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

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 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.

SUBMITTER: Schwaerzer GK

PROVIDER: S-EPMC6684604 | biostudies-literature | 2019 Aug

REPOSITORIES: biostudies-literature

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Aortic pathology from protein kinase G activation is prevented by an antioxidant vitamin B<sub>12</sub> analog.

Schwaerzer Gerburg K GK Kalyanaraman Hema H Casteel Darren E DE Dalton Nancy D ND Gu Yusu Y Lee Seunghoe S Zhuang Shunhui S Wahwah Nisreen N Schilling Jan M JM Patel Hemal H HH Zhang Qian Q Makino Ayako A Milewicz Dianna M DM Peterson Kirk L KL Boss Gerry R GR Pilz Renate B RB

Nature communications 20190806 1

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<sup>R177Q/+</sup> aortas show increased smooth muscle cell apoptosis, elastin fiber breaks, and oxidative stress compared to aortas from wild type littermates. Tran ...[more]

PMID: 31387997

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Project description:Vitamin B12 is synthesized only by certain bacteria and archaeon, but not by plants. The synthesized vitamin B12 is transferred and accumulates in animal tissues, which can occur in certain plant and mushroom species through microbial interaction. In particular, the meat and milk of herbivorous ruminant animals (e.g. cattle and sheep) are good sources of vitamin B12 for humans. Ruminants acquire vitamin B12, which is considered an essential nutrient, through a symbiotic relationship with the bacteria present in their stomachs. In aquatic environments, most phytoplankton acquire vitamin B12 through a symbiotic relationship with bacteria, and they become food for larval fish and bivalves. Edible plants and mushrooms rarely contain a considerable amount of vitamin B12, mainly due to concomitant bacteria in soil and/or their aerial surfaces. Thus, humans acquire vitamin B12 formed by microbial interaction via mainly ruminants and fish (or shellfish) as food sources. In this review, up-to-date information on vitamin B12 sources and bioavailability are also discussed. Impact statement To prevent vitamin B12 (B12) deﬁciency in high-risk populations such as vegetarians and elderly subjects, it is necessary to identify foods that contain high levels of B12. B12 is synthesized by only certain bacteria and archaeon, but not by plants or animals. The synthesized B12 is transferred and accumulated in animal tissues, even in certain plant tissues via microbial interaction. Meats and milks of herbivorous ruminant animals are good sources of B12 for humans. Ruminants acquire the essential B12 through a symbiotic relationship with bacteria inside the body. Thus, we also depend on B12-producing bacteria located in ruminant stomachs. While edible plants and mushrooms rarely contain a considerable amount of B12, mainly due to concomitant bacteria in soil and/or their aerial surfaces. In this mini-review, we described up-to-date information on B12 sources and bioavailability with reference to the interaction of microbes as B12-producers.

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

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Aortic pathology from protein kinase G activation is prevented by an antioxidant vitamin B<sub>12</sub> analog.

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

Publications

Aortic pathology from protein kinase G activation is prevented by an antioxidant vitamin B<sub>12</sub> analog.

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OmicsDI is part of the ELIXIR infrastructure

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