The goal of this project is to understandthe mechanisms that drive downregulation of the transcription factor, CREB in pulmonary hypertension (PH) and the contribution of this event to pulmonary artery (PA) remodeling. We have previously shown that CREB levels are diminished in smooth muscle cells (SMCs) from remodeled, hypertensive PAs. Inhibition of CREB in SMCs increased their proliferation, migration, and collagen and elastin production. Loss of CREB in SMCs is stimulated by PDGF, which induces proteasomal degradation of CREB. Finally, rosiglitazone (ROSI) prevents remodeling of the PA wall in response to chronic hypoxia. New preliminary data links these observations into a coherent model for the regulation of SMC phenotype. First, PDGF-induced CREB depletion in SMCs is mediated by casein kinase 2 (CK2). Second, ROSI prevents CREB depletion by blocking PDGF induction of CK2. Third, PA remodeling is associated with the appearance macrophages in the PA adventitia. The accumulation of these cells is blocked by ROSI, which also attenuate PA remodeling in response to chronic hypoxia. Fourth, depletion of CREB augments the expression of adhesion molecules and cytokines linked to the accumulation of macrophages in systemic arteries. Therefore we hypothesize the existence of a regulatory cascade in which PDGF elicits the depletion of CREB via increased expression of CK2. Loss of CREB in SMCs results in SMC proliferation, collagen and elastin synthesis, and decreased SMC marker expression. Loss of CREB also promotes the recruitment of macrophages to the PA wall, which exacerbates PA remodeling. ROSI inhibits this cascade by preventing PDGF-induced CK2 expression.
Four specific aims will test these hypotheses.
Aim 1 will test whether SMC loss of CREB is mechanistically linked to the development of PH in animals.
Aim 2 will examine whether ROSI regulates CREB and CK2 in SMCs via the nuclear receptor, PPARy.
Aim 3 will determine whether downregulation of CK2 and upregulation of CREB mediate the protective effects of ROSI on SMC phenotype. Finally, Aim 4 will examine the ability of ROSI or macrophage depletion to suppress PA remodeling and the development of PH in SMC CREB loss-of-funotion mice.
(Seeinstructions): Despite major advances in the treatment of cardiopulmonary conditions, hypoxia-induced pulmonary hypertension (PH) remains a deadly disease that is largely unresponsive to current treatments. In order to generate innovative treatments it is critical to understand the mechanisms that lead to disease progression. This project will identify novel pathways and their contributions to the pathogenesis of PH.
|SchÃ¤fer, Michal; Myers, Cynthia; Brown, R Dale et al. (2016) Pulmonary Arterial Stiffness: Toward a New Paradigm in Pulmonary Arterial Hypertension Pathophysiology and Assessment. Curr Hypertens Rep 18:4|
|Bartels, Karsten; Brown, R Dale; Fox, Daniel L et al. (2016) Right Ventricular Longitudinal Strain Is Depressed in a Bovine Model of Pulmonary Hypertension. Anesth Analg 122:1280-6|
|Voelkel, Norbert F; Tamosiuniene, Rasa; Nicolls, Mark R (2016) Challenges and opportunities in treating inflammation associated with pulmonary hypertension. Expert Rev Cardiovasc Ther 14:939-51|
|Graham, Brian B; Robinson, Jeffrey C; Tuder, Rubin M (2016) Fatty Acid Metabolism, Bone Morphogenetic Protein Receptor Type 2, and the Right Ventricle. Am J Respir Crit Care Med 194:655-6|
|Horita, Henrick; Wysoczynski, Christina L; Walker, Lori A et al. (2016) Nuclear PTEN functions as an essential regulator of SRF-dependent transcription to control smooth muscle differentiation. Nat Commun 7:10830|
|PlecitÃ¡-HlavatÃ¡, Lydie; Tauber, Jan; Li, Min et al. (2016) Constitutive Reprogramming of Fibroblast Mitochondrial Metabolism in Pulmonary Hypertension. Am J Respir Cell Mol Biol 55:47-57|
|Keller, Amy C; Knaub, Leslie A; McClatchey, P Mason et al. (2016) Differential Mitochondrial Adaptation in Primary Vascular Smooth Muscle Cells from a Diabetic Rat Model. Oxid Med Cell Longev 2016:8524267|
|Stenmark, Kurt R; Frid, Maria; Perros, FrÃ©dÃ©ric (2016) Endothelial-to-Mesenchymal Transition: An Evolving Paradigm and a Promising Therapeutic Target in PAH. Circulation 133:1734-7|
|McClatchey, P Mason; Keller, Amy C; Bouchard, Ron et al. (2016) Fully automated software for quantitative measurements of mitochondrial morphology. Mitochondrion 26:58-71|
|Bruns, Danielle R; Buttrick, Peter M; Walker, Lori A (2016) Genetic ablation of interleukin-18 does not attenuate hypobaric hypoxia-induced right ventricular hypertrophy. Am J Physiol Lung Cell Mol Physiol 310:L542-50|
Showing the most recent 10 out of 90 publications