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Wu, Connie

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Wu

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Connie

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Wu, Connie
Author's Publications: search.filters.isAuthorOfPublication.cd61985c-1881-4dd7-a796-95d72a69de9a

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Now showing 1 - 7 of 7
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    MicroRNA miR-425 is a negative regulator of atrial natriuretic peptide
    (BioMed Central, 2013) Arora, Pankaj; Wu, Connie; Bloch, Donald; Davis-Dusenbury, Brandi N; Spagnolli, Ester; Hata, Akiko; Vandenwijngaert, Sara; Swinnen, Melissa; Janssens, Stefan; Buys, Emmanuel; Bloch, Kenneth; Newton-Cheh, Christopher; Wang, Thomas Jue-Fuu
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    LMKB/MARF1 Localizes to mRNA Processing Bodies, Interacts with Ge-1, and Regulates IFI44L Gene Expression
    (Public Library of Science, 2014) Bloch, Donald; Li, Pingcheng; Bloch, Emily G.; Berenson, Daniel F.; Galdos, Rita L.; Arora, Pankaj; Malhotra, Rajeev; Wu, Connie; Yang, Weihong
    The mRNA processing body (P-body) is a cellular structure that regulates the stability of cytoplasmic mRNA. MARF1 is a murine oocyte RNA-binding protein that is associated with maintenance of mRNA homeostasis and genomic stability. In this study, autoantibodies were used to identify Limkain B (LMKB), the human orthologue of MARF1, as a P-body component. Indirect immunofluorescence demonstrated that Ge-1 (a central component of the mammalian core-decapping complex) co-localized with LMKB in P-bodies. Two-hybrid and co-immunoprecipitation assays were used to demonstrate interaction between Ge-1 and LMKB. The C-terminal 120 amino acids of LMKB mediated interaction with Ge-1 and the N-terminal 1094 amino acids of Ge-1 were required for interaction with LMKB. LMKB is the first protein identified to date that interacts with this portion of Ge-1. LMKB was expressed in human B and T lymphocyte cell lines; depletion of LMKB increased expression of IFI44L, a gene that has been implicated in the cellular response to Type I interferons. The interaction between LMKB/MARF1, a protein that contains RNA-binding domains, and Ge-1, which interacts with core-decapping proteins, suggests that LMKB has a role in the regulation of mRNA stability. LMKB appears to have different functions in different cell types: maintenance of genomic stability in developing oocytes and possible dampening of the inflammatory response in B and T cells.
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    Atrial natriuretic peptide is negatively regulated by microRNA-425
    (American Society for Clinical Investigation, 2013) Arora, Pankaj; Wu, Connie; Khan, Abigail May; Bloch, Donald; Davis-Dusenbery, Brandi N; Ghorbani, Anahita; Spagnolli, Ester; Martinez, Andrew; Ryan, Allicia; Tainsh, Laurel T.; Kim, Samuel M; Rong, Jian; Huan, Tianxiao; Freedman, Jane E.; Levy, Daniel; Miller, Karen; Hata, Akiko; Del Monte, Federica; Vandenwijngaert, Sara; Swinnen, Melissa; Janssens, Stefan; Holmes, Tara M.; Buys, Emmanuel; Bloch, Kenneth; Newton-Cheh, Christopher; Wang, Thomas Jue-Fuu
    Numerous common genetic variants have been linked to blood pressure, but no underlying mechanism has been elucidated. Population studies have revealed that the variant rs5068 (A/G) in the 3′ untranslated region of NPPA, the gene encoding atrial natriuretic peptide (ANP), is associated with blood pressure. We selected individuals on the basis of rs5068 genotype (AG vs. AA) and fed them a low- or high-salt diet for 1 week, after which they were challenged with an intravenous saline infusion. On both diets, before and after saline administration, ANP levels were up to 50% higher in AG individuals than in AA individuals, a difference comparable to the changes induced by high-salt diet or saline infusion. In contrast, B-type natriuretic peptide levels did not differ by rs5068 genotype. We identified a microRNA, miR-425, that is expressed in human atria and ventricles and is predicted to bind the sequence spanning rs5068 for the A, but not the G, allele. miR-425 silenced NPPA mRNA in an allele-specific manner, with the G allele conferring resistance to miR-425. This study identifies miR-425 as a regulator of ANP production, raising the possibility that miR-425 antagonists could be used to treat disorders of salt overload, including hypertension and heart failure.
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    Weight Loss, Saline Loading, and the Natriuretic Peptide System
    (Ovid Technologies (Wolters Kluwer Health), 2015) Arora, P.; Reingold, J.; Baggish, Aaron; Guanaga, Derek Philip; Wu, Connie; Ghorbani, Anahita; Song, Y.; Chen-Tournaux, A.; Khan, A. M.; Tainsh, L. T.; Buys, Emmanuel; Williams, Jonathan; Heublein, D. M.; Burnett, J. C.; Semigran, Marc J.; Bloch, K. D.; Scherrer-Crosbie, Marielle; Newton-Cheh, Christopher; Kaplan, Lee; Wang, T. J.
