Cover Image

JCAD promotes arterial thrombosis through PI3K/Akt modulation: a translational study

Variants of the junctional cadherin 5 associated (JCAD) locus associate with acute coronary syndromes. JCAD promotes experimental atherosclerosis through the large tumor suppressor kinase 2 (LATS2)/Hippo pathway. This study investigates the role of JCAD in arterial thrombosis.JCAD knockout (Jcad−/−)...

Full description

Saved in:
Bibliographic Details
Main Authors: Liberale, Luca (Author) , Puspitasari, Yustina M (Author) , Ministrini, Stefano (Author) , Akhmedov, Alexander (Author) , Kraler, Simon (Author) , Bonetti, Nicole R (Author) , Beer, Georgia (Author) , Vukolic, Ana (Author) , Bongiovanni, Dario (Author) , Han, Jiaying (Author) , Kirmes, Kilian (Author) , Bernlochner, Isabell (Author) , Pelisek, Jaroslav (Author) , Beer, Jürg H (Author) , Jin, Zheng-Gen (Author) , Pedicino, Daniela (Author) , Liuzzo, Giovanna (Author) , Stellos, Konstantinos (Author) , Montecucco, Fabrizio (Author) , Crea, Filippo (Author) , Lüscher, Thomas F (Author) , Camici, Giovanni G (Author)
Format: Article (Journal)
Language:English
Published: 21 May 2023
In: European heart journal
Year: 2023, Volume: 44, Issue: 20, Pages: 1818-1833
ISSN:1522-9645
DOI:10.1093/eurheartj/ehac641
Online Access:Verlag, lizenzpflichtig, Volltext: https://doi.org/10.1093/eurheartj/ehac641
Verlag, lizenzpflichtig, Volltext: https://academic.oup.com/eurheartj/article/44/20/1818/6873858?login=true
Get full text
Author Notes:Luca Liberale, Yustina M. Puspitasari, Stefano Ministrini, Alexander Akhmedov, Simon Kraler, Nicole R. Bonetti, Georgia Beer, Ana Vukolic, Dario Bongiovanni, Jiaying Han, Kilian Kirmes, Isabell Bernlochner, Jaroslav Pelisek, Jürg H. Beer, Zheng-Gen Jin, Daniela Pedicino, Giovanna Liuzzo, Konstantinos Stellos, Fabrizio Montecucco, Filippo Crea, Thomas F. Lüscher, and Giovanni G. Camici
Description
Summary:Variants of the junctional cadherin 5 associated (JCAD) locus associate with acute coronary syndromes. JCAD promotes experimental atherosclerosis through the large tumor suppressor kinase 2 (LATS2)/Hippo pathway. This study investigates the role of JCAD in arterial thrombosis.JCAD knockout (Jcad−/−) mice underwent photochemically induced endothelial injury to trigger arterial thrombosis. Primary human aortic endothelial cells (HAECs) treated with JCAD small interfering RNA (siJCAD), LATS2 small interfering RNA (siLATS2) or control siRNA (siSCR) were employed for in vitro assays. Plasma JCAD was measured in patients with chronic coronary syndrome or ST-elevation myocardial infarction (STEMI). Jcad−/− mice displayed reduced thrombogenicity as reflected by delayed time to carotid occlusion. Mechanisms include reduced activation of the coagulation cascade [reduced tissue factor (TF) expression and activity] and increased fibrinolysis [higher thrombus embolization episodes and D-dimer levels, reduced vascular plasminogen activator inhibitor (PAI)-1 expression]. In vitro, JCAD silencing inhibited TF and PAI-1 expression in HAECs. JCAD-silenced HAECs (siJCAD) displayed increased levels of LATS2 kinase. Yet, double JCAD and LATS2 silencing did not restore the control phenotype. si-JCAD HAECs showed increased levels of phosphoinositide 3-kinases (PI3K)/ proteinkinase B (Akt) activation, known to downregulate procoagulant expression. The PI3K/Akt pathway inhibitor—wortmannin—prevented the effect of JCAD silencing on TF and PAI-1, indicating a causative role. Also, co-immunoprecipitation unveiled a direct interaction between JCAD and Akt. Confirming in vitro findings, PI3K/Akt and P-yes-associated protein levels were higher in Jcad−/− animals. Lastly, as compared with chronic coronary syndrome, STEMI patients showed higher plasma JCAD, which notably correlated positively with both TF and PAI-1 levels.JCAD promotes arterial thrombosis by modulating coagulation and fibrinolysis. Herein, reported translational data suggest JCAD as a potential therapeutic target for atherothrombosis.
Item Description:Online vorab veröffentlicht: 05. Dezember 2022
Gesehen am 02.07.2024
Physical Description:Online Resource
ISSN:1522-9645
DOI:10.1093/eurheartj/ehac641

Similar Items