Pulmonary artery smooth muscle cell senescence is a pathogenic mechanism for pulmonary hypertension in chronic lung disease.: Role of Cell Senescence in Pulmonary Hypertension

Abstract : Rationale: Senescence of pulmonary artery smooth muscle cells (PA-SMCs) caused by telomere shortening or oxidative stress may contribute to pulmonary hypertension associated with chronic lung diseases. Objective: To investigate whether cell senescence contributes to pulmonary vessel remodeling and pulmonary hypertension in chronic obstructive pulmonary disease (COPD). Methods and Results: In 124 patients with COPD investigated by right heart catheterization, we found a negative correlation between leukocyte telomere length and pulmonary hypertension severity. In-depth investigations of lung vessels and derived cultured PA-SMCs showed greater severity of remodeling and increases in senescent p16-positive and p21-positive PA-SMCs and proliferating Ki67-stained cells in 14 patients with COPD compared to 13 age-matched and sex-matched control subjects who smoke. Cultured PA-SMCs from COPD patients displayed accelerated senescence, with fewer cell population doublings, an increased percentage of β-galactosidase-positive cells, shorter telomeres, and higher p16 protein levels at an early cell passage compared to PA-SMCs from controls. Both in situ and in vitro PA-SMC senescence criteria correlated closely with the degree of pulmonary vessel wall hypertrophy. Because senescent PA-SMCs stained for p16 and p21 were virtually confined to the media near the Ki67-positive cells, which predominated in the neointima and hypertrophied media, we evaluated whether senescent cells affected normal PA-SMC functions. We found that senescent PA-SMCs stimulated the growth and migration of normal target PA-SMCs through the production and release of paracrine soluble and insoluble factors. Conclusion: PA-SMC senescence is an important contributor to the process of pulmonary vascular remodeling that underlies pulmonary hypertension in chronic lung disease.
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Circulation Research, American Heart Association, 2011, 109 (5), pp.543-53. 〈10.1161/CIRCRESAHA.111.241299〉
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Hibo Noureddine, Guillaume Gary-Bobo, Marco Alifano, Elisabeth Marcos, Mirna Saker, et al.. Pulmonary artery smooth muscle cell senescence is a pathogenic mechanism for pulmonary hypertension in chronic lung disease.: Role of Cell Senescence in Pulmonary Hypertension. Circulation Research, American Heart Association, 2011, 109 (5), pp.543-53. 〈10.1161/CIRCRESAHA.111.241299〉. 〈inserm-00618219〉

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