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.
|Cohrs, Randall J; Lee, Katherine S; Beach, Addilynn et al. (2017) Targeted Genome Sequencing Reveals Varicella-Zoster Virus Open Reading Frame 12 Deletion. J Virol 91:|
|Lapel, Martin; Weston, Philip; Strassheim, Derek et al. (2017) Glycolysis and oxidative phosphorylation are essential for purinergic receptor-mediated angiogenic responses in vasa vasorum endothelial cells. Am J Physiol Cell Physiol 312:C56-C70|
|Lin, Y-C; Sung, Y K; Jiang, X et al. (2017) Simultaneously Targeting Myofibroblast Contractility and Extracellular Matrix Cross-Linking as a Therapeutic Concept in Airway Fibrosis. Am J Transplant 17:1229-1241|
|Tuder, Rubin M (2017) Pulmonary vascular remodeling in pulmonary hypertension. Cell Tissue Res 367:643-649|
|Loomis, Zoe; Eigenberger, Paul; Redinius, Katherine et al. (2017) Correction: Hemoglobin induced cell trauma indirectly influences endothelial TLR9 activity resulting in pulmonary vascular smooth muscle cell activation. PLoS One 12:e0173652|
|Murakami, A; Wang, L; Kalhorn, S et al. (2017) Context-dependent role for chromatin remodeling component PBRM1/BAF180 in clear cell renal cell carcinoma. Oncogenesis 6:e287|
|de Bourcy, Charles F A; Dekker, Cornelia L; Davis, Mark M et al. (2017) Dynamics of the human antibody repertoire after B cell depletion in systemic sclerosis. Sci Immunol 2:|
|Cree-Green, Melanie; Gupta, Abhinav; Coe, Gregory V et al. (2017) Insulin resistance in type 2 diabetes youth relates to serum free fatty acids and muscle mitochondrial dysfunction. J Diabetes Complications 31:141-148|
|Jansing, Nicole L; McClendon, Jazalle; Henson, Peter M et al. (2017) Unbiased Quantitation of Alveolar Type II to Alveolar Type I Cell Transdifferentiation during Repair after Lung Injury in Mice. Am J Respir Cell Mol Biol 57:519-526|
|Loomis, Zoe; Eigenberger, Paul; Redinius, Katherine et al. (2017) Hemoglobin induced cell trauma indirectly influences endothelial TLR9 activity resulting in pulmonary vascular smooth muscle cell activation. PLoS One 12:e0171219|
Showing the most recent 10 out of 117 publications