scholarly journals Inhibition of Vascular Smooth Muscle Growth by the Soluble Guanylyl Cyclase Activator BAY 60–2770

2013 ◽  
Vol 27 (S1) ◽  
Author(s):  
Danielle Nicole Martin ◽  
Shaquria P Adderley ◽  
Chintamani N Joshi ◽  
William Durante ◽  
David A Tulis
Keyword(s):  
Smooth Muscle ◽  
Vascular Smooth Muscle ◽  
Guanylyl Cyclase ◽  
Muscle Growth ◽  
Soluble Guanylyl Cyclase ◽  
Cyclase Activator

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.

TNF-alpha and IFN-gamma induce expression of nitric oxide synthase in cultured rat medullary interstitial cells

1995 ◽  
Vol 269 (2) ◽  
pp. F212-F217 ◽  
Author(s):  
K. S. Lau ◽  
O. Nakashima ◽  
G. R. Aalund ◽  
L. Hogarth ◽  
K. Ujiie ◽  
...  
Keyword(s):  
Nitric Oxide ◽  
Smooth Muscle ◽  
Nitric Oxide Synthase ◽  
Vascular Smooth Muscle ◽  
Guanylyl Cyclase ◽  
Soluble Guanylyl Cyclase ◽  
Tnf Alpha ◽  
No Production ◽  
Ifn Gamma ◽  
Oxide Synthase

Cytokines increase the expression of the inducible (type II) nitric oxide synthase (NOS) in macrophages, liver, and renal epithelial cells. Previously, we found that cultured rat medullary interstitial cells (RMIC) contain high levels of soluble guanylyl cyclase. To determine whether these cells can also produce NO, we studied the effects of tumor necrosis factor-alpha (TNF-alpha) and interferon-gamma (IFN-gamma) on NO production, NOS II mRNA, and NOS II protein expression. Both TNF-alpha and IFN-gamma, in the presence of a low concentration of the other cytokine, caused dose-dependent increases in NO production. Exposure to TNF-alpha and IFN-gamma stimulated the production of NOS II mRNA, as determined by Northern blotting. Restriction mapping of reverse transcription-polymerase chain reaction products indicated that normal cells contained macrophage NOS II, whereas cytokine-stimulated cells contained primarily vascular smooth muscle NOS II and some macrophage NOS II. The appearance of NOS II protein was demonstrated by Western blotting. RMIC cell guanosine 3',5'-cyclic monophosphate accumulation increased 129-fold in response to the cytokines. NOS inhibitors decreased nitrite production. We conclude that 1) TNF-alpha and IFN-gamma induce the expression of vascular smooth muscle NOS II and production of NO in RMIC, and 2) NO acts as an autocrine activator of the soluble guanylyl cyclase in RMIC.

scholarly journals Age Impairs Soluble Guanylyl Cyclase Function in Mouse Mesenteric Arteries

2021 ◽  
Vol 22 (21) ◽  
pp. 11412
Author(s):  
Cheng Zhong ◽  
Minze Xu ◽  
Sengül Boral ◽  
Holger Summer ◽  
Falk-Bach Lichtenberger ◽  
...  
Keyword(s):  
Smooth Muscle ◽  
Vascular Smooth Muscle ◽  
Mrna Expression ◽  
Guanylyl Cyclase ◽  
Pde5 Inhibitor ◽  
Soluble Guanylyl Cyclase ◽  
Mesenteric Arteries ◽  
No Donor ◽  
Diabetic Vasculopathy ◽  
Endothelial Nitric Oxide

