Activation of lung p53 by Nutlin-3a prevents and reverses experimental pulmonary hypertension.

نویسندگان

  • Nathalie Mouraret
  • Elisabeth Marcos
  • Shariq Abid
  • Guillaume Gary-Bobo
  • Mirna Saker
  • Amal Houssaini
  • Jean-Luc Dubois-Rande
  • Laurent Boyer
  • Jorge Boczkowski
  • Geneviève Derumeaux
  • Valérie Amsellem
  • Serge Adnot
چکیده

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.

برای دانلود متن کامل این مقاله و بیش از 32 میلیون مقاله دیگر ابتدا ثبت نام کنید

ثبت نام

اگر عضو سایت هستید لطفا وارد حساب کاربری خود شوید

منابع مشابه

New hope for Nutlin-3a therapy for pulmonary arterial hypertension

Pulmonary Arterial Hypertension (PH) is a chronic, progressive, and fatal lung disease characterized by narrowing of pulmonary arteries associated with muscular thickening and intimal proliferation, known as remodeling. If untreated, the 5-year survival rate of PH is 34% (McLaughlin et al., 2002). Unfortunately, there is no systematic strategy established to effectively manage this devastating ...

متن کامل

Small molecule inhibition of HDM2 leads to p53-mediated cell death in retinoblastoma cells.

PURPOSE To determine the efficacy of inducing p53-mediated cell death in retinoblastoma cells by Nutlin 3A, a small molecule HDM2 inhibitor. METHODS Retinoblastoma cell lines WERI-RB-1 and Y79 were treated with Nutlin 3A. Cell viability assays, Western blot analyses, confocal microscopy, and flow cytometry were performed to measure cell survival, p53 protein levels, activation of downstream t...

متن کامل

Inhibition of p53-murine double minute 2 interaction by nutlin-3A stabilizes p53 and induces cell cycle arrest and apoptosis in Hodgkin lymphoma.

PURPOSE p53 is frequently expressed but rarely mutated in Hodgkin and Reed-Sternberg (HRS) cells of Hodgkin's lymphoma (HL). p53 protein levels are regulated by murine double minute 2 (MDM2) through a well-established autoregulatory feedback loop. In this study, we investigated the effects of nutlin-3A, a recently developed small molecule that antagonizes MDM2 and disrupts the p53-MDM2 interact...

متن کامل

MDM2 inhibitor Nutlin-3a suppresses proliferation and promotes apoptosis in osteosarcoma cells.

Restoring p53 activity by inhibiting the interaction between p53 and the mouse double minutes clone 2 (MDM2) offers an attractive approach to cancer therapy. Nutlin-3a is a small-molecule inhibitor that inhibits MDM2 binding to p53 and subsequent p53-dependent DNA damage signaling. In this study, we determined the efficacy of Nutlin-3a in inducing p53-mediated cell death in osteosarcoma (OS) ce...

متن کامل

ذخیره در منابع من


  با ذخیره ی این منبع در منابع من، دسترسی به آن را برای استفاده های بعدی آسان تر کنید

برای دانلود متن کامل این مقاله و بیش از 32 میلیون مقاله دیگر ابتدا ثبت نام کنید

ثبت نام

اگر عضو سایت هستید لطفا وارد حساب کاربری خود شوید

عنوان ژورنال:
  • Circulation

دوره 127 16  شماره 

صفحات  -

تاریخ انتشار 2013