Details

Autor(en) / Beteiligte

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

Titel

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

Ist Teil von

• Nature communications, 2019-08, Vol.10 (1), p.1-13, Article 3533

Ort / Verlag

London: Nature Publishing Group

Erscheinungsjahr

2019

Quelle

Elektronische Zeitschriftenbibliothek (Open access)

Beschreibungen/Notizen

• 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. Prkg1 R177Q/+ 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 B 12 -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.