Molecular Variants of Soluble Guanylyl Cyclase Affecting Cardiovascular Risk

Wobst, Jana; Rumpf, P; Dang, Tan An; Segura-Puimedon, Maria; Erdmann, Jeanette; Schunkert, Heribert

doi:10.1253/circj.cj-15-0025

Cited by 12 publications

(4 citation statements)

References 66 publications

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“…Moreover, smooth muscle cell–specific inducible knockout of sGC β in mice results in hypertension, suggesting sGC expression in smooth muscle cells is critical for modulating vascular tone ( Groneberg et al, 2010 ). Genome-wide association studies of single nucleotide polymorphisms also identified genetic variants within the sGC genes GUCY1A3 and GUCY1B3 as being associated with a high risk for cardiovascular disease ( Ehret et al, 2011 ; Wobst et al, 2015 ; Shendre et al, 2017 ). Of translational importance, small-molecule sGC modulators have been developed for clinical use to restore disease-associated loss of sGC activity and cGMP production to varying degrees of success ( Yoshina et al, 1978 ; Stasch et al, 2001 ; Frey et al, 2008 ; Meurer et al, 2009 ; Mittendorf et al, 2009 ).…”

Section: Introductionmentioning

confidence: 99%

Antagonism of Forkhead Box Subclass O Transcription Factors Elicits Loss of Soluble Guanylyl Cyclase Expression

et al. 2019

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Nitric oxide (NO) stimulates soluble guanylyl cyclase (sGC) activity, leading to elevated intracellular cyclic guanosine 39,59-monophosphate (cGMP) and subsequent vascular smooth muscle relaxation. It is known that downregulation of sGC expression attenuates vascular dilation and contributes to the pathogenesis of cardiovascular disease. However, it is not well understood how sGC transcription is regulated. Here, we demonstrate that pharmacological inhibition of Forkhead box subclass O (FoxO) transcription factors using the smallmolecule inhibitor AS1842856 significantly blunts sGC a and b mRNA expression by more than 90%. These effects are concentration-dependent and concomitant with greater than 90% reduced expression of the known FoxO transcriptional targets, glucose-6-phosphatase and growth arrest and DNA damage protein 45 a (Gadd45a). Similarly, sGC a and sGC b protein expression showed a concentration-dependent downregulation. Consistent with the loss of sGC a and b mRNA and protein expression, pretreatment of vascular smooth muscle cells with the FoxO inhibitor decreased sGC activity measured by cGMP production following stimulation with an NO donor. To determine if FoxO inhibition resulted in a functional impairment in vascular relaxation, we cultured mouse thoracic aortas with the FoxO inhibitor and conducted ex vivo two-pin myography studies. Results showed that aortas have significantly blunted sodium nitroprusside-induced (NO-dependent) vasorelaxation and a 42% decrease in sGC expression after 48-hour FoxO inhibitor treatment. Taken together, these data are the first to identify that FoxO transcription factor activity is necessary for sGC expression and NO-dependent relaxation.

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Section: Introductionmentioning

confidence: 99%

Antagonism of Forkhead Box Subclass O Transcription Factors Elicits Loss of Soluble Guanylyl Cyclase Expression

et al. 2019

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“…Эта молекула является одним из наиболее важных элементов внутриклеточных сигнальных каскадов в сосудистой системе [9,10]. Оксид азота был впервые описан как биоактивная молекула благодаря его способности стимулировать растворимую гуанилатциклазу (р-ГЦ) [11,12]. Исследования, проведенные за последние 30 лет, показали значительное разнообразие передачи сигналов с помощью NO в сосудистой системе, которое включает, кроме активации р-ГЦ, также и S-нитрозирования белков [13].…”

Section: роль оксид азота в регуляции кровообращения и микрореологии unclassified

The role of gaseous mediators (CO, NO and H2S) in the regulation of blood circulation: analysis of the participation of blood cell microrheology

Muravyov

2021

Regional blood circulation and microcirculation

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Among the signaling molecules involved in the regulation of intra- and intercellular systems in various types of cells, a special place is occupied by gaseous compounds – gasotransmitters (GTs). Currently, the most studied are three molecules: nitrogen oxide (NO), carbon monoxide (CO) and hydrogen sulfide (H2S). For them, the enzymatic systems of intracellular synthesis and degradation have been determined, the physiological effect has been proved, and the intracellular mechanisms have been determined. Changes in the work of these mechanisms under the influence of GTs causes the development of physiological and/or pathophysiological reactions. These GTs are involved in the regulation of various organs and systems of the human body under normal and pathological conditions, including the structure and function of the circulatory system. In this article, special attention is paid to the influence of all three GTs and their donors on the vascular and hemorheological aspect of the work of blood circulation, and especially on an underdeveloped problem – the microrheology of erythrocytes. It has been shown that all three GTs, along with the well-known vasodilating effect, reduce the adhesion and aggregation of platelets and leukocytes, as well as moderately stimulate the deformability of erythrocytes and strongly inhibit their aggregation. The performed analysis of the data indicates that, along with the specific signaling cascades for each GT, the use of a common signaling pathway associated with soluble guanylate cyclase and NO synthase was also revealed in microrheological responses. The intersection of signaling pathways triggered by NO, CO and H2S on common effectors, as well as their interaction with each other (cross-talk), can determine the final, resulting functional response of the cell.

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“…42 To date, 2 α subunits (encoded by guanylate cyclase GUCY1A2 or GUCY1A3) and 2 β subunits (encoded by GUCY1B2 and GUCY1B3) have been identified, and the heterodimers α1β1 and α2β1 appear to be the 2 most physiologically relevant isoforms. 35,42 An in vivo study using knockout mice showed that loss of the β1 subunit causes a complete loss of sGC and results in elevated SBP (mean 130 mmHg vs 104 mmHg for WT mice) and a lack of aortic relaxation in response to NO donors. 43 Polymorphisms in the sGC subunit genes have been associated with hypertension and CAD.…”

Section: Guanylate Cyclase Subunitsmentioning

confidence: 99%

Genetics of NO Deficiency

Leineweber

Moosmang

Paulson

2017

The American Journal of Cardiology

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The nitric oxide-cyclic guanosine monophosphate (NO-cGMP) pathway plays a key role in regulating cardiovascular homeostasis, and genetic variants allocated to NO-cGMP pathway genes, leading to NO-cGMP deficiency, may influence the prevalence or course of cardiovascular disease. NO-cGMP deficiency can be caused by nitric oxide synthase substrate deficiency, substrate competition, defects, or uncoupling; endogenous inhibitors of nitric oxide synthase; decreased cGMP production; or increased cGMP degradation. This review presents evidence supporting the role of NO-cGMP deficiency in cardiovascular disease, including findings from genetic association studies for particular polymorphisms, haplotypes, and racial disparities. NO-cGMP pathway components including arginases, guanosine-5'-triphosphate cyclohydrolase 1, nitric oxide synthase, dimethylarginine dimethylaminohydrolases, soluble guanylyl cyclase, protein kinase G, phosphodiesterase 5, and natriuretic peptides will be discussed.

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Molecular Variants of Soluble Guanylyl Cyclase Affecting Cardiovascular Risk

Cited by 12 publications

References 66 publications

Antagonism of Forkhead Box Subclass O Transcription Factors Elicits Loss of Soluble Guanylyl Cyclase Expression

Antagonism of Forkhead Box Subclass O Transcription Factors Elicits Loss of Soluble Guanylyl Cyclase Expression

The role of gaseous mediators (CO, NO and H2S) in the regulation of blood circulation: analysis of the participation of blood cell microrheology

Genetics of NO Deficiency

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