TY - JOUR
T1 - Loss of soluble guanylyl cyclase in platelets contributes to atherosclerotic plaque formation and vascular inflammation
AU - Mauersberger, Carina
AU - Sager, Hendrik B.
AU - Wobst, Jana
AU - Dang, Tan An
AU - Lambrecht, Laura
AU - Koplev, Simon
AU - Stroth, Marlène
AU - Bettaga, Noomen
AU - Schlossmann, Jens
AU - Wunder, Frank
AU - Friebe, Andreas
AU - Björkegren, Johan L.M.
AU - Dietz, Lisa
AU - Maas, Sanne L.
AU - van der Vorst, Emiel P.C.
AU - Sandner, Peter
AU - Soehnlein, Oliver
AU - Schunkert, Heribert
AU - Kessler, Thorsten
N1 - Publisher Copyright:
© 2022, The Author(s).
PY - 2022/12
Y1 - 2022/12
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=85165092175&partnerID=8YFLogxK
U2 - 10.1038/s44161-022-00175-w
DO - 10.1038/s44161-022-00175-w
M3 - Article
AN - SCOPUS:85165092175
SN - 2731-0590
VL - 1
SP - 1174
EP - 1186
JO - Nature Cardiovascular Research
JF - Nature Cardiovascular Research
IS - 12
ER -