Increased Levels of Leukocyte-Derived MMP-9 in Patients with Stable Angina Pectoris

Abstract

ObjectiveThere is a growing interest for matrix metalloproteinases (MMPs) and their tissue inhibitors (TIMPs) in plasma as novel biomarkers in coronary artery disease (CAD). We aimed to identify the sources of MMP-8, MMP-9, TIMP-1 and TIMP-2 among peripheral blood cells and further explore whether gene expression or protein release was altered in patients with stable angina pectoris (SA).MethodsIn total, plasma MMP-9 was measured in 44 SA patients and 47 healthy controls. From 10 patients and 10 controls, peripheral blood mononuclear cells (PBMC) and neutrophils were isolated and stimulated ex vivo. MMPs, TIMPs and myeloperoxidase were measured in plasma and supernatants by ELISA. The corresponding gene expression was measured by real-time PCR.ResultsNeutrophils were the dominant source of MMP-8 and MMP-9. Upon moderate stimulation with IL-8, the neutrophil release of MMP-9 was higher in the SA patients compared with controls (p<0.05). In PBMC, the TIMP-1 and MMP-9 mRNA expression was higher in SA patients compared with controls, p<0.01 and 0.05, respectively. There were no differences in plasma levels between patients and controls except for TIMP-2, which was lower in patients, p<0.01.ConclusionMeasurements of MMPs and TIMPs in plasma may be of limited use. Despite similar plasma levels in SA patients and controls, the leukocyte-derived MMP-9 and TIMP-1 are significantly altered in patients. The findings indicate that the leukocytes are more prone to release and produce MMP-9 in symptomatic and angiographically verified CAD—a phenomenon that may have clinical implications in the course of disease.

Stress-induced release of matrix metalloproteinase-9 in patients with coronary artery disease: The possible influence of cortisol

“…In a previous study, we found that neutrophils in CAD patients were more prone to release MMP-9 ex vivo than were neutrophils from healthy controls. We also found that blood mononuclear cells in Lundberg AK 4 CAD patients had higher levels of MMP-9 mRNA compared with controls but that the secretion of MMP-9 ex vivo from mononuclear cells was negligible in both patients and controls (Jönsson et al 2011). …”

“…In the circulation, neutrophils are considered to be the major source (Jönsson et al 2011, Newby 2015. The enzyme is stored in a latent form in gelatinase-rich (or tertiary) granules of neutrophils and rapidly released following stimulation (Soehnlein 2012).…”

“…Neutrophil isolation was performed using Polymorphprep (Axis-Shield PoC AS, Oslo, Norway) as previously described (Jönsson et al 2011). Cell purity was assessed by microscopic examination.…”

miR-29b Participates in Early Aneurysm Development in Marfan Syndrome

“…16,17 In this study, both MMP-2 expression and activity were specifically upregulated in the AS segment of the Marfan aorta only, explaining the disruption of medial wall ELN isolated to this area. MMPs are secreted by leukocytes and SMCs, 27,28 and MMP-2 can degrade both elastin and collagen. 29 The absence of aortic wall inflammatory cell infiltration in our model suggests that MMPs are secreted locally.…”

Methodological Considerations for Utilizing Plasma Matrix Metalloproteinase-9 as a Biomarker in Acute Vascular Syndromes

“…For example, a prospective study by Jefferis et al in an older age group of patients did not find a significant association between serum MMP9 levels and the risk of incident myocardial infarction and stroke; 5 Tayebjee et al reported a lack of correlation between MMP9 and severity of coronary artery disease demonstrated on coronary angiography; 6 and Jonsson et al reported an increased level of MMP9 expression by neutrophils in SAP patients compared to healthy controls but failed to demonstrate any difference in the plasma levels of MMP9 between the two groups. 7 One possible explanation for the disparity of findings in clinical studies of MMP9 in coronary artery disease lies in the pre-analytical issues known to affect measurement of MMP9 in blood samples. The level of MMP9 is typically higher in serum compared to plasma.…”