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

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.

doi:10.1038/s41467-019-11389-1

Nat Commun

2019

DOI: 10.1038/s41467-019-11389-1

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

Gerburg K. Schwaerzer

¹

,

Hema Kalyanaraman

²

,

Darren E. Casteel

³

et al.

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 aor… Show more

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Cited by 41 publications

(69 citation statements)

References 69 publications

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“…Recent findings from our laboratory have shed light on how the NO–sGC–PRKG signalling pathway mediates aortopathy in a mouse model of Marfan syndrome and identified sGC and PRKG1 as potential therapeutic targets for intervention in human Marfan syndrome (de la Fuente‐Alonso et al, 2021). These findings are consistent with recent studies demonstrating that a gain‐of‐function mutation in PRKG1 predisposes to thoracic aortic aneurysm and dissection by disrupting the contractile unit (Guo et al, 2013; Schwaerzer et al, 2019), suggesting that NO–sGC–PRKG signalling might be an essential factor not only in Marfan syndrome but also in non‐syndromic familial thoracic aortic aneurysm and dissection. In an apparent paradox, Marfan syndrome mice expressing constitutively active eNOS ( Nos3 S1176D ) or overexpressing eNOS showed a slower rate of aortic growth than control Marfan syndrome mice, suggesting that endothelial NO release might be beneficial for the aorta in Marfan syndrome mice (Sellers et al, 2018).…”

Section: No–sgc–prkgi Signalling In Marfan Syndromesupporting

confidence: 92%

The NO signalling pathway in aortic aneurysm and dissection

Toral

¹

,

Fuente‐Alonso

²

,

Campanero

³

et al. 2021

British J Pharmacology

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Exaggerated anticipatory anxiety is common in social anxiety disorder (SAD). Neuroimaging studies have revealed altered neural activity in response to social stimuli in SAD, but fewer studies have examined neural activity during anticipation of feared social stimuli in SAD. The current study examined the time course and magnitude of activity in threat processing brain regions during speech anticipation in socially anxious individuals and healthy controls (HC). Method Participants (SAD n = 58; HC n = 16) underwent functional magnetic resonance imaging (fMRI) during which they completed a 90s control anticipation task and 90s speech anticipation task.

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“…Recent findings from our laboratory have shed light on how the NO–sGC–PRKG signalling pathway mediates aortopathy in a mouse model of Marfan syndrome and identified sGC and PRKG1 as potential therapeutic targets for intervention in human Marfan syndrome (de la Fuente‐Alonso et al, 2021). These findings are consistent with recent studies demonstrating that a gain‐of‐function mutation in PRKG1 predisposes to thoracic aortic aneurysm and dissection by disrupting the contractile unit (Guo et al, 2013; Schwaerzer et al, 2019), suggesting that NO–sGC–PRKG signalling might be an essential factor not only in Marfan syndrome but also in non‐syndromic familial thoracic aortic aneurysm and dissection. In an apparent paradox, Marfan syndrome mice expressing constitutively active eNOS ( Nos3 S1176D ) or overexpressing eNOS showed a slower rate of aortic growth than control Marfan syndrome mice, suggesting that endothelial NO release might be beneficial for the aorta in Marfan syndrome mice (Sellers et al, 2018).…”

Section: No–sgc–prkgi Signalling In Marfan Syndromesupporting

confidence: 92%

The NO signalling pathway in aortic aneurysm and dissection

Toral

¹

,

Fuente‐Alonso

²

,

Campanero

³

et al. 2021

British J Pharmacology

Get access via publisher Add to dashboard Cite

Exaggerated anticipatory anxiety is common in social anxiety disorder (SAD). Neuroimaging studies have revealed altered neural activity in response to social stimuli in SAD, but fewer studies have examined neural activity during anticipation of feared social stimuli in SAD. The current study examined the time course and magnitude of activity in threat processing brain regions during speech anticipation in socially anxious individuals and healthy controls (HC). Method Participants (SAD n = 58; HC n = 16) underwent functional magnetic resonance imaging (fMRI) during which they completed a 90s control anticipation task and 90s speech anticipation task.

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“…To study another form of cardiac stress, we subjected 4-to 5-monthold male Prkg1 RQ/+ mice and their wild type littermates to pressure overload by transaortic constriction. As previously reported, about one third of the Prkg1 RQ/+ mice succumbed to aortic rupture within 2 weeks after transaortic constriction, whereas none of the wild type mice died (Schwaerzer et al, 2019). Transaortic constriction produced similar aortic pressure gradients in both genotypes (Figure 6a).…”

Section: Aging Male Prkg1 Rq/+ Mice Show Mild Cardiac Structural Chan...supporting

confidence: 84%

“…However, this modest reduction in age‐related left ventricle hypertrophy was not apparent in female mutant mice (Figure S3c–h). Heart rates were the same in 12‐month‐old wild type and Prkg1 RQ/+ mice (Schwaerzer et al, 2019) and we found no differences between the two genotypes in the weights of heart, lung and kidney normalized to either body weight or tibia length (Table S2A,B).…”

Section: Resultssupporting

confidence: 63%

Constitutive protein kinase G activation exacerbates stress‐induced cardiomyopathy

Schwaerzer

¹

,

Casteel

²

,

Cividini

³

et al. 2021

British J Pharmacology

Self Cite

Get access via publisher Add to dashboard Cite

Exaggerated anticipatory anxiety is common in social anxiety disorder (SAD). Neuroimaging studies have revealed altered neural activity in response to social stimuli in SAD, but fewer studies have examined neural activity during anticipation of feared social stimuli in SAD. The current study examined the time course and magnitude of activity in threat processing brain regions during speech anticipation in socially anxious individuals and healthy controls (HC). Method Participants (SAD n = 58; HC n = 16) underwent functional magnetic resonance imaging (fMRI) during which they completed a 90s control anticipation task and 90s speech anticipation task.

show abstract

“…Meanwhile, as a risk factor for aortic dissection, aortic root diameter increases with age [20]. Animal experiments have demonstrated that aortic medial degeneration leads to age-dependent aortic dilation and, under hypertensive stress, results in aortic dissection [21]. In our study, patients with TBAD who underwent TEVAR surgery in the NTAD group had a higher prevalence of smoking, hypertension type III aortic arch, and an enlarged ascending aorta compared to the TAD group.…”

Section: Discussionmentioning

confidence: 48%

Traumatic Aortic Dissection as a Unique Clinical Entity: A Single-Center Retrospective Study

Gang

¹

,

Lun

²

,

Pang

³

et al. 2023

JCM

2

0

Get access via publisher Add to dashboard Cite

Exaggerated anticipatory anxiety is common in social anxiety disorder (SAD). Neuroimaging studies have revealed altered neural activity in response to social stimuli in SAD, but fewer studies have examined neural activity during anticipation of feared social stimuli in SAD. The current study examined the time course and magnitude of activity in threat processing brain regions during speech anticipation in socially anxious individuals and healthy controls (HC). Method Participants (SAD n = 58; HC n = 16) underwent functional magnetic resonance imaging (fMRI) during which they completed a 90s control anticipation task and 90s speech anticipation task.

show abstract

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