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Aortic disease in Marfan syndrome is caused by overactivation of sGC-PRKG signaling by NO

Authors: Andrea de la Fuente-Alonso; Marta Toral; Alvaro Alfayate; María Jesús Ruiz-Rodríguez; Elena Bonzón-Kulichenko; Gisela Teixido-Tura; Sara Martínez-Martínez; +14 Authors

Aortic disease in Marfan syndrome is caused by overactivation of sGC-PRKG signaling by NO

Abstract

AbstractThoracic aortic aneurysm, as occurs in Marfan syndrome, is generally asymptomatic until dissection or rupture, requiring surgical intervention as the only available treatment. Here, we show that nitric oxide (NO) signaling dysregulates actin cytoskeleton dynamics in Marfan Syndrome smooth muscle cells and that NO-donors induce Marfan-like aortopathy in wild-type mice, indicating that a marked increase in NO suffices to induce aortopathy. Levels of nitrated proteins are higher in plasma from Marfan patients and mice and in aortic tissue from Marfan mice than in control samples, indicating elevated circulating and tissue NO. Soluble guanylate cyclase and cGMP-dependent protein kinase are both activated in Marfan patients and mice and in wild-type mice treated with NO-donors, as shown by increased plasma cGMP and pVASP-S239 staining in aortic tissue. Marfan aortopathy in mice is reverted by pharmacological inhibition of soluble guanylate cyclase and cGMP-dependent protein kinase and lentiviral-mediated Prkg1 silencing. These findings identify potential biomarkers for monitoring Marfan Syndrome in patients and urge evaluation of cGMP-dependent protein kinase and soluble guanylate cyclase as therapeutic targets.

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Belgium, Spain
Keywords

Male, CYCLIC-GMP, Cardiopatia congènita, PROTEIN-KINASES, Fibrillin-1, General Physics and Astronomy, ENFERMEDADES::enfermedades cardiovasculares::enfermedades vasculares::aneurisma::aneurisma de la aorta::aneurisma de la aorta torácica, Aortic diseases, Muscle, Smooth, Vascular, Marfan Syndrome, Mice, Soluble Guanylyl Cyclase, Medicine and Health Sciences, Cyclic GMP, Aorta, Ultrasonography, ENFERMEDADES::enfermedades cardiovasculares::enfermedades cardiovasculares::enfermedades cardíacas::cardiopatías congénitas::síndrome de Marfan, Cyclic GMP-Dependent Protein Kinase Type I, PLASMA, Q, Gene Knockdown Techniques, Female, Aneurismes aòrtics, DISEASES::Cardiovascular Diseases::Vascular Diseases::Aneurysm::Aortic Aneurysm::Aortic Aneurysm, Thoracic, Science, ROOT DILATION, Primary Cell Culture, Myocytes, Smooth Muscle, Carbazoles, PEPTIDE IDENTIFICATION, Genetics and Molecular Biology, S-NITROSYLATION, Nitric Oxide, Article, MECHANISMS, Other subheadings::Other subheadings::Other subheadings::/antagonists & inhibitors, DISEASES::Cardiovascular Diseases::Cardiovascular Diseases::Heart Diseases::Heart Defects, Congenital::Marfan Syndrome, Animals, Humans, Nitric Oxide Donors, ANEURYSMS, BETA-BLOCKER THERAPY, CHEMICALS AND DRUGS::Amino Acids, Peptides, and Proteins::Peptides::Intracellular Signaling Peptides and Proteins::Guanylate Cyclase::Amino Acids, Peptides, and Proteins::Soluble Guanylyl Cyclase, NITRIC-OXIDE, Aortic Aneurysm, Thoracic, General Chemistry, Otros calificadores::Otros calificadores::Otros calificadores::/antagonistas & inhibidores, Aneurysm, COMPUESTOS QUÍMICOS Y DROGAS::aminoácidos, péptidos y proteínas::péptidos::péptidos y proteínas de señalización intracelular::guanilato ciclasa::aminoácidos, péptidos y proteínas::guanilil ciclasa soluble, Disease Models, Animal, General Biochemistry, Mutation, Biomarkers, Inhibidors enzimàtics - Ús terapèutic

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selected citations
These citations are derived from selected sources.
This is an alternative to the "Influence" indicator, which also reflects the overall/total impact of an article in the research community at large, based on the underlying citation network (diachronically).
BIP!Citations provided by BIP!
popularity
This indicator reflects the "current" impact/attention (the "hype") of an article in the research community at large, based on the underlying citation network.
BIP!Popularity provided by BIP!
influence
This indicator reflects the overall/total impact of an article in the research community at large, based on the underlying citation network (diachronically).
BIP!Influence provided by BIP!
impulse
This indicator reflects the initial momentum of an article directly after its publication, based on the underlying citation network.
BIP!Impulse provided by BIP!
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OpenAIRE UsageCountsViews provided by UsageCounts
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