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 and Renate B. Pilz ()
Additional contact information
Gerburg K. Schwaerzer: University of California San Diego
Hema Kalyanaraman: University of California San Diego
Darren E. Casteel: University of California San Diego
Nancy D. Dalton: University of California San Diego
Yusu Gu: University of California San Diego
Seunghoe Lee: University of California San Diego
Shunhui Zhuang: University of California San Diego
Nisreen Wahwah: University of California San Diego
Jan M. Schilling: University of California San Diego
Hemal H. Patel: University of California San Diego
Qian Zhang: University of California San Diego
Ayako Makino: University of California San Diego
Dianna M. Milewicz: University of Texas Health Science Center at Houston
Kirk L. Peterson: University of California San Diego
Gerry R. Boss: University of California San Diego
Renate B. Pilz: University of California San Diego

Nature Communications, 2019, vol. 10, issue 1, 1-13

Abstract: 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.

Date: 2019
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DOI: 10.1038/s41467-019-11389-1

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