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

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.
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https://www.hal.inserm.fr/inserm-00829264
Contributor : Georges Guellaen <>
Submitted on : Sunday, September 1, 2013 - 7:00:16 AM
Last modification on : Wednesday, August 19, 2020 - 11:16:42 AM
Long-term archiving on: : Monday, December 2, 2013 - 8:55:16 AM

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Nathalie Mouraret, Elisabeth Marcos, Shariq Abid, Guillaume Gary-Bobo, Mirna Saker, et al.. Activation of Lung p53 by Nutlin-3a Prevents and Reverses Experimental Pulmonary Hypertension.. Circulation, American Heart Association, 2013, 127 (16), pp.1664-76. ⟨10.1161/CIRCULATIONAHA.113.002434⟩. ⟨inserm-00829264⟩

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