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Graveline, Amanda

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Graveline

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Amanda

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Graveline, Amanda
Author's Publications: search.filters.isAuthorOfPublication.d140b473-ca3f-42f4-aeb5-49a6dd1d4746

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    Nitric oxide regulates pulmonary vascular smooth muscle cell expression of the inducible cAMP early repressor gene
    (Elsevier BV, 2011) Steinbicker, Andrea U.; Liu, Heling; Jiramongkolchai, Kim; Malhotra, Rajeev; Choe, Elizabeth Y.; Busch, Cornelius J.; Graveline, Amanda; Kao, Sonya M.; Nagasaka, Yasuko; Ichinose, Fumito; Buys, Emmanuel; Brouckaert, Peter; Zapol, Warren; Bloch, Kenneth
    Nitric oxide (NO) regulates vascular smooth muscle cell (VSMC) structure and function, in part by activating soluble guanylate cyclase (sGC) to synthesize cGMP. The objective of this study was to further characterize the signaling mechanisms by which NO regulates VSMC gene expression using transcription profiling. DNA microarrays were hybridized with RNA extracted from rat pulmonary artery smooth muscle cells (RPaSMC) exposed to the NO donor compound, S-nitroso-glutathione (GSNO). Many of the genes, whose expression was induced by GSNO, contain a cAMP-response element (CRE), of which one encoded the inducible cAMP early repressor (ICER). sGC and cAMP-dependent protein kinase, but not cGMP-dependent protein kinase, were required for NO-mediated phosphorylation of CRE-binding protein (CREB) and induction of ICER gene expression. Expression of a dominant-negative CREB in RPaSMC prevented the NO-mediated induction of CRE-dependent gene transcription and ICER gene expression. Pre-treatment of RPaSMC with the intracellular calcium (Ca2+) chelator, BAPTA-AM, blocked the induction of ICER gene expression by GSNO. The store-operated Ca2+ channel inhibitors, 2-ABP, and SKF-96365, reduced the GSNO-mediated increase in ICER mRNA levels, while 2-ABP did not inhibit GSNO-induced CREB phosphorylation. Our results suggest that induction of ICER gene expression by NO requires both CREB phosphorylation and Ca2+ signaling. Transcription profiling of RPaSMC exposed to GSNO revealed important roles for sGC, PKA, CREB, and Ca2+ in the regulation of gene expression by NO. The induction of ICER in GSNO-treated RPaSMC highlights a novel cross-talk mechanism between cGMP and cAMP signaling pathways.
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    Soluble Guanylate Cyclase-alpha1 Deficiency Selectively Inhibits the Pulmonary Vasodilator Response to Nitric Oxide and Increases the Pulmonary Vascular Remodeling Response to Chronic Hypoxia
    (Ovid Technologies (Wolters Kluwer Health), 2007) Vermeersch, Pieter; Buys, Emmanuel; Pokreisz, Peter; Marsboom, Glenn; Ichinose, Fumito; Sips, Patrick; Pellens, Marijke; Gillijns, Hilde; Swinnen, Marc; Graveline, Amanda; Collen, Desire; Dewerchin, Mieke; Brouckaert, Peter; Bloch, Kenneth; Janssens, Stefan
    BACKGROUND: Nitric oxide (NO) activates soluble guanylate cyclase (sGC), a heterodimer composed of alpha- and beta-subunits, to produce cGMP. NO reduces pulmonary vascular remodeling, but the role of sGC in vascular responses to acute and chronic hypoxia remains incompletely elucidated. We therefore studied pulmonary vascular responses to acute and chronic hypoxia in wild-type (WT) mice and mice with a nonfunctional alpha1-subunit (sGCalpha1-/-). METHODS AND RESULTS: sGCalpha1-/- mice had significantly reduced lung sGC activity and vasodilator-stimulated phosphoprotein phosphorylation. Right ventricular systolic pressure did not differ between genotypes at baseline and increased similarly in WT (22+/-2 to 34+/-2 mm Hg) and sGCalpha1-/- (23+/-2 to 34+/-1 mm Hg) mice in response to acute hypoxia. Inhaled NO (40 ppm) blunted the increase in right ventricular systolic pressure in WT mice (22+/-2 to 24+/-2 mm Hg, P<0.01 versus hypoxia without NO) but not in sGCalpha1-/- mice (22+/-1 to 33+/-1 mm Hg) and was accompanied by a significant rise in lung cGMP content only in WT mice. In contrast, the NO-donor sodium nitroprusside (1.5 mg/kg) decreased systemic blood pressure similarly in awake WT and sGCalpha1-/- mice as measured by telemetry (-37+/-2 versus -42+/-4 mm Hg). After 3 weeks of hypoxia, the increases in right ventricular systolic pressure, right ventricular hypertrophy, and muscularization of intra-acinar pulmonary vessels were 43%, 135%, and 46% greater, respectively, in sGCalpha1-/- than in WT mice (P<0.01). Increased remodeling in sGCalpha1-/- mice was associated with an increased frequency of 5'-bromo-deoxyuridine-positive vessels after 1 and 3 weeks (P<0.01 versus WT). CONCLUSIONS: Deficiency of sGCalpha1 does not alter hypoxic pulmonary vasoconstriction. sGCalpha1 is essential for NO-mediated pulmonary vasodilation and limits chronic hypoxia-induced pulmonary vascular remodeling.