Endothelial dysfunction (ED) comes with age, even without overt vessel damage such as that which occurs in atherosclerosis and diabetic vasculopathy. We hypothesized that aging would affect the downstream signalling of the endothelial nitric oxide (NO) system in the vascular smooth muscle (VSM). With this in mind, resistance mesenteric arteries were isolated from 13-week (juvenile) and 40-week-old (aged) mice and tested under isometric conditions using wire myography. Acetylcholine (ACh)-induced relaxation was reduced in aged as compared to juvenile vessels. Pretreatment with L-NAME, which inhibits nitrix oxide synthases (NOS), decreased ACh-mediated vasorelaxation, whereby differences in vasorelaxation between groups disappeared. Endothelium-independent vasorelaxation by the NO donor sodium nitroprusside (SNP) was similar in both groups; however, SNP bolus application (10−6 mol L−1) as well as soluble guanylyl cyclase (sGC) activation by runcaciguat (10−6 mol L−1) caused faster responses in juvenile vessels. This was accompanied by higher cGMP concentrations and a stronger response to the PDE5 inhibitor sildenafil in juvenile vessels. Mesenteric arteries and aortas did not reveal apparent histological differences between groups (van Gieson staining). The mRNA expression of the α1 and α2 subunits of sGC was lower in aged animals, as was PDE5 mRNA expression. In conclusion, vasorelaxation is compromised at an early age in mice even in the absence of histopathological alterations. Vascular smooth muscle sGC is a key element in aged vessel dysfunction.

Hyperpolarization of murine small caliber mesenteric arteries by activation of endothelial proteinase-activated receptor 2

2004 ◽  
Vol 82 (12) ◽  
pp. 1103-1112 ◽  
Author(s):  
John J McGuire ◽  
Morley D Hollenberg ◽  
Brian M Bennett ◽  
Chris R Triggle
Keyword(s):  
Smooth Muscle ◽  
Membrane Potential ◽  
Vascular Smooth Muscle ◽  
Blood Vessels ◽  
Guanylyl Cyclase ◽  
Soluble Guanylyl Cyclase ◽  
Isometric Tension ◽  
Mesenteric Arteries ◽  
Induced Hypotension ◽  
Protease Activated Receptor 2

Activation of endothelial proteinase-activated receptor 2 (PAR-2) relaxes vascular smooth muscle (VSM) and causes hypotension by nitric oxide (NO)–prostanoid-dependent and -independent mechanisms. We investigated whether endothelium-dependent hyperpolarization of VSM was the mechanism whereby resistance caliber arteries vasodilated independently of NO. VSM membrane potentials and isometric tension were measured concurrently to correlate the electrophysiological and mechanical changes in murine small caliber mesenteric arteries. In uncontracted arteries, the PAR-2 agonist, SLIGRL-NH2 (0.1 to 10 µmol/L), hyperpolarized the VSM membrane potential only in endothelium-intact arterial preparations. This response was unaltered by treatment of arteries with inhibitors of NO synthases (L-NAME), soluble guanylyl cyclase (ODQ), and cyclooxygenases (indomethacin). L-NAME, ODQ, and indomethacin also failed to inhibit SLIGRL-NH2-induced hyperpolarization and of cirazoline-contracted mesenteric arteries. However, in blood vessels that were depolarized and contracted with 30 mmol/L KCl, the effects of the SLIGRL-NH2 on membrane potential and tension were not observed. SLIGRL-NH2-induced hyperpolarization and relaxation was inhibited completely by the combination of apamin plus charybdotoxin, but only partially inhibited after treatment with the combination of barium plus ouabain, suggesting an important role for SKCa and IKCa channels and a lesser role for Kir channels and Na+/K+ ATPases in the hyperpolarization response. We concluded that activation of endothelial PAR-2 hyperpolarized the vascular smooth muscle (VSM) cells of small caliber arteries, without requiring the activation of NO synthases, cyclooxygenases, or soluble guanylyl cyclase. Indeed, this hyperpolarization may be a primary mechanism for PAR-2–induced hypotension in vivo.Key words: proteinase-activated receptor 2, protease-activated receptor 2, endothelium, vascular smooth muscle, hyperpolarization, blood vessels, transgenic mice, vasoactive peptides.

scholarly journals Modulation of nitric oxide-stimulated soluble guanylyl cyclase activity by cytoskeleton-associated proteins in vascular smooth muscle

2018 ◽  
Vol 156 ◽  
pp. 168-176 ◽  
Author(s):  
Alexander Kollau ◽  
Bernd Gesslbauer ◽  
Michael Russwurm ◽  
Doris Koesling ◽  
Antonius C.F. Gorren ◽  
...  
Keyword(s):  
Nitric Oxide ◽  
Smooth Muscle ◽  
Vascular Smooth Muscle ◽  
Guanylyl Cyclase ◽  
Soluble Guanylyl Cyclase ◽  
Cyclase Activity ◽  
Associated Proteins ◽  
Guanylyl Cyclase Activity
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