Mitogen-activated protein kinases activation in T lymphocytes of patients with acute coronary syndromes

Abstract

Current available biomarkers cannot identify myocardial ischemia without necrosis. To overcome this issue and to increase diagnostic power, we evaluated the activation of the three MAPK pathways, ERK1/2, JNK and p38, in T lymphocytes of patients with acute coronary syndromes (ACS). We included sixty consecutive patients affected by either unstable angina (UA, N = 22), Non- ST-segment elevation MI (NSTEMI, N = 19) or ST-segment elevation MI (STEMI, N = 19). Two separate groups of patients were matched as controls: healthy subjects (CTRL, N = 20) and patients with stable coronary artery disease (CAD, N = 21). MAPK activation in T lymphocytes, measured by phospho-ERK1/2, phospho-JNK and phospho-p38 levels, was assessed by flow cytometry analysis which revealed significantly increased phosphorylated levels of ERK1/2 in patients with UA, compared to controls. In UA patients no significant changes were detected for phospho-JNK compared to both control groups. NSTEMI and STEMI groups showed a statistically significant increase in both phospho-ERK1/2 and phospho-JNK, compared to control groups. All ACS groups demonstrated significantly increased phosphorylation of p38 compared to CTRL, but not CAD. ROC curves showed that a cut-off value of 22.5 intensity of fluorescence for phospho-ERK1/2 was able to significantly discriminate UA patients from patients with stable angina with 78% sensitivity and 90% specificity. Therefore, a differential MAPK activation in T lymphocytes denotes patients with ACS. Indeed, patients with unstable angina are identified with high specificity by activated ERK1/2 and normal JNK levels. These data could represent a valuable new molecular signature to be used as specific biomarkers for the diagnosis of unstable angina within ACS.

Integrative gene ontology and network analysis of coronary artery disease associated genes suggests potential role of ErbB pathway gene EGFR

“…MAPK1 belongs to the Ser-Thr kinases protein family and has been previously reported in different features of cardiac modeling and regulation of inflammation, cell proliferation and differentiation ( 55 , 56 ). The high activity of Erk1/2 has been observed in T-lymphocytes from CAD patients, including ST-elevation myocardial infarction (STEMI), Non-STEMI and unstable angina ( 57 ). A previous study demonstrated the EGFR-mediated cross-talk between MAPK and Akt1 signaling, which combined had an important role in abnormal vascular remodeling ( 58 ).…”

MicroRNA-1 Downregulation Increases Connexin 43 Displacement and Induces Ventricular Tachyarrhythmias in Rodent Hypertrophic Hearts

“…The renin-angiotensin system has been classically shown to be a major regulator of pathologic cardiac hypertrophy [6]. Indeed, Angiotensin II (AngII) is rapidly released from myocardial cells in response to cardiac damage and stretch; after binding to the AT1R, through Src, Ras, Gq and PKC mediation, it activates the maladaptive extracellular signal-regulated protein kinase 1/2 (ERK1/2) generating pathological cellular growth [20,30,46–49]. Valsartan, a classic non-competitive antagonist of the AT1R, has been widely used in the clinical setting for the treatment of patients with systemic hypertension and concentric cardiac hypertrophy [50].…”

Constructing differential co‑expression network to predict key pathways for myocardial infarction

“…Inflammation is able to cause biochemical responses (25) and then trigger MAPK, which plays important roles through phosphorylating intracellular substrates, thereby mediating signal transduction, as well as specific genetic responses to extracellular stimuli (26). MAPK activation in UA to a complete MAPK activation in MI, has been proved effective as a diagnostic test to discern the difference between ACS conditions (27). Accordingly, MAPK is a valuable molecular biomarker serving as specific signature for the diagnosis of UA/MI.…”