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

Abstract

Aims 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. Methods and results 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. Conclusions JCAD promotes arterial thrombosis by modulating coagulation and fibrinolysis. Herein, reported translational data suggest JCAD as a potential therapeutic target for atherothrombosis.

Expression of JCAD and EGFR in Perineurial Cell–Cell Junctions of Human Inferior Alveolar Nerve

“…17 The JCAD level in plasma samples from patients with ST-elevation myocardial infarction was higher than that in controls. 17 Although these current studies suggest that JCAD promotes endothelial dysfunction and triggers expression of proinflammatory genes in blood endothelial cells, 25 the function of JCAD in perineurium is unknown. Endoneurial microvessels are in direct communication with circulating blood and are considered to be blood–nerve barriers, while the perineurium restricts passive diffusion of interstitial fluid from the epineurium into the endoneurium and vice versa.…”

“…25 Recently, JCAD has been reported to possibly promote arterial thrombosis. 17 The JCAD level in plasma samples from patients with ST-elevation myocardial infarction was higher than that in controls. 17 Although these current studies suggest that JCAD promotes endothelial dysfunction and triggers expression of proinflammatory genes in blood endothelial cells, 25 the function of JCAD in perineurium is unknown.…”

“…Junctional cadherin 5 associated (JCAD, previously known as KIAA 1462) is an intracellular component of endothelial cell-cell junctions. 16 Some studies have focused on the role of JCAD in cardiovascular diseases [17][18][19] because a previous genome-wide association study reported that a single nucleotide polymorphism of JCAD was associated with coronary artery disease. 20 Although JCAD has been reported to express both endothelial and perineurial cell-cell junctions, 16 no attention has been focused on the role of JCAD in the perineurium.…”

Ginsenoside Rh4 alleviates idiopathic pulmonary fibrosis by enhancing the CXCL9–CXCR3 axis

“…An aberrant activation of the coagulation cascade results in an excessive generation of thrombi, impeding proper blood flow. Consequently, in the context of IPF, compromised perfusion due to thrombi exacerbates the condition, leading to impaired pulmonary circulation and ensuing hypoxia (Liberale et al., 2023). Moreover, the dysregulation of coagulation factors and fibrinolytic agents contributes to undue collagen buildup and scar tissue formation (Zhu et al., 2023).…”

JCAD deficiency delayed liver regenerative repair through the Hippo–YAP signalling pathway

“…From zebrafish to humans, the sequence of JCAD is highly conserved in vertebrates indicating that the protein might have important functions in pathophysiology. The role of JCAD has been identified in pathological process of coronary artery disease 6 as well as arterial thrombosis 7 . Our previous work revealed that JCAD was significantly increased in steatohepatitis‐associated hepatocellular carcinoma specimens, and promoted hepatoma cells and their derived xenografts proliferation and growth 8 .…”