Abstract 556: The Soluble Guanylyl Cyclase Activator Bay 60-2770 Inhibits Arterial Smooth Muscle Cell Migration in Protein Kinase G-dependent Manner

2016 ◽  
Vol 36 (suppl_1) ◽  
Author(s):  
Andrew Holt ◽  
Danielle Martin ◽  
Patti Shaver ◽  
Shaquria Adderley ◽  
Joshua Stone ◽  
...  
Keyword(s):  
Smooth Muscle ◽  
Cell Migration ◽  
Protein Kinase ◽  
Cyclic Gmp ◽  
Guanylyl Cyclase ◽  
Soluble Guanylyl Cyclase ◽  
Protein Kinase G ◽  
Growth Disorders ◽  
Arterial Smooth Muscle ◽  
Cyclase Activator

Atherosclerotic lower extremity peripheral artery disease (PAD) is among the most prevalent, morbid and mortal of all cardiovascular disorders. Pathologic arterial smooth muscle (ASM) cell migration is a major component of atherogenic PAD and efforts aimed at attenuating its progression are clinically essential. Cyclic nucleotide signaling has long been studied for its growth-mitigating properties in the setting of PAD and other vascular growth disorders. In this study we hypothesized that the novel, heme-independent soluble guanylyl cyclase activator BAY 60-2770 (BAY) inhibits ASM cell migration through phosphorylation of the protein kinase G (PKG) target and actin-binding protein vasodilator-stimulated phosphoprotein (VASP). In a rat model of injury-induced arterial growth, BAY significantly reduced neointima formation and luminal narrowing compared to vehicle (Veh)-treated control arteries after 2 weeks. Using rat and human ASM cells BAY significantly attenuated cell migration, reduced G:F actin, and increased cyclic GMP content, PKG activity and phosphorylated VASP at Ser239 (pVASP.S239) compared to Veh controls. Using site-directed mutagenesis, both full-length VASP-overexpressing (wild type, WT) and VASP.S239 phosphorylation-resistant mutants showed significantly reduced cell migration compared to naïve controls, however, there was no effect on cell migration between either VASP transfected group in the presence of BAY. Interestingly, both VASP mutants showed significantly increased PKG activity compared to naïve cells, and in turn pharmacologic PKG blockade in the presence of BAY fully reversed the inhibitory effect of BAY alone on cell migration. These data suggest BAY has capacity to inhibit ASM cell migration through cyclic GMP/PKG/VASP signaling yet through mechanisms independent of pVASP.S239. Findings from this study implicate BAY via cyclic GMP/PKG/VASP as a potential pharmacotherapeutic agent against aberrant ASM growth disorders such as PAD.

scholarly journals Protein Kinase G Phosphorylates Soluble Guanylyl Cyclase on Serine 64 and Inhibits Its Activity

2008 ◽  
Vol 28 (10) ◽  
pp. 1803-1810 ◽  
Author(s):  
Zongmin Zhou ◽  
Nazish Sayed ◽  
Anastasia Pyriochou ◽  
Charis Roussos ◽  
David Fulton ◽  
...  
Keyword(s):  
Protein Kinase ◽  
Guanylyl Cyclase ◽  
Soluble Guanylyl Cyclase ◽  
Protein Kinase G

scholarly journals Effects of the soluble guanylyl cyclase activator, YC-1, on vascular tone, cyclic GMP levels and phosphodiesterase activity

1999 ◽  
Vol 127 (1) ◽  
pp. 195-203 ◽  
Author(s):  
Jan Galle ◽  
Ulrike Zabel ◽  
Ulrich Hübner ◽  
Armin Hatzelmann ◽  
Birgit Wagner ◽  
...  
Keyword(s):  
Cyclic Gmp ◽  
Guanylyl Cyclase ◽  
Vascular Tone ◽  
Soluble Guanylyl Cyclase ◽  
Phosphodiesterase Activity ◽  
Cyclase Activator

scholarly journals Protein kinase G phosphorylates soluble guanylyl cyclase and inhibits its activity

2007 ◽  
Vol 7 (S1) ◽  
Author(s):  
Andreas Papapetropoulos ◽  
Zongmin Zhou ◽  
Nazish Sayed ◽  
Anastasia Pyriochou ◽  
Charis Roussos ◽  
...  
Keyword(s):  
Protein Kinase ◽  
Guanylyl Cyclase ◽  
Soluble Guanylyl Cyclase ◽  
Protein Kinase G

Gaseous Transmitter Regulation of Catecholamine Secretion by hypoxia in Murine Adrenal Chromaffin Cells

