Increased granzyme B production from peripheral blood mononuclear cells in patients with acute coronary syndrome

Tsuru, Rie; Kondo, Hideyuki; Hojo, Yukihiro; Gama, Miyuki; Mizuno, Osamu; Katsuki, Takaaki; Shimada, Kazuyuki; Kikuchi, Masatoshi; Yashiro, Takashi

doi:10.1136/hrt.2006.110023

Cited by 26 publications

(19 citation statements)

References 32 publications

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“…GrB is found in all regions of the atherosclerotic plaque in advanced atherosclerosis, where it appears to be produced by foam cells and macrophages (6,7). Plasma levels of GrB are also significantly elevated in atherosclerosis, with highest levels in patients with unstable plaques (8,9).…”

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confidence: 97%

Antihemostatic Activity of Human Granzyme B Mediated by Cleavage of von Willebrand Factor

Buzza

Dyson

Choi

et al. 2008

Journal of Biological Chemistry

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The cytotoxic lymphocyte protease granzyme B (GrB) is elevated in the plasma of individuals with diseases that elicit a cytotoxic lymphocyte-mediated immune response. Given the recently recognized ability of GrB to cleave extracellular matrix proteins, we examined the effect of GrB on the pro-hemostatic molecule von Willebrand factor (VWF). GrB delays ristocetininduced platelet aggregation and inhibits platelet adhesion and spreading on immobilized VWF under static conditions. It efficiently cleaves VWF at two sites within the A1-3 domains that are essential for the VWF-platelet interaction. Like the VWF regulatory proteinase ADAMTS-13, GrB-mediated cleavage is dependent upon VWF conformation. In vitro, GrB cannot cleave the VWF conformer found in solution, but cleavage is induced when VWF is artificially unfolded or presented as a matrix. GrB cleaves VWF with comparable efficiency to ADAMTS-13 and rapidly processes ultra-large VWF multimers released from activated endothelial cells under physiological shear. GrB also cleaves the matrix form of fibrinogen at several sites. These studies suggest extracellular GrB may help control localized coagulation during inflammation.

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mentioning

confidence: 97%

Antihemostatic Activity of Human Granzyme B Mediated by Cleavage of von Willebrand Factor

Buzza

Dyson

Choi

et al. 2008

Journal of Biological Chemistry

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“…29 Furthermore, a recent study has suggested a link between GZMB and unstable angina pectoris in which mononuclear cells from unstable angina pectoris patients exhibited greater GZMB production compared with cells from stable angina pectoris or healthy controls. 30 As GZMB has been previously found to retain its activity in plasma, 52 it is not unreasonable to propose a mechanism whereby chronic inflammation with macrophage infiltration and mast cell activation could lead to increased GZMB levels in and around the vessel wall. GZMB then cleaves ECM components such as fibrillin-1, contributing to the loss of elastic lamellae, medial degeneration, vessel wall instability, and subsequent aneurysm formation, after which further assault by GZMB on the adventitial layer that maintains the structural integrity of the vessel could lead to rupture of the aorta.…”

Section: Granzyme B In Aortic Aneurysm 1045mentioning

confidence: 99%

“…29 Furthermore, elevated GZMB production is observed in peripheral blood mononuclear cells isolated from patients with unstable angina pectoris compared with cells from patients with stable angina pectoris. 30 The current study used a well-established mouse model of angiotensin II (Ang II)-induced AAA. 31 In this model, macrophage accumulation in the media of the suprarenal aorta and dissection precede the formation of aneurysm and atherosclerosis in Ang II-infused apolipoprotein E-knockout (APOE-KO) mice.…”

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confidence: 99%

Perforin-Independent Extracellular Granzyme B Activity Contributes to Abdominal Aortic Aneurysm

Chamberlain

Ang

Boivin

et al. 2010

The American Journal of Pathology

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Granzyme B (GZMB) is a serine protease that is abundantly expressed in advanced human atherosclerotic lesions and may contribute to plaque instability. Perforin is a pore-forming protein that facilitates GZMB internalization and the induction of apoptosis. Recently a perforin-independent, extracellular role for GZMB has been proposed. In the current study , the role of GZMB in abdominal aortic aneurysm (AAA) was assessed. Apolipoprotein E (APOE)and APOE ؊/؊ ؋ perforin ؊/؊ double knockout (GDKO, PDKO) mice were generated to test whether GZMB exerted a causative role in aneurysm formation. To induce aneurysm, mice were given angiotensin II (1000 ng/kg/min) for 28 days. GZMB was found to be abundant in both murine and human AAA specimens. GZMB deficiency was associated with a decrease in AAA and increased survival compared with APOE-KO and PDKO mice. Although AAA rupture was observed frequently in APOE-KO (46.7%; n ‫؍‬ 15) and PDKO (43.3%; n ‫؍‬ 16) mice, rupture was rarely observed in GDKO (7.1%; n ‫؍‬ 14) mice. APOE-KO mice exhibited reduced fibrillin-1 staining compared with GDKO mice, whereas in vitro protease assays demonstrated that fibrillin-1 is a substrate of GZMB. As perforin deficiency did not affect the outcome, our results suggest that GZMB contributes to AAA pathogenesis via a perforin-independent mechanism involving extracellular matrix degradation and subsequent loss of vessel An aneurysm is a permanent focal dilatation of an artery that is associated with progressive weakening of the vessel wall. Approximately 80% of all aortic aneurysms occur in the abdominal region.1 Abdominal aortic aneurysm (AAA) is an increasingly common and frequently fatal clinical condition, responsible for more than 15,000 deaths per year in the United States.1 The most significant risk factors for AAA are male gender, cigarette smoking, age, family history, and atherosclerotic disease.2,3 The incidence of AAA measuring 2.9 to 4.9 cm in diameter ranges from 1.3% in men 45 to 54 years of age to 12.5% in men 75 to 84 years of age. In women, prevalence ranges from 0% to 5.2% in the same age groups. 2Rupture occurs in approximately 20% of AAA exceeding 5 cm in diameter but is expected in over 50% of AAA greater than 7 cm. 2

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“…13,14 Granulation tissue formed after myocardial infarction (MI) contains chronic inflammatory cells, and in recent studies, the activated Fas/FasL system and elevated levels of TNF-α released from inflammatory cells contributed to LV remodeling after AMI. 15,16 Interestingly, in our previous report we suggested that granzyme B plays an important role in triggering ACS by degrading coronary plaques, 17 amd we hypothesized that apoptosis-related molecules contribute to LV remodeling after AMI by inducing apoptosis and matrix degradation. In the present study, we focused on the role of granzyme B in LV remodeling after AMI.…”

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confidence: 99%

Elevation of Plasma Granzyme B Levels After Acute Myocardial Infarction

Kondo

Hojo

Tsuru

et al. 2009

Circ J

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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)

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Increased granzyme B production from peripheral blood mononuclear cells in patients with acute coronary syndrome

Abstract: These results suggest that granzyme B might play an important role in triggering acute coronary events by inducing apoptosis and the degradation of atherosclerotic coronary plaques.

Cited by 26 publications

References 32 publications

Antihemostatic Activity of Human Granzyme B Mediated by Cleavage of von Willebrand Factor

Antihemostatic Activity of Human Granzyme B Mediated by Cleavage of von Willebrand Factor

Perforin-Independent Extracellular Granzyme B Activity Contributes to Abdominal Aortic Aneurysm

Elevation of Plasma Granzyme B Levels After Acute Myocardial Infarction

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