PIM1 (Moloney Murine Leukemia Provirus Integration Site) Inhibition Decreases the Nonhomologous End-Joining DNA Damage Repair Signaling Pathway in Pulmonary Hypertension

Arterioscler Thromb Vasc Biol. 2020 Mar;40(3):783-801. doi: 10.1161/ATVBAHA.119.313763. Epub 2020 Jan 23.

Abstract

Objective: Pulmonary arterial hypertension (PAH) is a fatal disease characterized by the narrowing of pulmonary arteries (PAs). It is now established that this phenotype is associated with enhanced PA smooth muscle cells (PASMCs) proliferation and suppressed apoptosis. This phenotype is sustained in part by the activation of several DNA repair pathways allowing PASMCs to survive despite the unfavorable environmental conditions. PIM1 (Moloney murine leukemia provirus integration site) is an oncoprotein upregulated in PAH and involved in many prosurvival pathways, including DNA repair. The objective of this study was to demonstrate the implication of PIM1 in the DNA damage response and the beneficial effect of its inhibition by pharmacological inhibitors in human PAH-PASMCs and in rat PAH models. Approach and Results: We found in vitro that PIM1 inhibition by either SGI-1776, TP-3654, siRNA (silencer RNA) decreased the phosphorylation of its newly identified direct target KU70 (lupus Ku autoantigen protein p70) resulting in the inhibition of double-strand break repair (Comet Assay) by the nonhomologous end-joining as well as reduction of PAH-PASMCs proliferation (Ki67-positive cells) and resistance to apoptosis (Annexin V positive cells) of PAH-PASMCs. In vivo, SGI-1776 and TP-3654 given 3× a week, improved significantly pulmonary hemodynamics (right heart catheterization) and vascular remodeling (Elastica van Gieson) in monocrotaline and Fawn-Hooded rat models of PAH.

Conclusions: We demonstrated that PIM1 phosphorylates KU70 and initiates DNA repair signaling in PAH-PASMCs and that PIM1 inhibitors represent a therapeutic option for patients with PAH.

Keywords: DNA repair; apoptosis; hemodynamics; oncogenes; pulmonary arterial hypertension.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antihypertensive Agents / pharmacology
  • Apoptosis
  • Cell Proliferation
  • Cells, Cultured
  • DNA Damage*
  • DNA End-Joining Repair* / drug effects
  • Disease Models, Animal
  • Female
  • Histones / metabolism
  • Humans
  • Hypertension, Pulmonary / drug therapy
  • Hypertension, Pulmonary / enzymology*
  • Hypertension, Pulmonary / genetics
  • Hypertension, Pulmonary / pathology
  • Ku Autoantigen / metabolism
  • Male
  • Muscle, Smooth, Vascular / drug effects
  • Muscle, Smooth, Vascular / enzymology*
  • Muscle, Smooth, Vascular / pathology
  • Myocytes, Smooth Muscle / drug effects
  • Myocytes, Smooth Muscle / enzymology*
  • Myocytes, Smooth Muscle / pathology
  • Phosphoproteins / metabolism
  • Phosphorylation
  • Protein Kinase Inhibitors / pharmacology
  • Proto-Oncogene Proteins c-pim-1 / antagonists & inhibitors
  • Proto-Oncogene Proteins c-pim-1 / genetics
  • Proto-Oncogene Proteins c-pim-1 / metabolism*
  • Pulmonary Artery / enzymology
  • Pulmonary Artery / pathology
  • Rats, Sprague-Dawley
  • Vascular Remodeling

Substances

  • Antihypertensive Agents
  • H2AX protein, human
  • Histones
  • Phosphoproteins
  • Protein Kinase Inhibitors
  • gamma-H2AX protein, rat
  • PIM1 protein, human
  • Pim1 protein, rat
  • Proto-Oncogene Proteins c-pim-1
  • Xrcc6 protein, human
  • Xrcc6 protein, rat
  • Ku Autoantigen

Grant support