Oxidized DNA Precursors Cleanup by NUDT1 Contributes to Vascular Remodeling in Pulmonary Arterial Hypertension
| Autor: | Sarah-Eve Lemay, Roxane Paulin, Alice Bourgeois, Eve Tremblay, Renée Paradis, Geraldine Vitry, Karima Habbout, Marie-Claude Lampron, Olivier Boucherat, Sandra Breuils-Bonnet, Florence Roux-Dalvai, Yann Grobs, Charifa Awada, Tsukasa Shimauchi, Mark Orcholski, Valérie Nadeau, Steeve Provencher, François Potus, Sébastien Bonnet |
|---|---|
| Rok vydání: | 2020 |
| Předmět: |
Male
Cell Apoptosis Pharmacology Critical Care and Intensive Care Medicine medicine.disease_cause Muscle Smooth Vascular Tandem Mass Spectrometry Pyrophosphatases Pulmonary Arterial Hypertension Middle Aged Up-Regulation medicine.anatomical_structure 8-Hydroxy-2'-Deoxyguanosine Female Comet Assay Oxidation-Reduction Pulmonary and Respiratory Medicine Adult Programmed cell death DNA damage Blotting Western Myocytes Smooth Muscle In Vitro Techniques Pulmonary Artery Vascular Remodeling medicine Animals Humans RNA Messenger Aged Cell Proliferation business.industry Forkhead Box Protein M1 Editorials DNA medicine.disease Pulmonary hypertension Phosphoric Monoester Hydrolases Rats Comet assay Disease Models Animal Oxidative Stress DNA Repair Enzymes Terminal deoxynucleotidyl transferase Case-Control Studies business Oxidative stress Chromatography Liquid |
| Zdroj: | American Journal of Respiratory and Critical Care Medicine |
| ISSN: | 1535-4970 |
| Popis: | Rationale: Pulmonary arterial hypertension (PAH) is a life-threatening condition characterized by abnormally elevated pulmonary pressures and right ventricular failure. Excessive proliferation and resistance to apoptosis of pulmonary artery smooth muscle cells (PASMCs) is one of the most important drivers of vascular remodeling in PAH, for which available treatments have limited effectiveness.Objectives: To gain insights into the mechanisms leading to the development of the disease and identify new actionable targets.Methods: Protein expression profiling was conducted by two-dimensional liquid chromatography coupled to tandem mass spectrometry in isolated PASMCs from controls and patients with PAH. Multiple molecular, biochemical, and pharmacologic approaches were used to decipher the role of NUDT1 (nudrix hyrolase 1) in PAH.Measurements and Main Results: Increased expression of the detoxifying DNA enzyme NUDT1 was detected in cells and tissues from patients with PAH and animal models. In vitro, molecular or pharmacological inhibition of NUDT1 in PAH-PASMCs induced accumulation of oxidized nucleotides in the DNA, irresolvable DNA damage (comet assay), disruption of cellular bioenergetics (Seahorse), and cell death (terminal deoxynucleotidyl transferase dUTP nick end labeling assay). In two animal models with established PAH (i.e., monocrotaline and Sugen/hypoxia-treated rats), pharmacological inhibition of NUDT1 using (S)-Crizotinib significantly decreased pulmonary vascular remodeling and improved hemodynamics and cardiac function.Conclusions: Our results indicate that, by overexpressing NUDT1, PAH-PASMCs hijack persistent oxidative stress in preventing incorporation of oxidized nucleotides into DNA, thus allowing the cell to escape apoptosis and proliferate. Given that NUDT1 inhibitors are under clinical investigation for cancer, they may represent a new therapeutic option for PAH. |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|