    Background-—In epidemiologic studies, obesity has been associated with reduced natriuretic peptide (NP) concentrations. Reduced NP production could impair the ability of obese individuals to respond to salt loads, increasing the risk of hypertension and other disorders. We hypothesized that weight loss enhances NP production before and after salt loading. Methods and Results-—We enrolled 15 obese individuals (mean BMI 45 5.4 kg/m2) undergoing gastric bypass surgery. Before and 6 months after surgery, subjects were admitted to the clinical research center and administered a large-volume intravenous saline challenge. Echocardiography and serial blood sampling were performed. From the pre-operative visit to 6 months after surgery, subjects had a mean BMI decrease of 27%. At the 6-month visit, N-terminal pro-atrial NP (Nt-proANP) levels were 40% higher before, during, and after the saline infusion, compared with levels measured at the same time points during the pre-operative visit (P<0.001). The rise in Nt-pro-ANP induced by the saline infusion (50%) was similar both before and after surgery (saline, P<0.001; interaction, P=0.2). Similar results were obtained for BNP and Nt-proBNP; resting concentrations increased by 50% and 31%, respectively, after gastric bypass surgery. The increase in NP concentrations after surgery was accompanied by significant decreases in mean arterial pressure (P=0.004) and heart rate (P<0.001), and an increase in mitral annular diastolic velocity (P=0.02). Conclusion-—In obese individuals, weight loss is associated with a substantial increase in the “setpoint” of circulating NP concentrations. Higher NP concentrations could contribute to an enhanced ability to handle salt loads after weight loss.
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    Calcification of Vascular Smooth Muscle Cells and Imaging of Aortic Calcification and Inflammation
    (MyJove Corporation, 2016) O'Rourke, Caitlin; Shelton, Georgia; Hutcheson, Joshua; Burke, Megan F.; Martyn, Trejeeve; Thayer, Timothy E.; Shakartzi, Hannah R.; Buswell, Mary D.; Tainsh, Robert; Yu, Binglan; Bagchi, Aranya; Rhee, David Kwan; Wu, Connie; Derwall, Matthias; Buys, Emmanuel; Yu, Paul; Bloch, Kenneth; Aikawa, Elena; Bloch, Donald; Malhotra, Rajeev
    Cardiovascular disease is the leading cause of morbidity and mortality in the world. Atherosclerotic plaques, consisting of lipid-laden macrophages and calcification, develop in the coronary arteries, aortic valve, aorta, and peripheral conduit arteries and are the hallmark of cardiovascular disease. In humans, imaging with computed tomography allows for the quantification of vascular calcification; the presence of vascular calcification is a strong predictor of future cardiovascular events. Development of novel therapies in cardiovascular disease relies critically on improving our understanding of the underlying molecular mechanisms of atherosclerosis. Advancing our knowledge of atherosclerotic mechanisms relies on murine and cell-based models. Here, a method for imaging aortic calcification and macrophage infiltration using two spectrally distinct near-infrared fluorescent imaging probes is detailed. Near-infrared fluorescent imaging allows for the ex vivo quantification of calcification and macrophage accumulation in the entire aorta and can be used to further our understanding of the mechanistic relationship between inflammation and calcification in atherosclerosis. Additionally, a method for isolating and culturing animal aortic vascular smooth muscle cells and a protocol for inducing calcification in cultured smooth muscle cells from either murine aortas or from human coronary arteries is described. This in vitro method of modeling vascular calcification can be used to identify an characterize the signaling pathways likely important for the development of vascular disease, in the hopes of discovering novel targets for therapy.
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    Novel MicroRNA Regulators of Atrial Natriuretic Peptide Production
    (American Society for Microbiology, 2016) Wu, Connie; Arora, Pankaj; Agha, Obiajulu; Hurst, Liam A.; Allen, Kaitlin; Nathan, Daniel I.; Hu, Dongjian; Jiramongkolchai, Pawina; Smith, J. Gustav; Melander, Olle; Trenson, Sander; Janssens, Stefan P.; Domian, Ibrahim; Wang, Thomas J.; Bloch, Kenneth; Buys, Emmanuel; Bloch, Donald; Newton-Cheh, Christopher
    Atrial natriuretic peptide (ANP) has a central role in regulating blood pressure in humans. Recently, microRNA 425 (miR-425) was found to regulate ANP production by binding to the mRNA of NPPA, the gene encoding ANP. mRNAs typically contain multiple predicted microRNA (miRNA)-binding sites, and binding of different miRNAs may independently or coordinately regulate the expression of any given mRNA. We used a multifaceted screening strategy that integrates bioinformatics, next-generation sequencing data, human genetic association data, and cellular models to identify additional functional NPPA-targeting miRNAs. Two novel miRNAs, miR-155 and miR-105, were found to modulate ANP production in human cardiomyocytes and target genetic variants whose minor alleles are associated with higher human plasma ANP levels. Both miR-15 and miR-105 repressed NPPA mRNA in an allele-specific manner, with the minor allele of each respective variant conferrin resistance to the miRNA either by disruption of miRNA base pairing or by creation of wobble base pairing. Moreover, miR-15 enhanced the repressive effects of miR-425 on ANP production in human cardiomyocytes. Our study combines computational genomic, and cellular tools to identify novel miRNA regulators of ANP production that could be targeted to raise ANP levels which may have applications for the treatment of hypertension or heart failure.
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