Research ArticleClinical Studies
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Elevated Circulatory Levels of UL16 Binding Protein 1 Positive Microparticles Are Associated With Acute Myocardial Infarction and its Severity

SONGPOL HAOHAN, BURABHA PUSSADHAMMA, AMONRAT JUMNAINSONG, WIT LEUANGWATTHANANON, PATTARAPONG MAKARAWATE, CHANVIT LEELAYUWAT and NANTARAT KOMANASIN
In Vivo November 2024, 38 (6) 3033-3040; DOI: https://doi.org/10.21873/invivo.13787

Abstract

Background/Aim: Atherosclerosis is a vascular inflammatory disease characterized by the activation and stress of various inflammatory cells, leading to the development of coronary artery disease and subsequently acute myocardial infarction (AMI). Among AMI cases, ST-segment elevation myocardial infarction (STEMI) is typically more severe than non-STEMI (NSTEMI). UL16-binding proteins (ULBPs), which are NKG2D ligands, can be expressed on the surface of stressed and activated cells, prompting these cells to generate microparticles (MPs). Consequently, MPs carrying ULBPs, particularly ULBP1 (ULBP1+ MPs), may be released into the bloodstream. This study aimed to investigate the association between ULBP1+ MPs and the presence of AMI and its severity. Materials and Methods: We recruited 58 AMI patients and 45 age-matched control subjects. Levels of ULBP1+ MPs and ULBP1+ MPs originating from T lymphocytes (ULBP1+ TMPs) were measured using flow cytometry. Results: Both ULBP1+ MP and ULBP1+ TMP levels were significantly elevated in AMI patients compared to controls. Elevated levels of these MPs were independent risk factors for AMI with odds ratios (OR) of 4.3 (95%CI=1.5-12.3) for ULBP1+ MPs and 5.8 (95%CI=2.0-17.0) for ULBP1+ TMPs. Additionally, ULBP1+ TMP levels were significantly higher in STEMI patients compared to NSTEMI patients, with an independent association observed between ULBP1+ TMPs and STEMI (OR=3.9; 95%CI=1.2-12.8). Conclusion: Elevated levels of ULBP1+ MPs and ULBP1+ TMPs are associated with AMI and its severity. These biomarkers could serve as indicators of vulnerable plaques that lead to AMI.

Key Words:

Atherosclerosis is a vascular inflammatory disease initiated by endothelial dysfunction and exacerbated by the accumulation and activation of inflammatory cells, leading to coronary artery disease (CAD). The inflammatory process continuously occurs throughout the pathogenesis of the disease (1). The formation of atherosclerotic plaques develops over many years before clinical manifestations appear. Eventually, the rupture of these plaques results in the occlusion of coronary arteries by thrombus formation, leading to acute coronary syndrome (ACS) and acute myocardial infarction (AMI) (2).

The natural killer group 2, member D (NKG2D) receptor is an activating receptor found on various cell types, including natural killer cells, natural killer T cells, and CD8+ T cells (3). All these cells are recognized as contributors to the pathogenesis of atherosclerosis (4). NKG2D serves as a receptor for the major histocompatibility complex class I chain-related proteins A and B (MICA and MICB). Additionally, UL16-binding proteins (ULBPs), including ULBP1 to ULBP6, are known as NKG2D ligands, which have highly restricted expression in normal cells. Conversely, NKG2D ligands show increased expression on the surface of numerous cell types in response to stress, infection, and tumorigenesis (5). The interaction between NKG2D and its ligands promotes inflammation by releasing various cytokines and facilitating the cytotoxic functions of these cells (6). Previously, the role of the NKG2D system in atherosclerosis leading to CAD has been reported (7).

Circulating microparticles (MPs) are small vesicles that originate from cell membranes and are released by blood-related cells, including endothelial cells, leukocytes, platelets, erythrocytes, and smooth muscle cells. MPs are generally produced by various cell types during cell activation, stress, and apoptosis (8). Studies have demonstrated that elevated MP levels are associated with CAD and ACS (9, 10). In a previous study, the correlation between the presence of AMI and other NKG2D ligands expressed on MP surfaces, such as MICA and MICB, was investigated (11). In this study, we aimed to investigate the association between ULBP1 positive MPs (ULBP1+ MPs), another NKG2D ligand, and the presence of AMI. This investigation may potentially validate the relationship between the NKG2D system and AMI.

