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

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Andrea de la Fuente-Alonso ◽  
Marta Toral ◽  
Alvaro Alfayate ◽  
María Jesús Ruiz-Rodríguez ◽  
Elena Bonzón-Kulichenko ◽  
...  
Keyword(s):  
Protein Kinase ◽  
Marfan Syndrome ◽  
Guanylate Cyclase ◽  
Soluble Guanylate Cyclase ◽  
Aortic Tissue ◽  
Wild Type ◽  
Dependent Protein Kinase ◽  
No Donors ◽  
Cgmp Dependent Protein Kinase ◽  
Dependent Protein

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.

scholarly journals Nitric Oxide Regulation of Gene Transcription via Soluble Guanylate Cyclase and Type I cGMP-dependent Protein Kinase

1999 ◽  
Vol 274 (14) ◽  
pp. 9489-9493 ◽  
Author(s):  
Soha D. Idriss ◽  
Tanima Gudi ◽  
Dareen E. Casteel ◽  
Vladimir G. Kharitonov ◽  
Renate B. Pilz ◽  
...  
Keyword(s):  
Nitric Oxide ◽  
Protein Kinase ◽  
Gene Transcription ◽  
Guanylate Cyclase ◽  
Soluble Guanylate Cyclase ◽  
Type I ◽  
Dependent Protein Kinase ◽  
Cgmp Dependent Protein Kinase ◽  
Dependent Protein

Regulation of human neutrophil degranulation by LY-83583 and L-arginine: role of cGMP-dependent protein kinase

1993 ◽  
Vol 265 (1) ◽  
pp. C201-C211 ◽  
Author(s):  
T. A. Wyatt ◽  
T. M. Lincoln ◽  
K. B. Pryzwansky
Keyword(s):  
Protein Kinase ◽  
Soluble Guanylate Cyclase ◽  
Human Neutrophils ◽  
Enzyme Linked Immunosorbent Assay ◽  
Dependent Protein Kinase ◽  
Cgmp Dependent Protein Kinase ◽  
A 23187 ◽  
Neutrophil Degranulation ◽  
Dependent Protein ◽  
Ly 83583

The effects of guanosine 3',5'-cyclic monophosphate (cGMP) on the secretory response of activated human neutrophils were investigated using LY-83583, an inhibitor of soluble guanylate cyclase, and L-arginine, the precursor of nitric oxide formation. A 30% release of myeloperoxidase (MPO) and lactoferrin (LF) from the primary and specific granules, respectively, was detected by enzyme-linked immunosorbent assay in adhered neutrophils stimulated with 0.1 microM N-formyl-methionyl-leucyl-phenylalanine (FMLP) or 20 microM A-23187. LY-83583 (100 microM) inhibited the release of both LF and MPO after stimulation with FMLP or A-23187. Conversely, preincubation of neutrophils with 0.5 mM L-arginine augmented the release of LF and MPO in FMLP- and A-23187-stimulated cells. Concurrent with the increase in the degranulation response was an elevation of cGMP levels in L-arginine-treated cells, while stimulated cGMP levels were reduced in LY-83583-treated cells. Furthermore, cGMP-dependent protein kinase (G-kinase) activity was reduced in LY-83583-treated cells, as determined by the delay in G-kinase translocation to intermediate filaments and the inhibition of vimentin phosphorylation. Degranulation, elevation of cGMP levels, and targeting of G-kinase were also dependent on the concentration of A-23187 or FMLP. These data suggest that activators of neutrophil degranulation mediate this response through a cGMP-dependent protein kinase mechanism.

scholarly journals Relaxin Affects Smooth Muscle Biophysical Properties and Mechanical Activity of the Female Mouse Colon

Endocrinology ◽  
2015 ◽  
Vol 156 (12) ◽  
pp. 4398-4410 ◽  
Author(s):  
Roberta Squecco ◽  
Rachele Garella ◽  
Eglantina Idrizaj ◽  
Silvia Nistri ◽  
Fabio Francini ◽  
...  
Keyword(s):  
Nitric Oxide ◽  
Smooth Muscle ◽  
Protein Kinase ◽  
Guanylate Cyclase ◽  
Membrane Properties ◽  
Mechanical Activity ◽  
Biophysical Properties ◽  
Dependent Protein Kinase ◽  
Cgmp Dependent Protein Kinase ◽  
Dependent Protein

