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Tainsh, Robert

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Tainsh

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Robert

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Tainsh, Robert
Author's Publications: search.filters.isAuthorOfPublication.1207a2e1-3d14-4602-9817-cc32549426fd

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    Genetic modifiers of hypertension in soluble guanylate cyclase α1–deficient mice
    (American Society for Clinical Investigation, 2012) Buys, Emmanuel; Raher, Michael J.; Kirby, Andrew; Mohd, Shahid; Baron, David; Hayton, Sarah R.; Tainsh, Laurel T.; Sips, Patrick; Rauwerdink, Kristen M.; Yan, Qingshang; Tainsh, Robert; Shakartzi, Hannah R.; Stevens, Christine; Decaluwé, Kelly; Rodrigues-Machado, Maria da Gloria; Malhotra, Rajeev; Van de Voorde, Johan; Wang, Tong; Brouckaert, Peter; Daly, Mark; Bloch, Kenneth
    Nitric oxide (NO) plays an essential role in regulating hypertension and blood flow by inducing relaxation of vascular smooth muscle. Male mice deficient in a NO receptor component, the α1 subunit of soluble guanylate cyclase (sGCα1), are prone to hypertension in some, but not all, mouse strains, suggesting that additional genetic factors contribute to the onset of hypertension. Using linkage analyses, we discovered a quantitative trait locus (QTL) on chromosome 1 that was linked to mean arterial pressure (MAP) in the context of sGCα1 deficiency. This region is syntenic with previously identified blood pressure–related QTLs in the human and rat genome and contains the genes coding for renin. Hypertension was associated with increased activity of the renin-angiotensin-aldosterone system (RAAS). Further, we found that RAAS inhibition normalized MAP and improved endothelium-dependent vasorelaxation in sGCα1-deficient mice. These data identify the RAAS as a blood pressure–modifying mechanism in a setting of impaired NO/cGMP signaling.
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    Cardiovascular and pharmacological implications of haem-deficient NO-unresponsive soluble guanylate cyclase knock-in mice
    (Springer Nature, 2015) Thoonen, Robrecht; Cauwels, Anje; Decaluwe, Kelly; Geschka, Sandra; Tainsh, Robert; Delanghe, Joris; Hochepied, Tino; De Cauwer, Lode; Rogge, Elke; Voet, Sofie; Sips, Patrick; Karas, Richard H.; Bloch, Kenneth; Vuylsteke, Marnik; Stasch, Johannes-Peter; Van de Voorde, Johan; Buys, Emmanuel; Brouckaert, Peter
    Oxidative stress, a central mediator of cardiovascular disease, results in loss of the prosthetic haem group of soluble guanylate cyclase (sGC), preventing its activation by nitric oxide (NO). Here we introduce Apo-sGC mice expressing haem-free sGC. Apo-sGC mice are viable and develop hypertension. The haemodynamic effects of NO are abolished, but those of the sGC activator cinaciguat are enhanced in apo-sGC mice, suggesting that the effects of NO on smooth muscle relaxation, blood pressure regulation and inhibition of platelet aggregation require sGC activation by NO. Tumour necrosis factor (TNF)-induced hypotension and mortality are preserved in apo-sGC mice, indicating that pathways other than sGC signalling mediate the cardiovascular collapse in shock. Apo-sGC mice allow for differentiation between sGC-dependent and -independent NO effects and between haem-dependent and -independent sGC effects. Apo-sGC mice represent a unique experimental platform to study the in vivo consequences of sGC oxidation and the therapeutic potential of sGC activators.
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    Decreased Soluble Guanylate Cyclase Contributes to Cardiac Dysfunction Induced by Chronic Doxorubicin Treatment in Mice
    (Mary Ann Liebert Inc, 2017) Vandenwijngaert, Sara; Swinnen, Melissa; Walravens, Ann-Sophie; Beerens, Manu; Gillijns, Hilde; Caluwé, Ellen; Tainsh, Robert; Nathan, Daniel I.; Allen, Kaitlin; Brouckaert, Peter; Bartunek, Jozef; Scherrer-Crosbie, Marielle; Bloch, Kenneth; Bloch, Donald; Janssens, Stefan P.; Buys, Emmanuel
