Cytokine-Induced S-Nitrosylation of Soluble Guanylyl Cyclase and Expression of Phosphodiesterase 1A Contribute to Dysfunction of Longitudinal Smooth Muscle Relaxation

Abstract

The effect of proinflammatory cytokines on the expression and activity of soluble guanylyl cyclase (sGC) and cGMP-phosphodiesterases (PDEs) was determined in intestinal longitudinal smooth muscle. In control muscle cells, cGMP levels are regulated via activation of sGC and PDE5; the activity of the latter is regulated via feedback phosphorylation by cGMP-dependent protein kinase. In muscle cells isolated from muscle strips cultured with interleukin-1b (IL-1b) or tumor necrosis factor a (TNF-a) or obtained from the colon of TNBS (2,4,6-trinitrobenzene sulfonic acid)-treated mice, expression of inducible nitric oxide synthase (iNOS) was induced and sGC was S-nitrosylated, resulting in attenuation of nitric oxide (NO)-induced sGC activity and cGMP formation. The effect of cytokines on sGC S-nitrosylation and activity was blocked by the iNOS inhibitor 1400W [N-([3-(aminomethyl)phenyl]methyl)ethanimidamide dihydrochloride]. The effect of cytokines on cGMP levels measured in the absence of IBMX (3-isobutyl-1-methylxanthine), however, was partly reversed by 1400W or PDE1 inhibitor vinpocetine and completely reversed by a combination of 1400W and vinpocetine. Expression of PDE1A was induced and was accompanied by an increase in PDE1A activity in muscle cells isolated from muscle strips cultured with IL-1b or TNF-a or obtained from the colon of TNBStreated mice; the effect of cytokines on PDE1 expression and activity was blocked by, an inhibitor of nuclear factor kB activity. NO-induced muscle relaxation was inhibited in longitudinal muscle cells isolated from muscle strips cultured with IL-1b or TNF-a or obtained from the colon of TNBS-treated mice, and this inhibition was completely reversed by the combination of both 1400W and vinpocetine. Inhibition of smooth muscle relaxation during inflammation reflects the combined effects of decreased sGC activity via S-nitrosylation and increased cGMP hydrolysis via PDE1 expression.

Role of oxidative stress in oxaliplatin‐induced enteric neuropathy and colonic dysmotility in mice

“…Decreased basal tone and, thus, a larger resting diameter of the distal colon compromised the ability of smooth muscles to further relax. Similar findings have been observed following intestinal inflammation where smooth muscle relaxation in response to a NO donor was decreased (Van Bergeijk et al, ; Rajagopal et al, ). This compromised ability to relax was in part attributed to iNOS‐mediated protein nitrosylation (Rajagopal et al, ).…”

Nitric Oxide Synthase-2-Derived Nitric Oxide Drives Multiple Pathways of Breast Cancer Progression

“…Toward this end, the PDE5selective inhibitors, sildenafil, tadalafil, and MY5445, enhanced intracellular cGMP/PKG signaling, which correlated with abated cancer cell proliferation and increased apoptosis (145). Interestingly, cytokine-induced NOS2 led to Snitrosylation and inhibition of sGC activity, as well as reduced formation of cGMP and increased PDE1 in smooth muscle cells (110). These results suggest that high-flux NO derived from NOS2 abates cGMP signaling through S-nitrosylation and PDE mechanisms.…”

Oxidized soluble guanylyl cyclase causes erectile dysfunction in alcoholic mice

“…Oxidized sCG is presumably present in several diseased vessels (Beuve, 2017). However, while reduced response to NO, nitroprusside and/or sGC stimulators associated with sGC S‐nitrosylation has been reported following exposure to pathological stimuli including angiotensin II, aldosterone, IL‐1β or TNF‐α (Choi et al, 2011; Crassous et al, 2012; Maron et al, 2009; Rajagopal et al, 2015), increased response to sGC activators has not been shown. sGC oxidation associated with a reduced response to NO, NO donors or sGC stimulators with concomitant increased response to sGC activators has only been shown so far in artificial systems by oxidizing agents (Tawa et al, 2019) or in genetically modified animals such as the heme‐deficient sGC mice (Thoonen et al, 2015) or the CYB5R3−/− mice (Rahaman et al, 2017).…”