Materials and Methods

Study population and sample preparation. The study included 58 randomly selected AMI subjects aged 30 years or older, admitted to Queen Sirikit Heart Center of the Northeast Hospital, Khon Kaen University, Thailand. Additionally, 45 age-matched subjects without signs and symptoms of CAD were recruited as the control group. AMI was divided into two groups based on disease severity: NSTEMI and STEMI, with STEMI being typically more severe. Medical records of patients assessed by cardiologists were reviewed. Platelet-free plasma (PFP) was prepared for MP measurement as previously described (11). This study was approved by the Khon Kaen University Ethics Committee for Human Research (approval number HE571493). Informed consent was obtained from all participants. The study was conducted in accordance with the principles of the Declaration of Helsinki.

ULBP1 positive MPs analysis. The presence of ULBP1 on the surface of all MPs, including those derived from T lymphocytes, was investigated. Annexin V-PE (Thermo Fisher Scientific, Waltham, MA, USA) was used as specific marker for phosphatidylserine on MP surfaces (PS+ MPs). APC mouse anti-human ULBP1 (R&D Systems, Minneapolis, MN, USA) and FITC mouse anti-human CD3 (BioLegend, San Diego, CA, USA) were used as specific markers for ULBP1 and T lymphocytes, respectively. APC mouse IgG2A (R&D Systems) was used as the isotype control for anti-ULBP1.

Experiments were conducted in 5 ml polystyrene round-bottom tubes (BD Biosciences, San Jose, CA, USA). Fifty microliters of thawed PFP were mixed with 5 μl of Annexin V-PE, APC mouse anti-human ULBP1, FITC mouse anti-human CD3, and 50 μl of diluted Annexin V-binding buffer solution. The mixtures were homogenized and incubated for 15 min at room temperature in the dark. Subsequently, 200 μl of phosphate buffered saline (pH 7.4) and counting beads (Thermo Fisher Scientific) were added. The mixtures were immediately analyzed using a FACS Canto II flow cytometer (BD Biosciences). The size of MPs was determined using 1 μM polystyrene beads (Sigma-Aldrich, St. Louis, MO, USA). The levels of ULBP1+ MPs were reported as absolute numbers.

Statistical analysis. Data were analyzed using SPSS version 28.0.1.1 (IBM, SPSS Inc., Armonk, NY, USA). The normal distribution of continuous variables was tested using the one sample Kolmogorov-Smirnov test. Independent-sample t-tests and Mann-Whitney U-tests were used to test for differences in continuous variables between two independent groups. The Chi-square test was used to compare population proportions between two groups. Paired t-tests were used to determine differences between two variables for the same subject. Univariate and multivariate binary logistic regression analyses were employed to determine associations of potential risk factors with a binary outcome. The Spearman correlation was used to evaluate relationships between two continuous variables. A p-value less than 0.05 was considered statistically significant.

Results

Subject characteristics. The baseline characteristics and demographic data of AMI and control subjects are shown in Table I. Both groups were matched for age. The AMI group had a significantly higher proportion of male subjects, as well as higher rates of diabetes mellitus, hypertension, dyslipidemia, and smoking compared to the control group. Decreased levels of diastolic blood pressure, total cholesterol, and high-density lipoprotein cholesterol were observed in the control group compared to AMI patients. Conversely, significantly elevated fasting blood sugar and hs-CRP levels were observed in the AMI group. Baseline characteristics and demographic data of the AMI subgroups (NSTEMI and STEMI) are shown in Table II. Only the proportion of hypertension was significantly higher in the STEMI group compared to the NSTEMI group.

View this table:
Table I.

Baseline characteristics of the study population.

View this table:
Table II.

Baseline characteristics of acute myocardial infarction (AMI) patients categorized by disease severity.

