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Updated: Sep 10, 2025

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Essential role of protein kinase R in the pathogenesis of pulmonary veno-occlusive disease

Amit Prabhakar1, Rahul Kumar2, Meetu Wadhwa3

  • 1Cardiovascular Research Institute, UCSF, San Francisco, California, USA.

JCI Insight
|August 21, 2025
PubMed

Insights

Protein kinase R (PKR) drives pulmonary veno-occlusive disease (PVOD) pathogenesis by mediating the integrated stress response (ISR). PKR knockout mice were protected from disease, identifying PKR as a therapeutic target for PVOD.

Area of Science:

  • Cardiovascular Biology
  • Molecular Medicine
  • Pulmonary Hypertension Research

Background:

  • Pulmonary veno-occlusive disease (PVOD) is a rare, severe subtype of pulmonary arterial hypertension.
  • PVOD involves progressive remodeling of pulmonary arteries and veins, with no current therapies.
  • Previous studies implicated protein kinase R (PKR)-mediated integrated stress response (ISR) in driving endothelial dysfunction and vascular remodeling in a rat model.

Purpose of the Study:

  • To determine if PKR is the primary mediator of ISR and PVOD pathogenesis.
  • To investigate the role of PKR in MMC-induced pulmonary hypertension and vascular remodeling in mice.

Main Methods:

  • Treatment of control (Ctrl) and PKR knockout (KO) mice with mitomycin C (MMC).
  • Assessment of ISR activation, vascular remodeling, and pulmonary hypertension.
  • Proteomic analysis to evaluate protein synthesis perturbations.

Main Results:

  • Ctrl mice exhibited ISR activation, vascular remodeling, and pulmonary hypertension post-MMC treatment.
  • PKR KO mice showed no PVOD phenotypes after MMC exposure, indicating PKR dependency.
  • Proteomic analysis confirmed MMC-induced ISR attenuated protein synthesis in Ctrl but not KO mice.

Conclusions:

  • PKR-dependent ISR activation is a critical mechanism driving PVOD pathogenesis.
  • Perturbation of proteostasis is central to PVOD development.
  • PKR represents a promising therapeutic target for treating PVOD.
Keywords:
Cell biologyCell stressVascular biology

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