Evidence for, and Importance of, cGMP-Independent Mechanisms with NO and NO Donors on Blood Vessels and Platelets

Wanstall, Janet C.; Homer, Kerry L.; Doggrell, Sheila A

doi:10.2174/1570161052773933

Cited by 79 publications

(52 citation statements)

References 66 publications

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“…In this regard, increasing evidence indicates that NO regulates a variety of physiological functions in a cGMP-independent mechanism, including apoptosis and growth inhibition in vascular and endothelial cells (49). In addition, peroxynitrite, which is formed by the interaction of NO and superoxide anion (50), did not appear to be implicated in NO-induced decreased expression of NPR-C, because MnTBAP, a scavenger of peroxynitrite and superoxide dismutase mimetic agent, did not restore the expression of NPR-C toward control levels.…”

Section: Discussionmentioning

confidence: 99%

Nitric oxide attenuates the expression of natriuretic peptide receptor C and associated adenylyl cyclase signaling in aortic vascular smooth muscle cells: role of MAPK

Arejian

Li²,

Anand‐Srivastava³

2009

American Journal of Physiology-Heart and Circulatory Physiology

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Arejian M, Li Y, Anand-Srivastava MB. Nitric oxide attenuates the expression of natriuretic peptide receptor C and associated adenylyl cyclase signaling in aortic vascular smooth muscle cells: role of MAPK. Am J Physiol Heart Circ Physiol 296: H1859 -H1867, 2009. First published February 27, 2009 doi:10.1152/ajpheart.01108.2008We have earlier shown that the treatment of A10 vascular smooth muscle cells with S-nitroso-N-acetyl-penicillamine (SNAP); nitric oxide donor (NO) for 24 h decreased the expression of natriuretic peptide receptor C (NPR-C) and adenylyl cyclase signaling. The present study was undertaken to examine the implication of different signaling mechanisms in a NO-induced response. The treatment of A10 vascular smooth muscle cells with SNAP decreased the expression of NPR-C and Gi␣ proteins in a time-dependent manner. The expression of Gi␣ proteins was decreased at 6 h, whereas the expression of NPR-C was attenuated at 2 h. The NPR-C-mediated inhibition of adenylyl cyclase was attenuated (ϳ50%) after 2 h of treatment and was completely abolished after 6 h of treatment. The decreased expression of NPR-C and NPR-C-mediated attenuation of adenylyl cyclase after 2 h of treatment was reversed to control levels by PD-98059, a MEK inhibitor. SNAP also modulated the ERK1/2 phosphorylation in a time-dependent manner; an increase was observed up to 2 h, and, thereafter, the ERK1/2 phosphorylation was decreased. On the other hand, 1H-[1,2,4]oxadiazolo[4,3-a]quinoxalin-1-one and KT-5823 inhibitor of soluble guanylyl cyclase and protein kinase G, respectively, and Mn(III)tetrakis(4-benzoic acid)porphyrin, a scavenger of peroxynitrite, were unable to restore the SNAPinduced decreased expression of NPR-C protein and increased ERK1/2 phosphorylation to control levels. However, the decreased levels of phosphorylated ERK1/2 and Gi␣ proteins were restored to control levels by 8-bromo-cAMP. These results indicate that a temporal relationship follows between a NO-induced decreased expression of NPR-C and Gi␣ proteins. The decreased expression of NPR-C is mediated through cGMP-independent but MAPK-dependent pathway, whereas NO-induced decreased levels of cAMP may contribute to the decreased activation of MAPK and thereby decreased the expression of Gi␣ proteins. G proteins; mitogen-activated protein kinase NATRIURETIC PEPTIDES (NPs) are a family of three peptide hormones termed atrial NP (ANP), brain NP, and C-type NP, all of which are produced in mammalian hearts, including human hearts (31). ANP regulates a variety of physiological parameters, including blood pressure (7), by interacting with receptors on plasma membrane either to generate second messengers such as cAMP (2, 3) and cGMP (20,48) or to affect ion channels (7). Three types of NP receptors (NPRs) have been cloned; NPR-A (16) and NPR-B (15) subtypes are membranebound guanylate cyclases (130-180 kDa) that mediate the biological actions of NP through a regulation of intracellular cGMP levels (7), whereas NPR-C (4, 17) is a disulfide-bridged homodimer of 67-an...

