Loss of soluble guanylyl cyclase in platelets contributes to atherosclerotic plaque formation and vascular inflammation

Carina Mauersberger, Hendrik B. Sager, Jana Wobst, Tan An Dang, Laura Lambrecht, Simon Koplev, Marlène Stroth, Noomen Bettaga, Jens Schlossmann, Frank Wunder, Andreas Friebe, Johan L.M. Björkegren, Lisa Dietz, Sanne L. Maas, Emiel P.C. van der Vorst, Peter Sandner, Oliver Soehnlein, Heribert Schunkert, Thorsten Kessler

Research output: Contribution to journalArticlepeer-review

9 Scopus citations

Abstract

Variants in genes encoding the soluble guanylyl cyclase (sGC) in platelets are associated with coronary artery disease (CAD) risk. Here, by using histology, flow cytometry and intravital microscopy, we show that functional loss of sGC in platelets of atherosclerosis-prone Ldlr −/− mice contributes to atherosclerotic plaque formation, particularly via increasing in vivo leukocyte adhesion to atherosclerotic lesions. In vitro experiments revealed that supernatant from activated platelets lacking sGC promotes leukocyte adhesion to endothelial cells (ECs) by activating ECs. Profiling of platelet-released cytokines indicated that reduced platelet angiopoietin-1 release by sGC-depleted platelets, which was validated in isolated human platelets from carriers of GUCY1A1 risk alleles, enhances leukocyte adhesion to ECs. Importantly, pharmacological sGC stimulation increased platelet angiopoietin-1 release in vitro and reduced leukocyte recruitment and atherosclerotic plaque formation in atherosclerosis-prone Ldlr −/− mice. Therefore, pharmacological sGC stimulation might represent a potential therapeutic strategy to prevent and treat CAD.

Original languageEnglish
Pages (from-to)1174-1186
Number of pages13
JournalNature Cardiovascular Research
Volume1
Issue number12
DOIs
StatePublished - Dec 2022

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