ABSTRACT
OBJECTIVE: Senescent pulmonary artery smooth muscle cells (PA-SMCs) may contribute to the pathogenesis of pulmonary hypertension by producing secreted factors. The aim of this study was to explore the role in pulmonary hypertension of extracellular matrix proteins released by senescent PA-SMCs. APPROACH AND RESULTS: Polymerase chain reaction array analysis of human PA-SMCs undergoing replicative senescence revealed osteopontin upregulation, which mediated the stimulatory effect of senescent PA-SMC media and matrix on PA-SMC growth and migration. Osteopontin was upregulated in lungs from patients with chronic obstructive pulmonary disease or idiopathic pulmonary arterial hypertension. Prominent osteopontin immunostaining was noted in PA-SMCs that also stained for p16 at sites of vascular hypertrophy, and lung osteopontin levels correlated closely with age. Compared with younger mice, 1-year-old mice displayed higher lung osteopontin levels, right ventricular systolic pressure, pulmonary vessel muscularization, and numbers of PA-SMCs stained for p16 or p21 and also for osteopontin. No such changes with age were observed in osteopontin(-/-) mice, which developed attenuated pulmonary hypertension during hypoxia. Compared with cultured PA-SMCs from young mice, PA-SMCs from 1-year-old mice grew faster; a similar fast growth rate was seen with PA-SMCs from young mice stimulated by matrix or media from old mice. Differences between old/young mouse PA-SMC growth rates were suppressed by antiosteopontin antibodies. PA-SMCs from osteopontin(-/-) mice grew more slowly than did wild-type PA-SMCs; they were stimulated by wild-type PA-SMCs media and matrix, and this effect was stronger with PA-SMCs from older versus younger mice. CONCLUSIONS: Osteopontin is a key mediator released by senescent PA-SMCs and contributing to pulmonary hypertension progression.
Subject(s)
Cellular Senescence , Familial Primary Pulmonary Hypertension/metabolism , Muscle, Smooth, Vascular/metabolism , Myocytes, Smooth Muscle/metabolism , Osteopontin/metabolism , Adult , Age Factors , Aged , Animals , Case-Control Studies , Cell Movement , Cell Proliferation , Cells, Cultured , Disease Models, Animal , Extracellular Matrix Proteins/metabolism , Familial Primary Pulmonary Hypertension/pathology , Familial Primary Pulmonary Hypertension/physiopathology , Female , Genotype , Hemodynamics , Humans , Hyperplasia , Male , Mice, Inbred C57BL , Mice, Knockout , Middle Aged , Muscle, Smooth, Vascular/pathology , Muscle, Smooth, Vascular/physiopathology , Myocytes, Smooth Muscle/pathology , Osteopontin/deficiency , Osteopontin/genetics , Phenotype , Pulmonary Artery/metabolism , Pulmonary Artery/pathology , Pulmonary Artery/physiopathology , Signal Transduction , Up-Regulation , Ventricular Function, RightABSTRACT
The cardiac extracellular matrix (ECM) provides a platform for cells to maintain structure and function, which in turn maintains tissue function. In response to injury, the ECM undergoes remodeling that involves synthesis, incorporation, and degradation of matrix proteins, with the net outcome determined by the balance of these processes. The major goals of this review are a) to serve as an initial resource for students and investigators new to the cardiac ECM remodeling field, and b) to highlight a few of the key exciting avenues and methodologies that have recently been explored. While we focus on cardiac injury and responses of the left ventricle (LV), the mechanisms reviewed here have pathways in common with other wound healing models.
Subject(s)
Extracellular Matrix/metabolism , Myocardial Infarction/metabolism , Ventricular Remodeling , Wound Healing , Animals , Humans , Matrix Metalloproteinases/metabolismABSTRACT
The first Hawaii Asthma Research Consortium was held on 7 May 2001 at Tripler Army Medical Center. Researchers investigating asthma-related problems and program directors of asthma projects were solicited statewide to present their projects. Ten lecturers focused on research and asthma projects in Hawaii in 20-minute presentations. An informal ten-minute discussion followed each presentation to encourage audience questions about the project and to discuss possible collaboration efforts between institutions. The institutions that were represented include: American Lung Association-Hawaii, Kaiser Permanente Center for Health Research Hawaii, Kapiolani Medical Center, Tripler Army Medical Center, University of Hawaii at Manoa, and Waianae Coast Comprehensive Health Center.