2021 ◽  
Author(s):  
Anna Gridina ◽  
Xiaoyu Su ◽  
Shakil A. Khan ◽  
Ying-Jie Peng ◽  
Benjamin L Wang ◽  
...  
Keyword(s):  
Nervous System ◽  
Protein Kinase ◽  
Guanylyl Cyclase ◽  
Chromaffin Cells ◽  
Soluble Guanylyl Cyclase ◽  
Protein Kinase G ◽  
Adrenal Chromaffin Cells ◽  
Wild Type ◽  
Genetic Deletion ◽  
Adrenal Chromaffin

Emerging evidence suggests that gaseous molecules, carbon monoxide (CO) and hydrogen sulfide (H2S) generated by heme oxygenase-(HO)-2 and cystathionine γ-lyase (CSE), respectively, function as transmitters in the nervous system. Present study examined the roles of CO and H2S in hypoxia-induced catecholamine (CA) release from adrenal medullary chromaffin cells (AMC). Studies were performed on AMC from adult (≥6 weeks of age) wild type (WT), HO-2 null, CSE null and HO-2/CSE double null mice of either gender. CA secretion was determined by carbon fiber amperometry and [Ca2+]i by microflurometry using Fura-2. HO-2- and CSE immunoreactivities were seen in WT AMC, which were absent in HO-2 and CSE null mice. Hypoxia (medium pO2 30-38 mmHg) evoked CA release and elevated [Ca2+]i. The magnitude of hypoxic response was greater in HO-2 null mice and in HO inhibitor treated WT AMC compared to controls. H2S levels were elevated in HO-2 null AMC. Either pharmacological inhibition or genetic deletion of CSE prevented the augmented hypoxic responses of HO-2 null AMC and H2S donor rescued AMC responses to hypoxia in HO-2/CSE double null mice. CORM-3, a CO donor, prevented the augmented hypoxic responses in WT and HO-2 null AMC. CO donor reduced H2S levels in WT AMC. The effects of CO donor were blocked by either ODQ or 8pCT, inhibitors of soluble guanylyl cyclase (SGC) or protein kinase G, respectively. These results suggest that HO-2-derived CO inhibits hypoxia-evoked CA secretion from adult murine AMC involving soluble guanylyl cyclase (SGC)-protein kinase G (PKG)-dependent regulation of CSE- derived H2S.

Endothelium-derived NO, but not cyclic GMP, is required for hypoxic augmentation in isolated porcine coronary arteries

2011 ◽  
Vol 301 (6) ◽  
pp. H2313-H2321 ◽  
Author(s):  
Calvin K. Y. Chan ◽  
Judith Mak ◽  
Yuansheung Gao ◽  
Ricky Y. K. Man ◽  
Paul M. Vanhoutte
Keyword(s):  
Nitric Oxide ◽  
Protein Kinase ◽  
Coronary Arteries ◽  
Cyclic Gmp ◽  
Guanylyl Cyclase ◽  
Calcium Influx ◽  
Soluble Guanylyl Cyclase ◽  
Isometric Tension ◽  
Nitric Oxide Donor ◽  
Atpase Inhibitor

The present study investigated the mechanism underlying the transient potentiation of vasoconstriction by hypoxia in isolated porcine coronary arteries. Isometric tension was measured in rings with or without endothelium. Hypoxia (Po2 <30 mmHg) caused a transient further increase in tension (hypoxic augmentation) in contracted (with U46619) preparations. The hypoxic response was endothelium dependent and abolished by inhibitors of nitric oxide synthase [ Nω-nitro-l-arginine methyl ester (l-NAME)] or soluble guanylyl cyclase (ODQ and NS2028). The addition of DETA NONOate (nitric oxide donor) in the presence of l-NAME restored the hypoxic augmentation, suggesting the involvement of the nitric oxide pathway. However, the same was not observed after incubation with 8-bromo-cyclic GMP, atrial natriuretic peptide, or isoproterenol. Assay of the cyclic GMP content showed no change upon exposure to hypoxia in preparations with and without endothelium. Incubation with protein kinase G and protein kinase A inhibitors did not inhibit the hypoxic augmentation. Thus the hypoxic augmentation is dependent on nitric oxide and soluble guanylyl cyclase but independent of cyclic GMP. The hypoxic augmentation persisted in calcium-free buffer and in the presence of nifedipine, ruling out a role for extracellular calcium influx. Hypoxia did not alter the intracellular calcium concentration, as measured by confocal fluorescence microscopy. This observation and the findings that hypoxic augmentation is enhanced by thapsigargin (sarco/endoplasmic reticulum calcium ATPase inhibitor) and inhibited by HA1077 or Y27632 (Rho kinase inhibitors) demonstrate the involvement of calcium sensitization in the phenomenon.

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