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

Fuente-Alonso, Andrea de la; Toral, Marta; Alfayate, Alvaro; Ruiz-Rodríguez, Maria Jesús; Bonzón-Kulichenko, Elena; Teixidó-Turà, Gisela; Martı́nez-Martı́nez, Sara; Méndez-Olivares, María José; López-Maderuelo, Dolores; Gonzalez-Valdes, I.; García‐Izquierdo, Eusebio; Mingo, Susana; Martín, Cristina; Muiño-Mosquera, Laura; Backer, Julie De; Nistal, J. Francisco; Forteza, Alberto; Evangelista, Arturo; Vázquez, Jesús; Campanero, Miguel R.; Redondo, Juan Miguel

doi:10.1038/s41467-021-22933-3

Cited by 35 publications

(39 citation statements)

References 91 publications

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“…Attenuated TAA pathology in Fbn1 C1041G/+ ; Nox4 −/− mice provided genetic proof of ROS involvement [ 40 ]. Redondo’s laboratory reported high iNOS expression levels in the aortic media of both MFS patients and Fbn1 C1041G/+ mice [ 42 , 43 ]. Since iNOS is upregulated during oxidative stress and inflammation, this observation suggests the presence of a local pro-inflammatory state in the MFS aorta.…”

Section: Endothelial Dysfunctionmentioning

confidence: 99%

“…Since iNOS is upregulated during oxidative stress and inflammation, this observation suggests the presence of a local pro-inflammatory state in the MFS aorta. Furthermore, they showed that iNOS-derived NO drives aneurysm formation in Fbn1 C1041G/+ mice through upregulation of sGC/cGMP/PKG-I axis, and that pharmacological and/or genetic inhibition of different components of this signaling axis prevented TAA development [ 43 ]. Inhibition and even reversion of arterial disease in Fbn1 C1041G/+ mice by lentiviral mediated Prkg1 silencing greatly contrast the relatively modest attenuation of TAA pathology observed in Fbn1 C1041G/+ ; Nox4 −/− mice [ 40 , 43 ].…”

Section: Endothelial Dysfunctionmentioning

confidence: 99%

“…Furthermore, they showed that iNOS-derived NO drives aneurysm formation in Fbn1 C1041G/+ mice through upregulation of sGC/cGMP/PKG-I axis, and that pharmacological and/or genetic inhibition of different components of this signaling axis prevented TAA development [ 43 ]. Inhibition and even reversion of arterial disease in Fbn1 C1041G/+ mice by lentiviral mediated Prkg1 silencing greatly contrast the relatively modest attenuation of TAA pathology observed in Fbn1 C1041G/+ ; Nox4 −/− mice [ 40 , 43 ]. This difference may reflect the relative contributions of ROS augmentation and iNOS hyperactivity to TAA pathology or the genetic strategies used to inactivate the Nox4 and Prkg1 genes.…”

Section: Endothelial Dysfunctionmentioning

confidence: 99%

“…The reproducibility of jugular vein injection to deliver high-titer lentiviral vectors to the aorta is also controversial [ 44 , 45 ]. Another puzzling finding is how forced expression of lentivirus transduced genes in Fbn1 C1041G/+ mice could completely reverse (as opposed to slowing down) the degenerative process of a fibrillin-1 deficient ECM [ 42 , 43 ]. Although the aforementioned pathological findings have yet to be mechanistically connected to one another, we can at least speculate that endothelial dysfunction in Fbn1 C1041G/+ mice might be accounted for by impaired eNOS-derived NO production associated with augmented ROS that stimulates iNOS-derived NO production in the media.…”

Section: Endothelial Dysfunctionmentioning

confidence: 99%

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Pathophysiology and Therapeutics of Thoracic Aortic Aneurysm in Marfan Syndrome

et al. 2022

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About 20% of individuals afflicted with thoracic aortic disease have single-gene mutations that predispose the vessel to aneurysm formation and/or acute aortic dissection often without associated syndromic features. One widely studied exception is Marfan syndrome (MFS) in which mutations in the extracellular protein fibrillin-1 cause additional abnormalities in the heart, eyes, and skeleton. Mouse models of MFS have been instrumental in delineating major cellular and molecular determinants of thoracic aortic disease. In spite of research efforts, translating experimental findings from MFS mice into effective drug therapies for MFS patients remains an unfulfilled promise. Here, we describe a series of studies that have implicated endothelial dysfunction and improper angiotensin II and TGFβ signaling in driving thoracic aortic disease in MFS mice. We also discuss how these investigations have influenced the way we conceptualized possible new therapies to slow down or even halt aneurysm progression in this relatively common connective tissue disorder.

