Cellular mechanisms of cyclic nucleotide-induced vasorelaxation

Brophy, Colleen M.; Whitney, Eric; Lamb, Shannon; Beall, Arthur C.

doi:10.1016/s0741-5214(97)70361-6

Cited by 24 publications

(15 citation statements)

References 16 publications

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“…The data are compiled from seven individual experiments. conditions and under conditions where the intracellular Ca 2ϩ is low and fixed (12,14). However, the phosphorylation of HSP20 does not increase in a muscle that is uniquely refractory to cyclic nucleotide-dependent vasorelaxation, human umbilical artery smooth muscle (15).…”

Section: Discussionmentioning

confidence: 99%

“…In addition, the extent of phosphorylation of these two proteins increases during forskolin or sodium nitroprusside-induced vasorelaxation under circumstances where the intracellular Ca 2ϩ concentrations are low and fixed (12). Finally, there is no increase in the extent of the phosphorylation of these two proteins in human umbilical artery smooth muscle, a muscle that is uniquely refractory to cyclic nucleotide-dependent vasorelaxation (15).…”

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confidence: 99%

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Cyclic Nucleotide-dependent Vasorelaxation Is Associated with the Phosphorylation of a Small Heat Shock-related Protein

Beall

Kato

Goldenring

et al. 1997

Journal of Biological Chemistry

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138

136

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Activation of cyclic nucleotide-dependent signaling pathways leads to the relaxation of various smooth muscles. One of the major phosphorylation events associated with cyclic nucleotide-dependent vasorelaxation in bovine trachealis and carotid artery smooth muscle is the phosphorylation of two 20-kDa phosphoproteins with pI values of 5.7 and 5.9 (previously designated pp8 and pp3, respectively). The present studies sought to determine the identities of pp3 and pp8 in vascular smooth muscle. The phosphopeptide maps for the pp8 and pp3 proteins were similar. Preparative two-dimensional gel electrophoresis and amino acid sequencing of a peptide fragment of the pp3 protein revealed a sequence identical to a 20-kDa heat shock-related protein (HSP20) previously purified from skeletal muscle. Western blot and immunoprecipitation analysis with anti-HSP20 antibodies demonstrated that the pp3 and pp8 proteins are phosphorylated forms of HSP20. In addition, HSP20 could be phosphorylated in vitro by both cAMP-dependent protein kinase and cGMP-dependent protein kinase. These data suggest that the phosphorylation of the heat shock-related protein HSP20 is associated with cyclic nucleotide-dependent relaxation of vascular smooth muscle.Activation of cyclic nucleotide-dependent signaling pathways leads to the relaxation of vascular smooth muscle. Isoproterenol, prostacyclin, and forskolin stimulate the adenylate cyclase/ cAMP pathway and activate cAMP-dependent protein kinase (PKA) 1 (1). Nitric oxide, atrial natriuretic peptide, sodium nitroprusside, and nitroglycerin stimulate the guanylate cyclase/ cGMP pathway and activate cGMP-dependent protein kinase (PKG) (2).A number of investigators have sought to identify the protein targets for PKA and PKG that are involved in smooth muscle relaxation. Two sites of particular interest have emerged. First, the phosphorylation of myosin light chain kinase by PKA decreases its sensitivity to activation by Ca 2ϩ -calmodulin, leading to a decrease in the phosphorylation of the myosin light chains (3). Second, PKA and/or PKG activation leads to changes in the activities of one or more Ca 2ϩ channels and/or Ca 2ϩ pumps, thereby reducing the intracellular Ca 2ϩ concentrations (4, 5). However, there is no simple correlation between the extent of myosin light chain phosphorylation and the state of contraction of vascular smooth muscle (6, 7). On the other hand, cyclic nucleotide-dependent relaxation of intact muscle strips can occur under conditions where the Ca 2ϩ concentration is fixed at either a low or a high concentration (8 -12).The relaxation of several different types of smooth muscles by forskolin or sodium nitroprusside is associated with an increase in the extent of phosphorylation of two 20-kDa proteins with pI values of 5.9 and 5.7, previously described as proteins 3 (pp3) and 8 (pp8), respectively (13,14). In addition, the extent of phosphorylation of these two proteins increases during forskolin or sodium nitroprusside-induced vasorelaxation under circumstances where the intrace...

