease. Therefore, mechanisms linking systemic inflammatory diseases and atherosclerosis may be best understood at the level of the endothelium. Multiple factors, including circulating inflammatory cytokines, TNF-α (tumor necrosis factor-α), reactive oxygen species, oxidized LDL (low density lipoprotein), autoantibodies and traditional risk factors directly and indirectly activate endothelial cells, leading to impaired vascular relaxation, increased leukocyte adhesion, increased endothelial permeability and generation of a pro-thrombotic state. Pharmacologic agents directed against TNF-α-mediated inflammation may decrease the risk of endothelial dysfunction and cardiovascular disease in these patients. Understanding the precise mechanisms driving endothelial dysfunction in patients with systemic inflammatory diseases may help elucidate the pathogenesis of atherosclerosis in the general population. © 2014 by the authors; licensee MDPI, Basel, Switzerland.

Sheehan A.L.,University of Iowa | Carrell S.,University of Iowa | Johnson B.,University of Iowa | Stanic B.,University of Iowa | And 3 more authors.
Atherosclerosis | Year: 2011

Objective: Examine the contribution of Nox1 NADPH oxidase to atherogenesis. Methods and results: Male apolipoprotein E deficient mice (ApoE-/-) and male mice deficient in both apolipoprotein E and Nox1 (ApoE-/- Nox1-/y) received an atherogenic diet for 18 weeks. Mean blood pressures, body weights, and serum cholesterol levels were similar between the two groups of mice. Deficiency of Nox1 decreased superoxide levels and reduced lesion area in the aortic arch from 43% (ApoE-/-) to 28% (ApoE-/- Nox1-/y). The reduction in lesion size at the level of the aortic valve in ApoE-/-/Nox1-/y was accompanied by a decrease in macrophage infiltration as compared to ApoE-/- mice. Carotid artery ligation in ApoE-/- mice induced accelerated intimal hyperplasia with decreased cellular proliferation and increased collagen content in the neointima of vessels deficient in Nox1. Conclusions: Nox1-derived ROS modify lesion composition and contribute to lesion size in a murine model of atherosclerosis. © 2011.

Leather H.,University of Florida | Walden E.O.,University of Florida | Laplant K.D.,Veterans Affair Medical Center
Journal of the National Cancer Institute | Year: 2010

Background: Randomized controlled trials (RCTs) improve clinical care through evidence-based results. Guidelines exist for RCT result reporting, but specific details of therapeutic administration promote clinical application and reproduction of the trial design. We assess the reporting methodology in RCTs published in major oncology journals. Methods: Ten essential elements of RCT reporting were identified and included drug name, dose, route, cycle length, maximum number of cycles, premedication, growth factor support, patient monitoring parameters, and dosing adjustments for hematologic and organ-specific toxicity. All therapy-based oncology RCTs published between 2005 and 2008 in the New England Journal of Medicine (NEJM), Journal of Clinical Oncology (JCO), Journal of the National Cancer Institute (JNCI), Blood, and Cancer were analyzed for inclusion of these 10 elements. Results: Of 339 identified articles, 262 were included in the final analysis (165 from JCO, 31 from NEJM, 27 from Cancer, 20 from JNCI, and 19 from Blood). Premedication, growth factor support, and dose adjustments for toxicities were each reported less than half of the time. Only 30 articles (11%) met the main objective of complete data reporting (ie, all 10 essential elements) and was highest in JNCI (5/20; 25%), followed by Cancer (5/27; 18%), JCO (18/165; 11%), Blood (1/19; 5%), and NEJM (1/31; 3%). The presence of an online appendix did not substantially improve complete reporting. Conclusions: RCTs published in major oncology journals do not consistently report essential therapeutic details necessary for translation of the trial findings to clinical practice. Potential solutions to improve reporting include modification of submission guidelines, use of online appendices, and providing open access to trial protocols. © The Author 2010. Published by Oxford University Press. All rights reserved.

Jiang S.,University of Iowa | Streeter J.,University of Iowa | Schickling B.M.,University of Iowa | Zimmerman K.,University of Iowa | And 3 more authors.
Cardiovascular Research | Year: 2014

AimsIschaemic preconditioning (IPC) is an adaptive mechanism that renders the myocardium resistant to injury from subsequent hypoxia. Although reactive oxygen species (ROS) contribute to both the early and late phases of IPC, their enzymatic source and associated signalling events have not yet been understood completely. Our objective was to investigate the role of the Nox1 NADPH oxidase in cardioprotection provided by IPC.Methods and resultsWild-type (WT) and Nox1-deficient mice were treated with three cycles of brief coronary occlusion and reperfusion, followed by prolonged occlusion either immediately (early IPC) or after 24 h (late IPC). Nox1 deficiency had no impact on the cardioprotection afforded by early IPC. In contrast, deficiency of Nox1 during late IPC resulted in a larger infarct size, cardiac remodelling, and increased myocardial apoptosis compared with WT hearts. Furthermore, expression of Nox1 in WT hearts increased in response to late IPC. Deficiency of Nox1 abrogated late IPC-mediated activation of cardiac nuclear factor-κB (NF-κB) and induction of tumour necrosis factor-α (TNF-α) in the heart and circulation. Finally, knockdown of Nox1 in cultured cardiomyocytes prevented TNF-α induction of NF-κB and the protective effect of IPC on hypoxia-induced apoptosis.ConclusionsOur data identify a critical role for Nox1 in late IPC and define a previously unrecognized link between TNF-α and NF-κB in mediating tolerance to myocardial injury. These findings have clinical significance considering the emergence of Nox1 inhibitors for the treatment of cardiovascular disease. © 2014 The Author.

Discover hidden collaborations