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Section: Discussionmentioning

confidence: 99%

Nitric oxide attenuates the expression of natriuretic peptide receptor C and associated adenylyl cyclase signaling in aortic vascular smooth muscle cells: role of MAPK

Arejian

Li²,

Anand‐Srivastava³

2009

American Journal of Physiology-Heart and Circulatory Physiology

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“…Similar to its role in smooth muscle, NO has been postulated to mediate platelet inhibition by cGMP-dependent as well as cGMPindependent mechanisms (9,(21)(22)(23). The Western blot in Fig.…”

Section: Lack Of Glycerol Trinitrate (Gtn)-induced Decrease In Systolmentioning

confidence: 94%

“…Besides these cGMP-mediated effects, NO is thought to mediate a variety of effects via cGMP-independent mechanisms in the cardiovascular system (for a review, see ref. 9). …”

mentioning

confidence: 99%

Fatal gastrointestinal obstruction and hypertension in mice lacking nitric oxide-sensitive guanylyl cyclase

Friebe

Mergia

Dangel

et al. 2007

Proc. Natl. Acad. Sci. U.S.A.

215

225

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The signaling molecule nitric oxide (NO), first described as endothelium-derived relaxing factor (EDRF), acts as physiological activator of NO-sensitive guanylyl cyclase (NO-GC) in the cardiovascular, gastrointestinal, and nervous systems. Besides NO-GC, other NO targets have been proposed; however, their particular contribution still remains unclear. Here, we generated mice deficient for the ␤1 subunit of NO-GC, which resulted in complete loss of the enzyme. GC-KO mice have a life span of 3-4 weeks but then die because of intestinal dysmotility; however, they can be rescued by feeding them a fiber-free diet. Apparently, NO-GC is absolutely vital for the maintenance of normal peristalsis of the gut. GC-KO mice show a pronounced increase in blood pressure, underlining the importance of NO in the regulation of smooth muscle tone in vivo. The lack of an NO effect on aortic relaxation and platelet aggregation confirms NO-GC as the only NO target regulating these two functions, excluding cGMP-independent mechanisms. Our knockout model completely disrupts the NO/cGMP signaling cascade and provides evidence for the unique role of NO-GC as NO receptor.cardiovascular ͉ knockout mice ͉ cGMP ͉ platelet aggregation ͉ smooth muscle relaxation T he nitric oxide (NO)/cGMP signaling cascade regulates a plethora of physiological functions in the cardiovascular, neuronal, and gastrointestinal systems (1-3). In the vascular system, NO, first recognized as endothelium-derived relaxing factor (EDRF; ref. 4), has been shown to mediate smooth muscle relaxation and inhibition of platelet aggregation. NO is synthesized by the family of NO synthases which exist in endothelial, neuronal, and inducible forms. The prominent receptor known to date is the enzyme NO-sensitive guanylyl cyclase (NO-GC). Stimulation of NO-GC by NO results in the production of the second messenger, cGMP, which exerts its effects via cGMPdependent kinases, channels, or phosphodiesterases (5-8). Besides these cGMP-mediated effects, NO is thought to mediate a variety of effects via cGMP-independent mechanisms in the cardiovascular system (for a review, see ref. 9).To gain further insight into the NO/cGMP signaling cascade, mice deficient in NO synthases (NOS) have been generated (10)(11)(12)(13)(14). Although these mouse lines have tremendously helped to understand NO/cGMP signaling, it is still not known which of NO's effects are mediated via NO-GC and thus cGMP, or alternatively, via pathways not involving cGMP.To address this point and to further investigate the physiological role of the enzyme and of the NO/cGMP signaling cascade in vivo, we generated an NO-GC-deficient mouse line. NO-GC is a heterodimer made up of two subunits, ␣ and ␤. Two isoforms are known to exist (␣ 1 ␤ 1 and ␣ 2 ␤ 1 ; ref. 15) in which the ␤ 1 subunit acts as the dimerizing partner for either ␣ subunit. ␣ subunits in the absence of the ␤ 1 subunit do not form dimers and are not catalytically active. Thus, deletion of the ␤ 1 subunit should completely eliminate NO-GC and yield a mouse line ...

