Nitric oxide as a second messenger in parathyroid hormone-related protein signaling

Kalinowski, Leszek; Dobrucki, Lawrence W.; Maliński, Tadeusz

doi:10.1677/joe.0.1700433

Cited by 44 publications

(38 citation statements)

References 37 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…These experiments demonstrate that NO liberated from spermine NONOate can influence vascular reactivity and serve to identify a physiologically relevant dose of spermine NONOate (100 nM) used in subsequent experiments. Concentrations of NO in the nanomolar range are consistent with previously reported measurements from endothelial cells in vitro and in vivo (Kalinowski et al, 2001;Balbatun et al, 2003;Kalinowski et al, 2003). Spermine NONOate, but not spermine, the polyamine remaining from the liberation of NO from spermine NONOate, inhibited ATP release from rabbit and human erythrocytes in response to decreased oxygen tension (Figs.…”

Section: Discussionsupporting

confidence: 90%

Nitric Oxide Inhibits ATP Release from Erythrocytes

Olearczyk

Ellsworth²,

Stephenson³

et al. 2004

J Pharmacol Exp Ther

View full text Add to dashboard Cite

Erythrocytes have been reported to release ATP from intracellular stores into the surrounding environment in response to decreased oxygen tension and mechanical deformation. This erythrocyte-derived ATP can then act on purinergic receptors present on vascular endothelial cells, resulting in the synthesis and bidirectional release of nitric oxide (NO). NO released abluminally produces relaxation of vascular smooth muscle, thereby increasing vascular caliber, leading to a decrease in deformation-induced ATP release from erythrocytes. In contrast, NO released into the vascular lumen could interact directly with formed elements in the blood, including the erythrocyte. Here, we investigate the hypothesis that NO functions in a negative-feedback manner to inhibit ATP release from the erythrocyte. The NO donor N-(2-aminoethyl)-N-(2-hydroxy-2-nitrosohydrazino)-1,2-ethylenediamine (spermine NONOate) decreased total pulmonary resistance in a dose-dependent manner when administered to isolated perfused rabbit lungs. ATP release from rabbit erythrocytes in response to decreased oxygen tension or mechanical deformation was inhibited by preincubation with spermine NONOate (100 nM, 20 min). Importantly, incubating rabbit erythrocytes with spermine (100 nM, 20 min), the polyamine remaining after the liberation of NO from spermine NONOate, did not affect decreased oxygen tension-induced ATP release. Mechanical deformation-induced ATP release was also inhibited when erythrocytes were preincubated with spermine NONOate. However, NO-depleted spermine NONOate had no effect on mechanical deformation-induced ATP release from rabbit erythrocytes. These data provide support for the hypothesis that NO inhibits ATP release from erythrocytes, thereby identifying an additional role of NO in the regulation of vascular resistance.The erythrocyte, via its ability to release ATP, has been identified as a potential regulator of vascular resistance (Ellsworth et al., 1995;Sprague et al., 1996). The release of ATP from intracellular stores into the surrounding environment is reported to occur in response to distinct physiological stimuli. One such stimulus, mechanical deformation, can occur as the erythrocyte passes through small resistance vessels and capillaries of the microcirculation or in response to increases in linear flow velocity. Sprague et al. (1996) reported that both rabbit and human erythrocytes release ATP in response to mechanical deformation produced by passage of erythrocytes through filters with an average pore size of 5 m. Human and hamster erythrocytes have also been reported to release ATP in response to decreased oxygen tension and/or reduced pH (Bergfeld and Forrester, 1992;Ellsworth et al., 1995), environments the erythrocyte would encounter as it traverses skeletal muscle and other oxygenconsuming organs.Once released from the erythrocyte into the circulation, ATP can activate purinergic receptors, specifically those of the P 2y subfamily, present on the vascular endothelium, resulting in the synthesis and release...

show abstract

Section: Discussionsupporting

confidence: 90%

Nitric Oxide Inhibits ATP Release from Erythrocytes

Olearczyk

Ellsworth²,

Stephenson³

et al. 2004

J Pharmacol Exp Ther

View full text Add to dashboard Cite

show abstract

“…It was already known that PTHrP-(1-34) acts through a known G protein-coupled receptor and can activate PKA, PKC, intracellular calcium, and nitric oxide pathways in different cell types (1,16,19). It was reasonable to surmise that the two PTHrP peptides might share signaling mechanisms, because both reduced caspase-3 activation after UV irradiation in our previous study (11).…”

Section: Discussionmentioning

confidence: 82%

“…Parathyroid hormone can activate PKC through the action of phospholipase D (23, 25), but we did not examine this pathway and we did not measure PKC activation directly. Because PTHrP-(140 -173) augments cAMP levels, the peptide may interact with a G protein-coupled receptor, similar to the receptor for PTHrP-(1-34) (1,16,19). In addition to effects in lung cancer, our laboratory has found (2) that PTHrP-(140 -173) also exerts cell surface effects in prostate carcinoma cells, where it stimulated increases in inositol phosphates.…”

