Activation of Lung p53 by Nutlin-3a Prevents and Reverses Experimental Pulmonary Hypertension.Reportar como inadecuado

Activation of Lung p53 by Nutlin-3a Prevents and Reverses Experimental Pulmonary Hypertension. - Descarga este documento en PDF. Documentación en PDF para descargar gratis. Disponible también para leer online.

* Corresponding author 1 IMRB - Institut Mondor de Recherche Biomédicale 2 Service de Cardiologie 3 CarMeN - Laboratoire de recherche en cardiovasculaire, métabolisme, diabétologie et nutrition

Abstract : BACKGROUND: Induction of cellular senescence through activation of the p53 tumor suppressor protein is a new option for treating proliferative disorders. Nutlins prevent the ubiquitin ligase MDM2 murine double minute 2, a negative p53 regulator, from interacting with p53. We hypothesized that cell senescence induced by Nutlin-3a exerted therapeutic effects in pulmonary hypertension PH by limiting the proliferation of pulmonary artery smooth muscle cells PA-SMCs. METHODS AND RESULTS: Nutlin-3a treatment of cultured human PA-SMCs resulted in cell growth arrest with the induction of senescence but not apoptosis; increased phosphorylated p53 protein levels; and expression of p53 target genes including p21, Bax, BTG2, and MDM2. Daily intraperitoneal Nutlin-3a treatment for 3 weeks dose-dependently reduced PH, right ventricular hypertrophy, and distal pulmonary artery muscularization in mice exposed to chronic hypoxia or SU5416-hypoxia. Nutlin-3a treatment also partially reversed PH in chronically hypoxic or transgenic mice overexpressing the serotonin-transporter in SMCs SM22-5HTT+ mice. In these mouse models of PH, Nutlin-3a markedly increased senescent p21-stained PA-SMCs; lung p53, p21, and MDM2 protein levels; and p21, Bax, PUMA, BTG2, and MDM2 mRNA levels; but induced only minor changes in control mice without PH. Marked MDM2 immunostaining was seen in both mouse and human remodeled pulmonary vessels, supporting the use of Nutlins as a PH-targeted therapy. PH prevention or reversal by Nutlin-3a required lung p53 stabilization and increased p21 expression, as indicated by the absence of Nutlin-3a effects in hypoxia-exposed p53- and p21- mice. CONCLUSIONS: Nutlin-3a may hold promise as a prosenescence treatment targeting PA-SMCs in PH.

keyword : hypertension pulmonary cell senescence muscle remodeling

Autor: Nathalie Mouraret - Elisabeth Marcos - Shariq Abid - Guillaume Gary-Bobo - Mirna Saker - Amal Houssaini - Jean-Luc Dubois-Rande -



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