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

Gerburg K. Schwaerzer, Hema Kalyanaraman, Darren E. Casteel, Nancy D. Dalton, Yusu Gu, Seunghoe Lee, Shunhui Zhuang, Nisreen Wahwah, Jan M. Schilling, Hemal H. Patel, Qian Zhang, Ayako Makino, Dianna M. Milewicz, Kirk L. Peterson, Gerry R. Boss, Renate B. Pilz

Research output: Contribution to journalArticlepeer-review

2 Scopus citations

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.

Original languageEnglish (US)
Article number3533
JournalNature communications
Volume10
Issue number1
DOIs
StatePublished - Dec 1 2019

ASJC Scopus subject areas

  • Chemistry(all)
  • Biochemistry, Genetics and Molecular Biology(all)
  • Physics and Astronomy(all)

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