Section: Discussionmentioning

confidence: 99%

Parathyroid hormone-related protein regulates apoptosis in lung cancer cells through protein kinase A

Hastings¹,

Araiza²,

Burton³

et al. 2004

American Journal of Physiology-Cell Physiology

View full text Add to dashboard Cite

Parathyroid hormone-related protein (PTHrP)-(1–34) and PTHrP-(140–173) protect lung cancer cells from apoptosis after ultraviolet (UV) irradiation. This study evaluated upstream signaling in PTHrP-mediated alteration of lung cancer cell sensitivity to apoptosis. The two peptides increased cAMP levels in BEN lung cancer cells by 15–35% in a dose-dependent fashion, suggesting signaling through protein kinase A (PKA). In line with this view, the PKA inhibitor H89 abrogated the protective effects of PTHrP-(1–34) and PTHrP-(140–173) against caspase activation and DNA loss. PKA activation by forskolin, 3-isobutyl-1-methylxanthine (IBMX), or 8-(4-chlorophenylthio)adenosine 3′,5′-cyclic monophosphate attenuated and H89 augmented apoptosis after UV exposure as indicated by caspase-3 activation, cell DNA loss, and morphological criteria. Studies with IBMX and varying doses of forskolin indicated that small increases in cAMP, on the order of those generated by IBMX alone and the PTHrP peptides, were sufficient to protect lung cancer cells from apoptosis. In summary, PTHrP-(1–34) and PTHrP-(140–173) stimulate PKA in lung carcinoma cells and protect cells against UV-induced caspase-3 activation and DNA fragmentation. PKA activation by other means also induces resistance to apoptosis, and the protective effect of the PTHrP peptide is blocked by PKA inhibition. Thus PKA appears to have a role in the regulatory effects of PTHrP on lung cancer cell survival.

show abstract

“…Data on the effects of PTH on the vessel wall are controversial. Whereas short-term PTH administration seems to have a vasorelaxing effect, 8,32 its chronic elevation accompanied by excessive reactive oxygen species generation might contribute to vascular smooth muscle cell contraction 33 and to the impairment of the endothelial vasoprotective properties, thus promoting atherosclerosis. 34,35 Along this line, in PHPT patients, 12 reduced nitric oxide (NO) bioavailability has been associated with peripheral endothelial dysfunction reversible after parathyroidectomy.…”

Section: Discussionmentioning

confidence: 99%

Coronary Microvascular Dysfunction Induced by Primary Hyperparathyroidism is Restored After Parathyroidectomy

et al. 2012

View full text Add to dashboard Cite

Background-Symptomatic primary hyperparathyroidism (PHPT) is associated with increased cardiovascular mortality.However, data on the association between asymptomatic PHPT and cardiovascular risk are lacking. We assessed coronary flow reserve (CFR) as a marker of coronary microvascular function in asymptomatic PHPT of recent onset. Methods and Results-We studied 100 PHPT patients (80 women; age, 58Ϯ12 years) without cardiovascular disease and 50 control subjects matched for age and sex. CFR in the left anterior descending coronary artery was detected by transthoracic Doppler echocardiography, at rest, and during adenosine infusion. CFR was the ratio of hyperemic to resting diastolic flow velocity. CFR was lower in PHPT patients than in control subjects (3.0Ϯ0. 2).In multivariable linear regression analysis, PTH, age, and heart rate were the only factors associated with CFR (Pϭ0.04, Pϭ0.01, and Pϭ0.006, respectively). In multiple logistic regression analysis, only PTH increased the probability of CFR Յ2.5 (Pϭ0.03). In all PHPT patients with CFR Յ2.5, parathyroidectomy normalized CFR (3.3Ϯ0.7 versus 2.1Ϯ0.5; PϽ0.0001). Conclusions-PHPT patients have coronary microvascular dysfunction that is completely restored after parathyroidectomy. PTH independently correlates with the coronary microvascular impairment, suggesting a crucial role of the hormone in explaining the increased cardiovascular risk in PHPT.

show abstract

Nitric oxide as a second messenger in parathyroid hormone-related protein signaling

Cited by 44 publications

References 37 publications

Nitric Oxide Inhibits ATP Release from Erythrocytes

Nitric Oxide Inhibits ATP Release from Erythrocytes

Parathyroid hormone-related protein regulates apoptosis in lung cancer cells through protein kinase A

Coronary Microvascular Dysfunction Induced by Primary Hyperparathyroidism is Restored After Parathyroidectomy

Contact Info

Product

Resources

About