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Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

Cyclic Nucleotide-dependent Vasorelaxation Is Associated with the Phosphorylation of a Small Heat Shock-related Protein

Beall

Kato

Goldenring

et al. 1997

Journal of Biological Chemistry

Self Cite

138

136

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“…Inhibition of phosphatases leads to contractions of carotid artery smooth muscles that are refractory to relaxation with forskolin or sodium nitroprusside [17]. This limits the use of cell-permeable phosphatase inhibitors to examine the effects of phosphatase inhibition on cyclic nucleotide-dependent relaxation.…”

Section: Discussionmentioning

confidence: 99%

Small Heat Shock Proteins and Vasospasm in Human Umbilical Artery Smooth Muscle1

Brophy

Beall

Lamb

et al. 1997

Biology of Reproduction

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Human umbilical artery smooth muscle is uniquely refractory to cyclic nucleotide-dependent vasorelaxation. Small heat shock proteins (HSPs) have been implicated as contractile regulatory proteins. Thus, we hypothesized that alterations in the phosphorylation of small HSPs may contribute to human umbilical artery smooth muscle vasospasm. Physiologic contractile responses were determined in a muscle bath and compared with phosphorylation events determined with whole-cell phosphorylation and 2-dimensional gel electrophoresis. Precontraction of bovine carotid artery smooth muscle with serotonin followed by relaxation with forskolin was associated with increases in the phosphorylation of HSP27 and HSP20. Precontraction of umbilical artery with serotonin followed by forskolin treatment led to increases in the phosphorylation of HSP27. However, the umbilical artery smooth muscle did not relax, nor was there an increase in the phosphorylation of HSP20 with forskolin treatment. These data suggest that impaired cyclic nucleotide-dependent relaxation of umbilical artery smooth muscle is associated with a lack of phosphorylation of HSP20.

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“…The actions of cGMP are terminated by phosphodiesterases (PDE), which hydrolyses cGMP to 5′‐GMP (Brophy et al . ). The most abundant PDE in the pulmonary circulation is PDE5 (Thomas et al .…”

Section: The Nitric Oxide Pathwaymentioning

confidence: 97%

The principal pathways involved in the in vivo modulation of hypoxic pulmonary vasoconstriction, pulmonary arterial remodelling and pulmonary hypertension

Kylhammar

Rådegran

2016

Acta Physiologica

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Hypoxic pulmonary vasoconstriction (HPV) serves to optimize ventilation-perfusion matching in focal hypoxia and thereby enhances pulmonary gas exchange. During global hypoxia, however, HPV induces general pulmonary vasoconstriction, which may lead to pulmonary hypertension (PH), impaired exercise capacity, right-heart failure and pulmonary oedema at high altitude. In chronic hypoxia, generalized HPV together with hypoxic pulmonary arterial remodelling, contribute to the development of PH. The present article reviews the principal pathways in the in vivo modulation of HPV, hypoxic pulmonary arterial remodelling and PH with primary focus on the endothelin-1, nitric oxide, cyclooxygenase and adenine nucleotide pathways. In summary, endothelin-1 and thromboxane A may enhance, whereas nitric oxide and prostacyclin may moderate, HPV as well as hypoxic pulmonary arterial remodelling and PH. The production of prostacyclin seems to be coupled primarily to cyclooxygenase-1 in acute hypoxia, but to cyclooxygenase-2 in chronic hypoxia. The potential role of adenine nucleotides in modulating HPV is unclear, but warrants further study. Additional modulators of the pulmonary vascular responses to hypoxia may include angiotensin II, histamine, serotonin/5-hydroxytryptamine, leukotrienes and epoxyeicosatrienoic acids. Drugs targeting these pathways may reduce acute and/or chronic hypoxic PH. Endothelin receptor antagonists and phosphodiesterase-5 inhibitors may additionally improve exercise capacity in hypoxia. Importantly, the modulation of the pulmonary vascular responses to hypoxia varies between species and individuals, with hypoxic duration and age. The review also define how drugs targeting the endothelin-1, nitric oxide, cyclooxygenase and adenine nucleotide pathways may improve pulmonary haemodynamics, but also impair pulmonary gas exchange by interference with HPV in chronic lung diseases.

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Cellular mechanisms of cyclic nucleotide-induced vasorelaxation

Abstract: These results suggest that Ca(2+)-independent mechanisms may also modulate vascular smooth muscle relaxation. Two possible late phase signaling mechanisms include phosphatase activation and an increase in the phosphorylation of two 20 kDa phosphoproteins.

Cited by 24 publications

References 16 publications

Cyclic Nucleotide-dependent Vasorelaxation Is Associated with the Phosphorylation of a Small Heat Shock-related Protein

Cyclic Nucleotide-dependent Vasorelaxation Is Associated with the Phosphorylation of a Small Heat Shock-related Protein

Small Heat Shock Proteins and Vasospasm in Human Umbilical Artery Smooth Muscle1

The principal pathways involved in the in vivo modulation of hypoxic pulmonary vasoconstriction, pulmonary arterial remodelling and pulmonary hypertension

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