학술논문
CREB depletion in smooth muscle cells promotes medial thickening, adventitial fibrosis and elicits pulmonary hypertension.
Document Type
Academic Journal
Author
Garat CV; Cardiovascular Pulmonary Research Laboratory, Department of Medicine, University of Colorado, Aurora, CO, USA.; Division of Pulmonary Sciences and Critical Care Medicine, Department of Medicine, University of Colorado, Aurora, CO, USA.; Majka SM; Division of Pulmonary, Critical Care and Sleep Medicine, Department of Medicine, National Jewish Health, Denver, Denver, CO, USA.; Sullivan TM; Cardiovascular Pulmonary Research Laboratory, Department of Medicine, University of Colorado, Aurora, CO, USA.; Crossno JT Jr; Cardiovascular Pulmonary Research Laboratory, Department of Medicine, University of Colorado, Aurora, CO, USA.; Division of Pulmonary Sciences and Critical Care Medicine, Department of Medicine, University of Colorado, Aurora, CO, USA.; Reusch JEB; Cardiovascular Pulmonary Research Laboratory, Department of Medicine, University of Colorado, Aurora, CO, USA.; Division of Endocrinology, Department of Medicine, University of Colorado, Aurora, CO, USA.; Klemm DJ; Cardiovascular Pulmonary Research Laboratory, Department of Medicine, University of Colorado, Aurora, CO, USA.; Division of Pulmonary Sciences and Critical Care Medicine, Department of Medicine, University of Colorado, Aurora, CO, USA.; Geriatric Research, Education and Clinical Center, Veterans Administration, Eastern Colorado Health Care System, Aurora, CO, USA.
Source
Publisher: Wiley Country of Publication: United States NLM ID: 101557243 Publication Model: eCollection Cited Medium: Print ISSN: 2045-8932 (Print) Linking ISSN: 20458932 NLM ISO Abbreviation: Pulm Circ Subsets: PubMed not MEDLINE
Subject
Language
English
ISSN
2045-8932
Abstract
Levels of the cAMP-responsive transcription factor, CREB, are reduced in medial smooth muscle cells in remodeled pulmonary arteries from hypertensive calves and rats with chronic hypoxia-induced pulmonary hypertension. Here, we show that chronic hypoxia fails to promote CREB depletion in pulmonary artery smooth muscle cells or elicit significant remodeling of the pulmonary arteries in mice, suggesting that sustained CREB expression prevents hypoxia-induced pulmonary artery remodeling. This hypothesis was tested by generating mice, in which CREB was ablated in smooth muscle cells. Loss of CREB in smooth muscle cells stimulated pulmonary artery thickening, right ventricular hypertrophy, profound adventitial collagen deposition, recruitment of myeloid cells to the adventitia, and elevated right ventricular systolic pressure without exposure to chronic hypoxia. Isolated murine CREB-null smooth muscle cells exhibited serum-independent proliferation and hypertrophy in vitro and medium conditioned by CREB-null smooth muscle cells stimulated proliferation and expression of extracellular matrix proteins by adventitial fibroblasts. We conclude that CREB governs the pathologic switch from homeostatic, quiescent smooth muscle cells to proliferative, synthetic cells that drive arterial remodeling contributing to the development or pulmonary hypertension.
(© The Author(s) 2020.)
(© The Author(s) 2020.)