Elevation of Plasma Granzyme B Levels After Acute Myocardial Infarction

Abstract

Background: Apoptosis is reported to play an important role in left ventricular (LV) remodeling after acute myocardial infarction (AMI). Granzyme B is a member of the serine esterase family, which has an important role in cellular apoptosis and extracellular matrix degradation. Methods and Results: Peripheral blood samples were obtained from 33 patients with a first-onset AMI treated by percutaneous coronary intervention (mean age: 61.4±8.7 years old) on days 1, 7 and 14 after onset. Plasma levels of tumor necrosis factor (TNF)-α, a soluble form of the Fas ligand (sFasL), and granzyme B were measured. TIMI grade 3 recanalization was accomplished in all patients within 12 h after onset. The LV end-diastolic volume index (LVEDVI) was calculated on day 1 and at 6 months after onset. Plasma levels of TNF-α, sFasL and granzyme B increased significantly on days 7 and 14 after onset of AMI. Stepwise multivariate regression analysis showed that the plasma granzyme B level on day 14 is a significant explanatory variable for changes in the LVEDVI. Conclusions: Plasma levels of granzyme B increased after AMI, which might be an important factor in the progression of late LV remodeling after AMI. (Circ J 2009; 73: 503 -507)

Intracellular versus extracellular granzyme B in immunity and disease: challenging the dogma

“…They also found that sustained levels of GrB was an independent factor for late-stage left ventricular remodeling. 234 The mechanisms by which GrB may contribute to plaque stability include ECM fragmentation, release of ECM-sequestered cytokines, and/or induction of macrophage or SMC apoptosis in the fibrous cap. To the latter point, Choy et al 135 showed, using a cell culture model, that GrB could induce SMC apoptosis in the absence of perforin through the disruption of SMC-ECM interactions and induction of anoikis.…”

Granzyme B releases vascular endothelial growth factor from extracellular matrix and induces vascular permeability

“…Although traditionally viewed as a pro-apoptotic intracellular protease used by cytotoxic lymphocytes to induce target cell apoptosis, we and others have demonstrated the important role of extracellular GZMB activity in a number of chronic inflammatory diseases (reviewed in [15, 16]). GZMB accumulates in the ECM of inflamed tissues and is present in several bodily fluids in chronic diseases such atherosclerosis, chronic obstructive pulmonary disease (COPD) and RA [17, 18]. ECM proteolysis by GZMB leads to impaired tissue integrity in diseases.…”

Granzymes in age-related cardiovascular and pulmonary diseases

“…Elevated GrB plasma levels were detected in patients after acute myocardial infarction 38 and in patients with unstable carotid plaques, which correlated to increased cerebrovascular events. 39 However, a causative role for granzymes in atherosclerosis and plaque rupture requires further study as increased GrB in the plasma may, as discussed below, represent a potential extracellular role for this protease in disease.…”

“…68,69 Increased levels of circulating GrK are also associated with dengue fever. 68 In atherosclerosis, elevated GrB plasma levels are detected in patients with acute coronary syndromes 38 whereas GrB plasma levels are significantly higher in patients with unstable carotid plaques compared with those with stable lesions, and correspond to an increased incidence of cerebrovascular events. 39 These studies suggest that extracellular GrB activity contributes to ECM degradation and promotes plaque instability and rupture.…”