Aortic pathology from protein kinase G activation is prevented by an antioxidant vitamin B12 analog

Nat Commun. 2019 Aug 6;10(1):3533. doi: 10.1038/s41467-019-11389-1.

Abstract

People heterozygous for an activating mutation in protein kinase G1 (PRKG1, p.Arg177Gln) develop thoracic aortic aneurysms and dissections (TAAD) as young adults. Here we report that mice heterozygous for the mutation have a three-fold increase in basal protein kinase G (PKG) activity, and develop age-dependent aortic dilation. Prkg1R177Q/+ aortas show increased smooth muscle cell apoptosis, elastin fiber breaks, and oxidative stress compared to aortas from wild type littermates. Transverse aortic constriction (TAC)-to increase wall stress in the ascending aorta-induces severe aortic pathology and mortality from aortic rupture in young mutant mice. The free radical-neutralizing vitamin B12-analog cobinamide completely prevents age-related aortic wall degeneration, and the unrelated anti-oxidant N-acetylcysteine ameliorates TAC-induced pathology. Thus, increased basal PKG activity induces oxidative stress in the aorta, raising concern about the widespread clinical use of PKG-activating drugs. Cobinamide could be a treatment for aortic aneurysms where oxidative stress contributes to the disease, including Marfan syndrome.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Acetylcysteine / administration & dosage
  • Animals
  • Aorta, Thoracic / diagnostic imaging
  • Aorta, Thoracic / drug effects
  • Aorta, Thoracic / pathology
  • Aortic Aneurysm, Thoracic / genetics
  • Aortic Aneurysm, Thoracic / pathology
  • Aortic Aneurysm, Thoracic / prevention & control*
  • Aortic Dissection / genetics
  • Aortic Dissection / pathology
  • Aortic Dissection / prevention & control*
  • Cobamides / administration & dosage*
  • Cyclic GMP-Dependent Protein Kinase Type I / genetics*
  • Cyclic GMP-Dependent Protein Kinase Type I / metabolism
  • Disease Models, Animal
  • Echocardiography
  • Female
  • Free Radical Scavengers / administration & dosage*
  • Gain of Function Mutation
  • Gene Knock-In Techniques
  • HEK293 Cells
  • Humans
  • Male
  • Marfan Syndrome / complications
  • Marfan Syndrome / genetics
  • Mice
  • Mice, Transgenic
  • Myocytes, Smooth Muscle
  • Oxidative Stress / drug effects
  • Oxidative Stress / genetics
  • Primary Cell Culture

Substances

  • Cobamides
  • Free Radical Scavengers
  • cobinamide
  • Cyclic GMP-Dependent Protein Kinase Type I
  • PRKG1 protein, human
  • Prkg1 protein, mouse
  • Acetylcysteine