Ramona Vinci

Matrix metalloproteinase-9 might affect adaptive immunity in non-ST segment elevation acute coronary syndromes by increasing CD31 cleavage on CD4+ T-cells

Abstract Aims In patients with acute coronary syndrome (ACS), the higher activity of effector T-cells suggests that mechanisms involving adaptive immunity dysregulation might play a role in coronary instability. The shedding of the functional CD31 domain 1–5 leads to uncontrolled lymphocyte activation. In experimental models, matrix metalloproteinase-9 (MMP-9) has been implicated in endothelial CD31 cleavage. Interestingly, higher serum levels of MMP-9 have been observed in ACS. We aim to investigate the mechanisms underlying CD31 dysregulation in ACS. Methods and results To assess CD31 cleavage on CD4+ T-cells, we analysed by flow cytometry CD4+ T-cells of 30 ACS, 25 stable angina (SA) patients, and 28 controls (CTRL) using two different CD31 antibodies that specifically recognize domain 1–5 or the non-functional membrane-proximal domain 6. The ratio between the domains was significantly lower in ACS than in SA and CTRL (Pu2009=u20090.002 ACS vs. SA; Pu2009=u20090.002 ACS vs. CTRL). After stimulation with anti-CD3/CD28, the 1–5/6 domain ratio was significantly lower in ACS than in SA (Pu2009=u20090.005). ELISA of supernatants obtained from T-cell receptor-stimulated CD4+ T-cells showed higher production of MMP-9 in ACS than in SA (Pu2009<u20090.001). CD31 domain 1–5 expression in activated CD4+ T-cells from ACS patients increased after treatment with a specific MMP-9 inhibitor (Pu2009=u20090.042). Conclusion Our study suggest that enhanced MMP-9 release plays a key role in determining the cleavage and shedding of the functional CD31 domain 1–5 in CD4+ T-cells of ACS patients. This mechanism might represent an important therapeutic target to modulate T-cell dysregulation in ACS.

Alterations of Hyaluronan Metabolism in Acute Coronary Syndrome: Implications for Plaque Erosion

BACKGROUNDnSuperficial erosion currently causes at least one-third of acute coronary syndromes (ACS), and its incidence is increasing. Yet, the underlying mechanisms in humans are still largely unknown.nnnOBJECTIVESnThe authors sought to assess the role of hyaluronan (HA) metabolism in ACS.nnnMETHODSnPeripheral blood mononuclear cells were collected from ACS (nxa0=xa066), stable angina (SA) (nxa0=xa055), and control (CTRL) patients (nxa0=xa045). The authors evaluated: 1) gene expression of hyaluronidase 2 (HYAL2) (enzyme degrading high-molecular-weight HA to its proinflammatory 20-kDa isoform) and of CD44v1, CD44v4, and CD44v6 splicing variants of HA receptor; and 2) HYAL2 and CD44 protein expression. Moreover, they compared HYAL2 and CD44 gene expression in ACS patients with plaque erosion (intact fibrous cap and thrombus) and in ACS patients with plaque rupture, identified by optical coherence tomography analysis.nnnRESULTSnGene expression of HYAL2, CD44v1, and CD44v6 were significantly higher in ACS as compared with SA (pxa0=xa00.003, pxa0< 0.001, and pxa0=xa00.033, respectively) and CTRL subjects (pxa0< 0.001, pxa0< 0.001, and pxa0=xa00.009, respectively). HYAL2 protein expression was significantly higher in ACS than in SA (pxa0=xa00.017) and CTRL (pxa0=xa00.032), whereas no differences were found in CD44 protein expression. HYAL2 and CD44v6 gene expression was significantly higher in patients with plaque erosion than in those with plaque rupture (pxa0=xa00.015 and pxa0=xa00.029, respectively).nnnCONCLUSIONSnHYAL2 and CD44v6 splicing variants seem to play an important role in ACS, in particular when associated with plaque erosion. After further validation, HYAL2 might represent a potentially useful biomarker forxa0thexa0noninvasive identification of this mechanism of coronary instability.

MATRIX METALLOPROTEINASE 9 DRIVES THE SHEDDING OF CD31 IN ACUTE CORONARY SYNDROMES

Background: T-cells in acute coronary syndromes (ACS) show reduced expression and activity of the immunomodulatory molecule CD31 compared to patients with stable angina (SA). In T-cells, the shedding of the CD31 functional domains 1 to 5 leads to uncontrolled lymphocyte activation. A recent

HYALURONIC ACID, HYALURONIDASE-2 AND ACUTE CORONARY SYNDROMES: POSSIBLE CORRELATION WITH PLAQUE EROSION

Background: A recent experimental model of plaque instability suggests that endothelial activation and the exposure of the extracellular matrix are involved in the inflammatory process of plaque erosion. These data, together with the notion of an intense immunostaining on eroded autoptic coronary

Indoleamine 2,3-Dioxygenase (IDO) Enzyme Links Innate Immunity and Altered T-Cell Differentiation in Non-ST Segment Elevation Acute Coronary Syndrome

Atherosclerosis is a chronic inflammatory disease characterized by a complex interplay between innate and adaptive immunity. Dendritic cells (DCs) play a key role in T-cell activation and regulation by promoting a tolerogenic environment through the expression of the immunosuppressive enzyme indoleamine 2,3-dioxygenase (IDO), an intracellular enzyme involved in tryptophan catabolism. IDO expression and activity was analyzed in monocytes derived DCs (MDDCs) from non-ST segment elevation myocardial infarction (NSTEMI) patients, stable angina (SA) patients and healthy controls (HC) by real-time quantitative polymerase chain reaction (RT-qPCR) before and after in vitro maturation with lipopolysaccharide (LPS). The amount of tryptophan catabolite; kynurenine; was evaluated in the culture supernatants of mature-MDDCs by ELISA assay. Autologous mixed lymphocyte reaction (MLR) between mature-MDDCs and naïve T-cells was carried out to study the differentiation towards T-helper 1 (Th1) and induced regulatory T-cells (iTreg). Analysis of IDO mRNA transcripts in mature-MDDCs revealed a significant reduction in cells isolated from NSTEMI (625.0 ± 128.2; mean ± SEM) as compared with those from SA (958.5 ± 218.3; p = 0.041) and from HC (1183.6 ± 231.6; p = 0.034). Furthermore; the concentration of kynurenine was lower in NSTEMI patients (2.78 ± 0.2) and SA (2.98 ± 0.25) as compared with HC (5.1 ± 0.69 ng/mL; p = 0.002 and p = 0.016; respectively). When IDO-competent mature-MDDCs were co-cultured with allogeneic naïve T-cells, the ratio between the percentage of generated Th1 and iTreg was higher in NSTEMI (4.4 ± 2.9) than in SA (1.8 ± 0.6; p = 0.056) and HC (0.9 ± 0.3; p = 0.008). In NSTEMI, the tolerogenic mechanism of the immune response related to IDO production by activated MDDCs is altered, supporting their role in T-cell dysregulation.