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“…NO relaxes smooth muscles by activating sGC and increasing cGMP levels, but the signaling cascades that ultimately trigger relaxation appear to vary depending on the smooth muscle type (2,54,58). Several mechanisms by which NO and cGMP relax smooth muscle have been investigated: 1) IP 3 Rassociated cGMP kinase substrate (IRAG) phosphorylation by PKG (13); 2) a decrease in Ca 2ϩ sensitivity of the contractile apparatus (37, 49); 3) hyperpolarization of the smooth muscle cell membrane (48,52); and 4) lowering of [Ca 2ϩ ] i and elevation of [Ca 2ϩ ] SR by SERCA pump activation (7,8).…”

Section: Discussionmentioning

confidence: 99%

CaM kinase II activation and phospholamban phosphorylation by SNP in murine gastric antrum smooth muscles

Kim

Perrino²

2007

American Journal of Physiology-Gastrointestinal and Liver Physi

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and Thr 17 phosphorylation were ODQ sensitive. However, only PLBThr 17 phosphorylation was inhibited by CPA or KN-93. These results suggest that CaM kinase II activation and PLB phosphorylation participate in the relaxant effect of SNP on murine gastric antrum smooth muscles through a nitric oxide/guanylyl cyclase/cGMP pathway. Ca 2ϩ /calmodulin-dependent protein kinase II; phospholamban; nitric oxide THE GASTRIC ANTRUM undergoes spontaneous peristaltic contractions to accomplish the grinding, mixing, and gastric emptying functions of this part of the stomach. Slow wave propagation from the greater curvature of the orad corpus to the pylorus produces gastric peristalsis. Phasic contractions initiated by slow waves are the basis for gastric peristalsis (25). The normal pattern of slow wave propagation results from a gradient in intrinsic frequencies along the longitudinal axis of the stomach. The orad corpus is the dominant pacemaker in the human stomach and in animal models such as the dog and mouse (12,25,38) because it generates slow waves at the fastest rate. Conditions that affect the intrinsic pacemaker frequency in the antrum or produce arrhythmic activity in this region can result in a breakdown in functional coupling between the corpus and antrum and interfere with normal gastric emptying (6, 26).Insufficient gastric emptying produces pathophysiological problems such as functional dyspepsia, postsurgical gastroparesis, and diabetic gastroparesis (29, 51). Slow wave generation by myenteric interstitial cells of Cajal results in the activation of voltage-dependent Ca 2ϩ channels and the generation of phasic contractions of antrum smooth muscle cells (9,11,39,40). Thus, in addition to studies of the electrical coupling of myenteric interstitial cells of Cajal to smooth muscle cells, studies of the Ca 2ϩ -handling mechanisms of antrum smooth muscles will provide insights into gastric smooth muscle physiology and pathophysiology.The relaxant effects of nitric oxide (NO) and NO donors on smooth muscles are well established, but many details of the mechanism of NO-induced relaxation are still under investigation (54). One possible mechanism by which NO relaxes smooth muscle is by hyperpolarization of the smooth muscle cell plasma membrane. Porter et al. (43) reported that the NO donor sodium nitroprusside (SNP) increases Ca 2ϩ spark frequency and activates spontaneous transient outward currents (STOCs) via a NO/soluble guanylyl cyclase (sGC)/cGMP pathway in cerebral and coronary artery myocytes. Furthermore, SNP-induced relaxation of the rat gastric fundus is ryanodine sensitive and involves small-conductance Ca 2ϩ -activated K ϩ (K Ca ) channels (15). Similarly, in guinea pig gastric antrum myocytes, SNP increases intermediate-conductance K Ca current and enhances STOCs, which are sensitive to inositol (1,4,5)-trisphosphate receptor (IP 3 R) inhibitors (58). These findings suggest that sarcoplasmic reticulum (SR) Ca 2ϩ release plays a role in the nitrergic relaxation of smooth muscles.In several smooth muscles...

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Evidence for, and Importance of, cGMP-Independent Mechanisms with NO and NO Donors on Blood Vessels and Platelets

Cited by 79 publications

References 66 publications

Nitric oxide attenuates the expression of natriuretic peptide receptor C and associated adenylyl cyclase signaling in aortic vascular smooth muscle cells: role of MAPK

Nitric oxide attenuates the expression of natriuretic peptide receptor C and associated adenylyl cyclase signaling in aortic vascular smooth muscle cells: role of MAPK

Fatal gastrointestinal obstruction and hypertension in mice lacking nitric oxide-sensitive guanylyl cyclase

CaM kinase II activation and phospholamban phosphorylation by SNP in murine gastric antrum smooth muscles

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