ULBP1+ MPs analysis. Flow cytometric analysis of ULBP1+ MPs in AMI patients and controls is shown in Figure 1. The levels of ULBP1+ MPs and ULBP1+ MPs originating from T lymphocytes (ULBP1+ TMPs) were significantly elevated in AMI patients compared to controls (Figure 2). Independent associations of ULBP1+ MPs (crude OR=6.1; 95%CI=2.5-14.4 and adjusted OR=4.3; 95%CI=1.5-12.3) and ULBP1+ TMPs (crude OR=7.4; 95%CI=3.1-18.1 and adjusted OR=5.8; 95%CI=2.0-17.0) with the presence of AMI were demonstrated (Figure 3). The cut-off values for binary logistic regression analysis were determined by the median of the data. Regarding disease severity, ULBP1+ TMPs levels were significantly increased in the STEMI group compared to the NSTEMI group (Figure 4). Additionally, ULBP1+ TMPs were independently associated with the occurrence of STEMI (crude OR=3.1; 95%CI=1.1-9.2 and adjusted OR=3.9; 95%CI=1.2-12.8) (Figure 5). Interestingly, in this study, we found that the majority of ULBP1+ MPs originated from T lymphocytes (Figure 6). Finally, a significant positive correlation between ULBP1+ TMPs and hs-CRP was observed (Figure 7).

Figure 1.
Figure 1.

Flow cytometric analysis showing the levels of ULBP1+ microparticles (MPs) in acute myocardial infarction (AMI) and control. The populations of counting beads, all MPs, PS+ MPs, all ULBP1+ MPs, ULBP1+T lymphocyte-derived microparticles (TMPs) and ULBP1+ MPs from other sources are displayed in P1, P2, P3, P4, P5, and P6, respectively.

Figure 2.
Figure 2.

Scatter plots showing the median with interquartile range of the levels of ULPB1+ microparticles (MPs) (A) and ULPB1+ TMPs (B) in the control and acute myocardial infarction (AMI) subjects.

Figure 3.
Figure 3.

Crude odds ratios (A) and adjusted odds ratio (B and C) with 95% confidence intervals demonstrating the association of ULBP1+ microparticles (MPs) and ULBP1+ TMPs with acute myocardial infarction (AMI).

Figure 4.
Figure 4.

Scatter plots showing the median with interquartile range of the levels of ULPB1+ microparticles (MPs) (A) and ULPB1+ TMPs (B) in the ST-segment elevation myocardial infarction (STEMI) and non-STEMI (NSTEMI) patients.

Figure 5.
Figure 5.

Crude odds ratios (A) and adjusted odds ratio (B) with 95% confidence intervals demonstrating the association of ULBP1+ TMPs with ST-segment elevation myocardial infarction.

Figure 6.
Figure 6.

Scatter plots displaying the median with interquartile range of the percentages of ULPB1+ microparticles (MPs) originated from other cell sources and T lymphocytes.

Figure 7.
Figure 7.

Correlations between ULPB1+ microparticles (MPs) (A) and ULPB1+ TMPs (B) with hs-CRP in the study population.

Discussion

Previous studies have investigated the roles of the NKG2D system in atherosclerosis leading to CAD and ACS. The present study demonstrates a new aspect of the association between the NKG2D system and ACS by highlighting the relationships of ULBP1+ MPs with the presence of AMI and its severity. The levels of ULBP1+ MPs and ULBP1+ TMPs were significantly elevated in AMI patients compared to controls, and both parameters were identified as independent risk factors for the occurrence of AMI.

ACS is caused by atherosclerosis, a condition characterized by chronic inflammation and considered the most common stress-related disease. The progression of atherosclerosis is driven by the recruitment, activation, and accumulation of various inflammatory cell types. MPs are produced from the early stages to advanced lesions of atherosclerosis during cell activation, stress, and apoptosis. Simultaneously, ULBP1 can appear on cell surfaces under chronic activation and stress. Consequently, MPs carrying ULBP1 are produced and released into the bloodstream. Hence, ULBP1+ MPs might contribute to atherosclerosis leading to CAD and ACS, including AMI.