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Section: Endothelial Dysfunctionmentioning

confidence: 99%

Section: Endothelial Dysfunctionmentioning

confidence: 99%

Section: Endothelial Dysfunctionmentioning

confidence: 99%

Section: Endothelial Dysfunctionmentioning

confidence: 99%

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Pathophysiology and Therapeutics of Thoracic Aortic Aneurysm in Marfan Syndrome

et al. 2022

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“…According to studies, half-normal synthesis of normal protein (haploinsufficiency), rather than the production of the mutant protein, could be of key importance to reach the threshold loss of fibrillin-1 function required for clinical expression of the disorder [13]. Fibrillin-1 is a key component of extracellular microfibril, which provides a scaffold for elastic fiber formation and maturation [19,20]. Therefore, mutant fibrillin-1 impairs microfibril formation, resulting in medial degeneration, which is mirrored by poor alignment of elastin filaments, altered organization of lamellar units, the accumulation of proteoglycan and vascular smooth muscle cell (VSMC) death [21].…”

Section: Cause Of Marfan's Syndromementioning

confidence: 99%

Oxidative Stress-Related Susceptibility to Aneurysm in Marfan’s Syndrome

et al. 2021

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The involvement of highly reactive oxygen-derived free radicals (ROS) in the genesis and progression of various cardiovascular diseases, including arrhythmias, aortic dilatation, aortic dissection, left ventricular hypertrophy, coronary arterial disease and congestive heart failure, is well-established. It has also been suggested that ROS may play a role in aortic aneurysm formation in patients with Marfan’s syndrome (MFS). This syndrome is a multisystem disorder with manifestations including cardiovascular, skeletal, pulmonary and ocular systems, however, aortic aneurysm and dissection are still the most life-threatening manifestations of MFS. In this review, we will concentrate on the impact of oxidative stress on aneurysm formation in patients with MFS as well as on possible beneficial effects of some agents with antioxidant properties. Mechanisms responsible for oxidative stress in the MFS model involve a decreased expression of superoxide dismutase (SOD) as well as enhanced expression of NAD(P)H oxidase, inducible nitric oxide synthase (iNOS) and xanthine oxidase. The results of studies have indicated that reactive oxygen species may be involved in smooth muscle cell phenotype switching and apoptosis as well as matrix metalloproteinase activation, resulting in extracellular matrix (ECM) remodeling. The progression of the thoracic aortic aneurysm was suggested to be associated with markedly impaired aortic contractile function and decreased nitric oxide-mediated endothelial-dependent relaxation.

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The 10th International Conference on cGMP 2022: recent trends in cGMP research and development—meeting report

Friebe

Kraehling

Russwurm

et al. 2023

Naunyn-Schmiedeberg's Arch Pharmacol

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Increasing cGMP is a unique therapeutic principle, and drugs inhibiting cGMP-degrading enzymes or stimulating cGMP production are approved for the treatment of various diseases such as erectile dysfunction, coronary artery disease, pulmonary hypertension, chronic heart failure, irritable bowel syndrome, or achondroplasia. In addition, cGMP-increasing therapies are preclinically profiled or in clinical development for quite a broad set of additional indications, e.g., neurodegenerative diseases or different forms of dementias, bone formation disorders, underlining the pivotal role of cGMP signaling pathways. The fundamental understanding of the signaling mediated by nitric oxide-sensitive (soluble) guanylyl cyclase and membrane-associated receptor (particulate) guanylyl cyclase at the molecular and cellular levels, as well as in vivo, especially in disease models, is a key prerequisite to fully exploit treatment opportunities and potential risks that could be associated with an excessive increase in cGMP. Furthermore, human genetic data and the clinical effects of cGMP-increasing drugs allow back-translation into basic research to further learn about signaling and treatment opportunities. The biannual international cGMP conference, launched nearly 20 years ago, brings all these aspects together as an established and important forum for all topics from basic science to clinical research and pivotal clinical trials. This review summarizes the contributions to the “10th cGMP Conference on cGMP Generators, Effectors and Therapeutic Implications,” which was held in Augsburg in 2022 but will also provide an overview of recent key achievements and activities in the field of cGMP research.

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

Cited by 35 publications

References 91 publications

Pathophysiology and Therapeutics of Thoracic Aortic Aneurysm in Marfan Syndrome

Pathophysiology and Therapeutics of Thoracic Aortic Aneurysm in Marfan Syndrome

Oxidative Stress-Related Susceptibility to Aneurysm in Marfan’s Syndrome

The 10th International Conference on cGMP 2022: recent trends in cGMP research and development—meeting report

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