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Activation mechanism of human soluble guanylate cyclase by stimulators and activators.

ABSTRACT: Soluble guanylate cyclase (sGC) is the receptor for nitric oxide (NO) in human. It is an important validated drug target for cardiovascular diseases. sGC can be pharmacologically activated by stimulators and activators. However, the detailed structural mechanisms, through which sGC is recognized and positively modulated by these drugs at high spacial resolution, are poorly understood. Here, we present cryo-electron microscopy structures of human sGC in complex with NO and sGC stimulators, YC-1 and riociguat, and also in complex with the activator cinaciguat. These structures uncover the molecular details of how stimulators interact with residues from both β H-NOX and CC domains, to stabilize sGC in the extended active conformation. In contrast, cinaciguat occupies the haem pocket in the β H-NOX domain and sGC shows both inactive and active conformations. These structures suggest a converged mechanism of sGC activation by pharmacological compounds.

SUBMITTER: Liu R

PROVIDER: S-EPMC8448884 | biostudies-literature | 2021 Sep

REPOSITORIES: biostudies-literature

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Activation mechanism of human soluble guanylate cyclase by stimulators and activators.

Liu Rui R Kang Yunlu Y Chen Lei L

Nature communications 20210917 1

Soluble guanylate cyclase (sGC) is the receptor for nitric oxide (NO) in human. It is an important validated drug target for cardiovascular diseases. sGC can be pharmacologically activated by stimulators and activators. However, the detailed structural mechanisms, through which sGC is recognized and positively modulated by these drugs at high spacial resolution, are poorly understood. Here, we present cryo-electron microscopy structures of human sGC in complex with NO and sGC stimulators, YC-1 a ...[more]

PMID: 34535643

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Project description:Conjunctival fibrosis is a serious clinical concern implicated in a wide spectrum of eye diseases, including outcomes of surgery for pterygium and glaucoma. It is mainly driven by chronic inflammation that stimulates conjunctival fibroblasts to differentiate into myofibroblasts over time, leading to abnormal wound healing and scar formation. Soluble guanylate cyclase (sGC) stimulation was found to suppress transforming growth factor β (TGFβ)-induced myofibroblastic differentiation in various stromal cells such as skin and pulmonary fibroblasts, as well as corneal keratocytes. Here, we evaluated the in vitro effects of stimulation of the sGC enzyme with the cell-permeable pyrazolopyridinylpyrimidine compound BAY 41-2272 in modulating the TGFβ1-mediated profibrotic activation of human conjunctival fibroblasts. Cells were pretreated with the sGC stimulator before challenging with recombinant human TGFβ1, and subsequently assayed for viability, proliferation, migration, invasiveness, myofibroblast marker expression, and contractile properties. Stimulation of sGC significantly counteracted TGFβ1-induced cell proliferation, migration, invasiveness, and acquisition of a myofibroblast-like phenotype, as shown by a significant downregulation of FAP, ACTA2, COL1A1, COL1A2, FN1, MMP2, TIMP1, and TIMP2 mRNA levels, as well as by a significant reduction in α-smooth muscle actin, N-cadherin, COL1A1, and FN-EDA protein expression. In addition, pretreatment with the sGC stimulator was capable of significantly dampening TGFβ1-induced acquisition of a contractile phenotype by conjunctival fibroblasts, as well as phosphorylation of Smad3 and release of the proinflammatory cytokines IL-1β and IL-6. Taken together, our findings are the first to demonstrate the effectiveness of pharmacological sGC stimulation in counteracting conjunctival fibroblast-to-myofibroblast transition, thus providing a promising scientific background to further explore the feasibility of sGC stimulators as potential new adjuvant therapeutic compounds to treat conjunctival fibrotic conditions.

Project description:Background: Several studies have shown that soluble guanylate cyclase (sGC) stimulators have cardiovascular (CV) benefits. However, few bibliometric analyses have examined this field systematically. Our study aimed to examine the publications to determine the trends and hotspots in CV research on sGC stimulators. Methods: Publications on sGC stimulators in CV research were retrieved from the Web of Science Core Collection. VOSviewer and CiteSpace visualization software were used to analyze publication trends, countries (regions) and institutions, journals and cited journals, authors and cited references, as well as keywords. Results: A total of 1,212 literatures were obtained. From its first appearance in 1992-2021 (based on WOSCC record), the overall volume of publications has shown a gradual increasing trend. Nearly one-third were authored by American scholars, and most were published in Circulation, Circulation Research, and Proceedings of the National Academy of Sciences of the United States of America. Bayer Agency in Germany was the leading driving force, and has a high academic reputation in this field. Stasch JP has published the most related articles and been cited most frequently. Half of the top 10 co-cited references were published in the leading highly co-cited journal Circulation and New England Journal of Medicine. "NO," "allosteric regulation" and "free radicals" were the focus of previous research, "chronic thromboembolic pulmonary hypertension," "pulmonary hypertension" and "heart failure" were the main research hotspots. The key words "chronic thromboembolic pulmonary hypertension," "Pulmonary hypertension," "preserved ejection fraction" and "heart failure" appeared most recently as research frontiers. Conclusion: The research in the CV field of sGC stimulators was relatively comprehensive, and there was a close relationship among countries, research institutions and authors, but it is still in the exploratory stage in the treatment of CV disease. At present, most studies focus on the results of clinical trials. sGC stimulators in the treatment of heart failure, especially heart failure with preserved ejection fraction, may be the hotpots and Frontier at present and in the future, and should be closely monitored.

Dataset Information

Activation mechanism of human soluble guanylate cyclase by stimulators and activators.

Publications

Activation mechanism of human soluble guanylate cyclase by stimulators and activators.

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