Serum ubiquitin via CXC chemokine receptor 4 triggered cyclooxygenase-1 ubiquitination possibly involved in the pathogenesis of aspirin resistance

Abstract

Extracellular ubiquitin (Ub) with platelet aggregation property was found higher in acute myocardial infarction (AMI) patients. Here we detected the platelet functions and serum Ub levels in 250 AMI patients and 50 healthy volunteers before and after aspirin treatment. The influence of serum Ub on platelet functions was determined in vitro. We found that 47 out of 250 AMI patients showed aspirin resistance (AR) and 203 showed aspirin sensitivity (AS). During hospitalization, AR group had higher serum Ub levels than the AS group or the healthy group, and the serum Ub levels was related to the rates of thrombosis events. The patients with higher serum Ub levels showed that the platelets had more ubiquitinated platelets, higher contents of ubiquitinated proteins and ubiquitinated cyclooxygenase-1 (COX-1). The levels of ubiquitinated COX-1 in the platelets was inversely correlated with acetylated COX-1, the separated ubiquitinated COX-1 activity was approximately twofold or fourfold higher than the total COX-1(ubiquitinated COX-1 and COX-1) or COX-1. In vitro, we found that extracellular Ub, via the CXC chemokine receptor 4 (CXCR4) pathway, facilitated COX-1 to be ubiquitined and prevented aspirin to acetylate its target. Platelets had higher levels of ubiquitinated COX-1 showing poor response to aspirin. Such results were not detected in Ub-free serum or ovalbumin incubated platelets. Serum Ub, via the CXCR4 pathway, facilitated COX-1 to be ubiquitined and activated the platelets possibly involved in the pathogenesis of AR.

Heteromerization of chemokine (C-X-C motif) receptor 4 with α1A/B-adrenergic receptors controls α1-adrenergic receptor function

“…This implies that CXCR4 and also ACKR3 function as modulators of α 1 -AR. Whereas the molecular mechanisms through which ACKR3 influences α 1 -AR function remain to be determined, the observed effects of ubiquitin in the present study are in agreement with the findings that ubiquitin functions as a noncognate CXCR4 agonist that does not bind to ACKR3 (51,52,(59)(60)(61)(62)(63). The observation that CXCL12, which has a much higher affinity for ACKR3 than for CXCR4 (64), also enhanced the potency of PE in normal animals in vivo in the present study, whereas CXCL12 previously desensitized PE-mediated vasoconstriction of isolated arteries and reduced blood pressure during hemorrhagic shock (9), suggests that effects of CXCL12 depend on the relative functional contribution of CXCR4 and ACKR3 within the specific experimental or (patho)physiological environment (65).…”

Ubiquitin Urine Levels in Burn Patients

“…Furthermore, chemokine receptor CXCR4 is expressed in the proximale tubule and highly upregulated after renal injury (58, 59). As ubiquitin binding to CXCR4 leads to receptor mediated endocytosis of the receptor-ligand complex (23, 27, 29, 60), changes in the expression level of CXCR4 in the kidney could also contribute to the observed differences in ubiquitin excretion between burn patients with uncomplicated recovery and those who develop sepsis/MOF or die.…”

Use of thrombin generation test for monitoring hemostasis in coronary bypass surgery

“…Prolonged aspirin therapy is significant in the prevention and treatment of CAD [22, 24]. The antithrombotic action of aspirin (acetylsalicylic acid) is due to the inhibition of cyclooxygenase-1 [7].…”