Molecular signature of coronary stent thrombosis: oxidative stress and innate immunity cells

Abstract

The clinical impact of in-stent thrombosis is high because it is associated with high mortality and 20 % of the patients suffer a recurrent event within the two following years. The aim of this study was to characterise the morphologic and proteomic profile of in-stent thrombi (IST) in comparison to thrombi developed on native coronary arteries (CT) to identify a differential molecular signature. The study included 45 patients with ST-elevation-myocardial-infarction (STEMI) treated by primary-percutaneous-intervention and thrombus aspiration: 21 had IST and 24 had CT. Thrombi were characterised by morphologic immunohistochemical analysis and differential proteomic profiling (2-DE+MALDI-TOF/TOF). Bioinformatic analysis revealed differences in proteins related to oxidative-stress and cell death/survival. IST showed a higher content of structural proteins (gelsolin, actin-cytoplasmic-1, tropomyosin, and myosin) together with an imbalance in redox-homeostasis related proteins (increased superoxide-dismutase and decreased peroxiredoxin-2 thrombus content), and a coordinated increase of chaperones (HSP60 and HSC70) and cellular quality control-related proteins (26S-protease-regulatory-subunit-7). These changes were reflected into a significant decrease in HSC70 systemic levels and a significant increase in advanced-oxidation-protein-products (AOPP) indicative of increased oxidative stress-mediated protein damage in IST. Our results reveal an imbalance in redox-related proteins indicative of an exacerbated oxidative-stress that leads to an accumulation of AOPP serum levels in IST. Moreover, the coordinated increase in chaperones and regulatory proteins reflects the activation of intracellular protection mechanisms to maintain protein integrity in IST. The failure to counterbalance the stress situation could trigger cellular apoptosis leading to the destabilization of the thrombus and to a worse prognosis of IST-STEMI-patients.

Integrated Multichip Analysis and WGCNA Identify Potential Diagnostic Markers in the Pathogenesis of ST‐Elevation Myocardial Infarction

“…Owing to the lack of early diagnostic markers, the STEMI patients lose the great opportunity to treat, resulting in a poor prognosis. Moreover, studies find that immune cell infiltration is related to the development of STEMI [ 16 , 17 ]. Therefore, obtaining the specific diagnostic biomarkers and studying the immune cell infiltration of STEMI is important to better development of STEMI patients.…”

Potential molecular mechanism of ACE gene at different time points in STEMI patients based on genome-wide microarray dataset

“…Among them, STEMI accounts for a large proportion [17]. Not only the risk of death at the time of admission, but also the complications like dysfunction or rupture of papillary muscle, rupture of the heart, coronary stent thrombosis, malignant arrhythmia, post-infarction syndrome and heart failure give rise to the mortality [10, 18–20]. The biological and regulatory mechanisms in the early or post-myocardial infarction stages remain understudied.…”

“…But the molecular mechanisms responsible for the development and progression of STEMI remain unclear. The angiotensin converting enzyme (ACE) is associated with vasoconstriction, inflammation, vascular remodeling, thrombosis, apoptosis, and eventual plaque rupture [10]. The present study aimed to utilize bioinformatics to identify genes co-expressed with ACE genes and pathways associated with STEMI at different time points and to provide stage specific therapy for patients.…”

The Mechanisms of Restenosis and Relevance to Next Generation Stent Design

“…Regarding late stent thrombosis (LST) and very late stent thrombosis (VLST), the underlying mechanisms appear to be related to stent placement, and an increase in ROS is shown to be associated with stent thrombosis [133] that occurs post-placement. Furthermore, inflammation can trigger thrombosis, and conversely, thrombosis amplifies inflammation [134].…”