The hormone relaxin (RLX) has been reported to influence gastrointestinal motility in mice. However, at present, nothing is known about the effects of RLX on the biophysical properties of the gastrointestinal smooth muscle cells (SMCs). Other than extending previous knowledge of RLX on colonic motility, the purpose of this study was to investigate the ability of the hormone to induce changes in resting membrane potential (RMP) and on sarcolemmal ion channels of colonic SMCs of mice that are related to its mechanical activity. To this aim, we used a combined mechanical and electrophysiological approach. In the mechanical experiments, we observed that RLX caused a decay of the basal tone coupled to an increase of the spontaneous contractions, completely abolished by the guanylate cyclase inhibitor 1H-[1,2,4]oxadiazolo[4,3-a]-quinoxalin-1-one (ODQ). The electrophysiological results indicate for the first time that RLX directly affects the SMC biophysical properties inducing hyperpolarization of RMP and cycles of slow hyperpolarization/depolarization oscillations. The effects of RLX on RMP were abolished by ODQ as well as by a specific inhibitor of the cGMP-dependent protein kinase, KT5823. RLX reduced Ca2+ entry through the voltage-dependent L-type channels and modulated either voltage- or ATP-dependent K+ channels. These effects were abolished by ODQ, suggesting the involvement of the nitric oxide/guanylate cyclase pathway in the effects of RLX on RMP and ion channel modulation. These actions of RLX on membrane properties may contribute to the regulation of the proximal colon motility by the nitric oxide/cGMP/cGMP-dependent protein kinase pathway.

scholarly journals Estrogen-Induced Apoptosis of Breast Epithelial Cells Is Blocked by NO/cGMP and Mediated by Extranuclear Estrogen Receptors

Endocrinology ◽  
2010 ◽  
Vol 151 (12) ◽  
pp. 5602-5616 ◽  
Author(s):  
Irida Kastrati ◽  
Praneeth D. Edirisinghe ◽  
Gihani T. Wijewickrama ◽  
Gregory R. J. Thatcher
Keyword(s):  
Protein Kinase ◽  
Epithelial Cells ◽  
Estrogen Receptors ◽  
Cell Line ◽  
Mammary Epithelial ◽  
Dependent Protein Kinase ◽  
No Donors ◽  
Cgmp Dependent Protein Kinase ◽  
Dependent Protein ◽  
Induced Apoptosis

Estrogen action, via both nuclear and extranuclear estrogen receptors (ERs), induces a variety of cellular signals that are prosurvival or proliferative, whereas nitric oxide (NO) can inhibit apoptosis via caspase S-nitrosylation and via activation of soluble guanylyl cyclase to produce cGMP. The action of 17β-estradiol (E2) at ER is known to elicit NO signaling via activation of NO synthase (NOS) in many tissues. The MCF-10A nontumorigenic, mammary epithelial cell line is genetically stable and insensitive to estrogenic proliferation. In this cell line, estrogens or NOS inhibitors alone had no significant effect, whereas in combination, apoptosis was induced rapidly in the absence of serum; the presence of inducible NOS was confirmed by proteomic analysis. The application of pharmacological agents determined that apoptosis was dependent upon NO/cGMP signaling via cyclic GMP (cGMP)-dependent protein kinase and could be replicated by inhibition of the phosphatidylinositol 3 kinase/serine-threonine kinase pathway prior to addition of E2. Apoptosis was confirmed by nuclear staining and increased caspase-3 activity in E2 + NOS inhibitor-treated cells. Apoptosis was partially inhibited by a pure ER antagonist and replicated by agonists selective for extranuclear ER. Cells were rescued from E2-induced apoptosis after NOS blockade, by NO-donors and cGMP pathway agonists; preincubation with NO donors was required. The NOS and ER status of breast cancer tissues is significant in etiology, prognosis, and therapy. In this study, apoptosis of preneoplastic mammary epithelial cells was triggered by estrogens via a rapid, extranuclear ER-mediated response, after removal of an antiapoptotic NO/cGMP/cGMP-dependent protein kinase signal.

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