Pulmonary hypertension (PHT) is characterized by active vasoconstriction and structural changes in the small pulmonary arteries (PAs);proliferation of pulmonary artery smooth muscle cells (PASMC) contribute to the remodeling. The abnormal pathophysiology in the pulmonary vasculature may relate to decreased cyclic nucleotide levels. Phosphodiesterases (PDEs) catalyze the hydrolysis of cAMP and cGMP. In PASMC isolated from patients with PHT an increase in the expression of PDE1A and PDE1C, at least in part, accounts for lower agonist-induced cAMP levels and increased proliferation. The goal of this proposal is to study the expression, function, regulation, and therapeutic potential of PDE1 isoforms using PASMC isolated from PHT patients, and from an animal model for PHT [monocrotaline (MCT)-treated rats]. The objective of the proposal is to show that PDE1 contributes to the remodeling of the PA and that PDE1 isoforms represent novel targets for the treatment of PHT.
The Specific Aims are: 1) Define the expression, localization and activity of PDE1 isoforms in human and rat PAs, focusing on PASMC, and determine if this is altered in PHT, 2) Determine the functional impact of increased PDE1 isoforms in human and rat PHT-PASMC, 3) Identify mechanisms that regulate PDE1 expression in human- and rat-PASMC, 4) Assess, using an animal model of PHT, if administration of PDE1 inhibitors can provide a therapeutic approach for PHT. Immunohistochemistry, real-time PCR, Western blotting, and PDE assays will be used to define the expression of PDE1 isoforms in human and rat lung, in particular in PASMC, and changes with PHT. The functional response of inhibition or over expression of PDE1 isoforms will be assessed by measuring cAMP, cGMP, proliferation, and apoptosis in the presence and absence of PDE1A- or PDE1 C-targeted siRNA or PDE1C adenovirus. Gel shift assay will be used to determine the transcriptional regulation of PDE1C by Nuclear factor of activated T-cells (NFAT). Finally, PDE1 inhibitors for PHT will be tested in vivo in MCT-treated rats. This proposal has the potential to reveal new aspects regarding the cellular signaling that contribute to PHT and provide novel information to support the therapeutic potential of PDE1 inhibitors in the disease, which currently has no cure.

National Institute of Health (NIH)
National Heart, Lung, and Blood Institute (NHLBI)
Research Transition Award (R00)
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Special Emphasis Panel (NSS)
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Colombini-Hatch, Sandra
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University of California San Diego
Internal Medicine/Medicine
Schools of Medicine
La Jolla
United States
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Murray, Fiona; Insel, Paul A (2013) Targeting cAMP in chronic lymphocytic leukemia: a pathway-dependent approach for the treatment of leukemia and lymphoma. Expert Opin Ther Targets 17:937-49
Guibinga, Ghiabe-Henri; Murray, Fiona; Barron, Nikki (2013) HPRT-deficiency dysregulates cAMP-PKA signaling and phosphodiesterase 10A expression: mechanistic insight and potential target for Lesch-Nyhan Disease? PLoS One 8:e63333
Li, Jinghong; Lin, Ko-Wei; Murray, Fiona et al. (2013) Regulation of cytotoxic T lymphocyte antigen 4 by cyclic AMP. Am J Respir Cell Mol Biol 48:63-70
Guibinga, Ghiabe-Henri; Murray, Fiona; Barron, Nikki et al. (2013) Deficiency of the purine metabolic gene HPRT dysregulates microRNA-17 family cluster and guanine-based cellular functions: a role for EPAC in Lesch-Nyhan syndrome. Hum Mol Genet 22:4502-15
Insel, Paul A; Murray, Fiona; Yokoyama, Utako et al. (2012) cAMP and Epac in the regulation of tissue fibrosis. Br J Pharmacol 166:447-56
Li, Xiangli; Murray, Fiona; Koide, Naoki et al. (2012) Divergent requirement for Gαs and cAMP in the differentiation and inflammatory profile of distinct mouse Th subsets. J Clin Invest 122:963-73
Insel, P A; Snead, A; Murray, F et al. (2012) GPCR expression in tissues and cells: are the optimal receptors being used as drug targets? Br J Pharmacol 165:1613-6
Rieg, Timo; Gerasimova, Maria; Murray, Fiona et al. (2012) Natriuretic effect by exendin-4, but not the DPP-4 inhibitor alogliptin, is mediated via the GLP-1 receptor and preserved in obese type 2 diabetic mice. Am J Physiol Renal Physiol 303:F963-71
Insel, P A; Zhang, L; Murray, F et al. (2012) Cyclic AMP is both a pro-apoptotic and anti-apoptotic second messenger. Acta Physiol (Oxf) 204:277-87
Murray, Fiona (2012) The interplay of multiple molecular and cellular components is necessary for compartmentalization of cAMP. Focus on "Assessment of cellular mechanisms contributing to cAMP compartmentalization in pulmonary microvascular endothelial cells". Am J Physiol Cell Physiol 302:C837-8

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