    Aims: The use of doxorubicin, a potent chemotherapeutic agent, is limited by cardiotoxicity. We tested the hypothesis that decreased soluble guanylate cyclase (sGC) enzyme activity contributes to the development of doxorubicin-induced cardiotoxicity. Results: Doxorubicin administration (20 mg/kg, intraperitoneally [IP]) reduced cardiac sGC activity in wild-type (WT) mice. To investigate whether decreased sGC activity contributes to doxorubicin-induced cardiotoxicity, we studied mice with cardiomyocyte-specific deficiency of the sGC a1-subunit (mice with cardiomyocyte-specific deletion of exon 6 of the sGCa1 allele [sGCa1-/-CM]). After 12 weeks of doxorubicin administration (2 mg/kg/week IP), left ventricular (LV) systolic dysfunction was greater in sGCa1-/-CM than WT mice. To further assess whether reduced sGC activity plays a pathogenic role in doxorubicin-induced cardiotoxicity, we studied a mouse model in which decreased cardiac sGC activity was induced by cardiomyocyte-specific expression of a dominant negative sGCa1 mutant (DNsGCa1) upon doxycycline removal (Tet-off). After 8 weeks of doxorubicin administration, DNsGCa1tg/+, but not WT, mice displayed LV systolic dysfunction and dilatation. The difference in cardiac function and remodeling between DNsGCa1tg/+ and WT mice was even more pronounced after 12 weeks of treatment. Further impairment of cardiac function was attenuated when DNsGCa1 gene expression was inhibited (beginning at 8 weeks of doxorubicin treatment) by administering doxycycline. Furthermore, doxorubicin-associated reactive oxygen species generation was higher in sGCa1-deficient than WT hearts. Innovation and Conclusion: These data demonstrate that a reduction in cardiac sGC activity worsens doxorubicin-induced cardiotoxicity in mice and identify sGC as a potential therapeutic target. Various pharmacological sGC agonists are in clinical development or use and may represent a promising approach to limit doxorubicin-associated cardiotoxicity.
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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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    Soluble Guanylate Cyclase α1–Deficient Mice: A Novel Murine Model for Primary Open Angle Glaucoma
    (Public Library of Science, 2013) Ko, Yu-Chieh; Hayton, Sarah R.; Jones, Alexander; Tainsh, Laurel T.; Ren, Ruiyi; Giani, Andrea; Clerté, Maeva; Abernathy, Emma; de Waard, Nadine; Turcotte, Raphael; Nathan, Daniel; Loomis, Stephanie J.; Gong, Haiyan; Brouckaert, Peter; Buys, Emmanuel; Alt, Clemens; Tainsh, Robert; Oh, Dong-Jin; Malhotra, Rajeev; Arora, Pankaj; Yu, Binglan; Scherrer-Crosbie, Marielle; Kang, Jae Hee; Lin, Charles; Rhee, Douglas J; Wiggs, Janey; Gregory-Ksander, Meredith; Pasquale, Louis; Bloch, Kenneth; Ksander, Bruce
    Primary open angle glaucoma (POAG) is a leading cause of blindness worldwide. The molecular signaling involved in the pathogenesis of POAG remains unknown. Here, we report that mice lacking the \(α_1\) subunit of the nitric oxide receptor soluble guanylate cyclase represent a novel and translatable animal model of POAG, characterized by thinning of the retinal nerve fiber layer and loss of optic nerve axons in the context of an open iridocorneal angle. The optic neuropathy associated with soluble guanylate cyclase \(α_1\)–deficiency was accompanied by modestly increased intraocular pressure and retinal vascular dysfunction. Moreover, data from a candidate gene association study suggests that a variant in the locus containing the genes encoding for the \(α_1\) and \(β_1\) subunits of soluble guanylate cyclase is associated with POAG in patients presenting with initial paracentral vision loss, a disease subtype thought to be associated with vascular dysregulation. These findings provide new insights into the pathogenesis and genetics of POAG and suggest new therapeutic strategies for POAG.