Defective smooth muscle regulation in cGMP kinase I-deficient mice

Pfeifer, Alexander; Klatt, Peter; Maßberg, Steffen; Ny, Lars; Sausbier, Matthias; Hirneiß, Christoph; Wang, Ge‐Xing; Korth, Michael; Aszódi, Attila; Andersson, Karl‐Erik; Krombach, Fritz; Mayerhofer, Artur; Ruth, Peter; Fässler, Reinhard; Hofmann, Franz

doi:10.1093/emboj/17.11.3045

Cited by 479 publications

(495 citation statements)

References 40 publications

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“…Many of these responses are mediated by the activation of the cGMP-dependent kinase I. 5,14,17 The cGMPdependent protein kinase I has emerged as an important signal transduction mediator. 4,18,19 Subsequent cGMP-mediated phosphorylation of proteins appears to be involved in intracellular Ca 2 sequestration or removal.…”

Section: Discussionmentioning

confidence: 99%

Soluble guanylate cyclase and cGMP-dependent protein kinase I expression in the human corpus cavernosum

et al. 2000

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Nitric oxide (NO) as a mediator in smooth muscle cells causes rapid and robust increases in cGMP levels. The cGMP-dependent protein kinase I has emerged as an important signal transduction mediator for smooth muscle relaxation. The purpose of this study was to examine the existence and distribution of two key enzymes of the NOacGMP pathway, the cGMP-dependent kinase I (cGK I) and the soluble guanylate cyclase (sGC) in human cavernosal tissue.The expression of the enzymes were examined in corpus cavernosum specimens of 23 patients. Eleven potent patients suffered from penile deviations and were treated via Nesbit's surgical method. Nine long-term impotent patients underwent implantation of¯exible hydraulic prothesis. Three potent patients underwent trans-sexual operations. Expression of the sGC and cGK I were examined immunohistochemically using speci®c antibodies.In all specimens of cavernosal tissue a distinct immunoreactivity was observed in different parts and structures. We found a high expression of sGC and cGK I in smooth muscle cells of vessels and in the ®bromuscular stroma. The endothelium of the cavernosal sinus, of the cavernosal arteries, and the cavernosal nerve ®bers showed an immunoreactivity against sGC. The distribution analysis of cGK I revealed a predominately vesicular localization in smooth muscle cells. The examination of the endothelium showed no clear immunoreactivity against cGK I. There was no distinct difference in immunoreactivity and cellular distribution between potent and impotent patients.cGMP-dependent kinase I is predominately expressed in cavernosal smooth muscle cells. sGC is expressed in smooth muscle cells, endothelium and nerve ®bers of the corpus cavernosum. In this study, there is no correlation between the distribution of soluble guanylate cyclase and cGMP dependent kinase I in potent or impotent patients.

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Section: Discussionmentioning

confidence: 99%

Soluble guanylate cyclase and cGMP-dependent protein kinase I expression in the human corpus cavernosum

et al. 2000

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“…In turn, PKG I can mediate vasodilatation and inhibit platelet aggregation. 46,47 Addition of L-NAME diminishes the cGMP response, providing additional evidence that EPO stimulation of eNOS in endothelial cells is an important and necessary pathway for NO and subsequently cGMP production.…”

Section: Org Frommentioning

confidence: 94%

Erythropoietin and hypoxia stimulate erythropoietin receptor and nitric oxide production by endothelial cells

Beleslin-Čokić

Čokić²,

Yu³

et al. 2004

Blood

262

211

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Erythropoietin (EPO), a hypoxia-inducible cytokine, is required for survival, proliferation, and differentiation of erythroid progenitor cells. EPO can also stimulate proliferation and angiogenesis of endothelial cells that express EPO receptors (EPORs). In this study we investigated the EPO response of vascular endothelial cells at reduced oxygen tension (5% and 2%), in particular the effect of EPO on nitric oxide (NO) release. Endothelial nitric oxide synthase (eNOS) produces NO, which maintains blood pressure homeostasis and blood flow. We find that EPOR is inducible by EPO in primary human endothelial cells of vein (HUVECs) and artery (HUAECs) and cells from a human bone marrow microvascular endothelial line (TrHBMEC) to a much greater extent at low oxygen tension than in room air. We found a corresponding increase in eNOS expression and NO production in response to EPO during hypoxia. Stimulation of NO production was dose dependent on EPO concentration and was maximal at 5 U/mL. NO activates soluble guanosine cyclase to produce cyclic guanosine monophosphate (cGMP), and we observed that EPO induced cGMP activity. These results suggest that low oxygen tension increases endothelial cell capacity to produce NO in response to EPO by induction of both EPOR and eNOS. This effect of EPO on eNOS may be a physiologically relevant mechanism to counterbalance the hypertensive effects of increased hemoglobin-related NO destruction resulting from hypoxia-induced increased red cell

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“…Fleischhacker and colleagues have demonstrated that diabetic smooth muscle contractility is augmented due to changes in subcellular Ca 2+ distribution. Additionally, increased · O 2 -production in diabetes contributes to smooth muscle dysfunction via diminished activity and expression of soluble guanylyl cyclase (sGC) and cGMP-dependent protein kinase type I (cGKI) in VSMC [54,55] . VSMCs isolated from diabetic GK rats exhibit marked resistance to insulin-mediated upstream signaling via the IRS-1/ PI3K pathway.…”

Section: Vascular Dysfunction In Metabolic Syndrome (Hyper Lipidemia mentioning

confidence: 99%

Adiponectin resistance and vascular dysfunction in the hyperlipidemic state

Liang

2010

Acta Pharmacol Sin

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Insulin plays an important role in the stimulation of vascular nitric oxide production, with both short term (vasomotility and antithrombotic effects) and long term (smooth muscle cell growth and migration inhibition) benefits. Impaired vasodilatory response to insulin, the hallmark of vascular insulin resistance (IR), has important implications for circulatory pathophysiology. An association between adipokines and IR has been observed in both diabetic and nondiabetic states. Adiponectin (APN) is an insulin-sensitizing adipokine known to stimulate skeletal muscle fatty acid (FA) oxidation and reduce lipid accumulation. Recent demonstrations of potential cross-talk between APN and insulin in vascular function regulation are particularly interesting. The lipid accumulation observed after chronic high-fat (HF) diets and in the obese state may reduce vascular response to APN, a pathologic state termed as APN resistance. This review highlights the importance of insulin sensitivity and APN activity in the maintenance of endothelial function. It explores the relationships between vascular IR and APN resistance in the hyperlipidemic pathological condition, representative of the metabolic syndrome. The investigation of vascular insulin and APN resistance provides not only better understanding of vascular pathophysiology, but also an opportunity for therapeutic targeting in individuals affected by the metabolic syndrome.

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Defective smooth muscle regulation in cGMP kinase I-deficient mice

Cited by 479 publications

References 40 publications

Soluble guanylate cyclase and cGMP-dependent protein kinase I expression in the human corpus cavernosum

Soluble guanylate cyclase and cGMP-dependent protein kinase I expression in the human corpus cavernosum

Erythropoietin and hypoxia stimulate erythropoietin receptor and nitric oxide production by endothelial cells

Adiponectin resistance and vascular dysfunction in the hyperlipidemic state

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