Human NKG2D ligands include two members of the MIC family (MICA and MICB) and six members of the UL16 binding proteins. The expression of NKG2D ligands is highly restricted in healthy tissues but can be stimulated by various pathological conditions. Generally, NKG2D ligands are not expressed by T lymphocytes, but their expression can be induced by different stimuli. Previous studies demonstrated that MICA, MICB, and ULBP1-3, but not ULBP4, were present on both CD4+ and CD8+ T lymphocytes (12, 13). Interestingly, our study found that the majority of ULBP1+ MPs originated from T lymphocytes, with a median of 73.27% of total ULBP1+ MPs. Moreover, ULBP1+ TMPs were associated with AMI and disease severity when divided into NSTEMI and STEMI groups. Furthermore, ULBP1+ TMPs were an independent risk factor for the occurrence of AMI and STEMI. It is well known that T lymphocytes are major contributors to atherosclerosis leading to ACS. CD4+ T cells, particularly T helper 1 cells, play a significant role in atherosclerosis by producing large numbers of various cytokines (14, 15). CD8+ T cells contribute to atherosclerosis through the secretion of inflammatory cytokines and cytotoxic effects on smooth muscle and endothelial cells (16). The activation of CD4+ and CD8+ T cells has been found to be positively associated with elevated levels of CRP (17). In this study, we found that ULBP1+ TMPs were significantly correlated with hs-CRP, supporting the evidence that T cell responses in atherosclerosis promote ULBP1 expression on cell and MP surfaces.

The NKG2D system promotes inflammation through various mechanisms. The interaction between NKG2D and its ligands stimulates cytokine production from NK cells, including IFN-γ, TNF-α and granulocyte–macrophage colony-stimulating factor. Moreover, this interaction enhances the cytotoxic function of NK cells (18, 19). NKG2D effectively co-stimulates cytokine production by CD8+ T cells and induces their cytotoxic activity (20, 21).

The relationships between the NKG2D system and atherosclerosis have been reported. The NKG2D system is involved in the development and progression of atherosclerotic plaques. Interestingly, inhibition of NKG2D function reduces inflammation by lowering the levels of IL-6, IFN-γ, and IL-1β (7). Additionally, MICA/B can be detected in atherosclerotic plaques, particularly in advanced lesions prone to ACS events (22). The co-expression of MICA/MICB and ULBP1 has been reported (23, 24). Therefore, this evidence supports the potential co-occurrence of MICA/MICB and ULBP1 in the same disease. Our study, along with previous research (11), has demonstrated the expression of MICA/MICB and ULBP1 in AMI patients in the form of MICA/B+ MPs and ULBP1+ MPs.

Conclusion

This is the first report demonstrating the associations of ULBP1 expressed on MPs with AMI. The results reveal that ULBP1+ MPs and ULBP1+ TMPs are associated with the occurrence of AMI. Moreover, ULBP1+ TMPs are associated with disease severity and are considered an independent variable for occurrence of STEMI. Consequently, these parameters may serve as mediators in the pathogenesis of atherosclerosis, leading to ACS and AMI. In conclusion, ULBP1+ MPs could be applied as indicators of vulnerable plaques resulting in ACS symptoms and might be considered therapeutic targets to prevent the occurrence of ACS, including AMI.

Acknowledgements

This research was funded by the Young Researcher Development Project of Khon Kaen University Year 2022. The Authors would like to acknowledge Prof. Glenn Neville Borlace for editing the manuscript via KKU Publication Clinic, Khon Kaen University, Thailand.

Footnotes

  • Authors’ Contributions

    Conceptualization: SH, BP, AJ, PM, CL, and NK; Visualization: SH, AJ, CL and NK; Methodology: SH, AJ, CL and NK; Formal analysis: SH; Investigation: SH; Resources: BP, WL and PM; Writing - original draft: SH; Writing - review & editing: SH and NK; Supervision: SH and NK.

  • Funding

    This study was supported by the Young Researcher Development Project of Khon Kaen University Year 2022.

  • Conflicts of Interest

    The Authors declare that there are no conflicts of interest in relation to this study.

  • Received July 16, 2024.
  • Revision received August 13, 2024.
  • Accepted August 16, 2024.

This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY-NC-ND) 4.0 international license (https://creativecommons.org/licenses/by-nc-nd/4.0).

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Elevated Circulatory Levels of UL16 Binding Protein 1 Positive Microparticles Are Associated With Acute Myocardial Infarction and its Severity
SONGPOL HAOHAN, BURABHA PUSSADHAMMA, AMONRAT JUMNAINSONG, WIT LEUANGWATTHANANON, PATTARAPONG MAKARAWATE, CHANVIT LEELAYUWAT, NANTARAT KOMANASIN
In Vivo Nov 2024, 38 (6) 3033-3040; DOI: 10.21873/invivo.13787
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