Peripheral leucocytes and tissue gene expression of granzyme B/perforin system and serpinB9: Impact on inflammation and insulin resistance in coronary atherosclerosis.

AIM: The imbalance between proapoptotic granzyme B (GZB)/perforin (PRF) system and proteinase inhibitor-9 (PI-9; serpinB9); the only known inhibitor of human GZB, has been demonstrated in atherosclerosis. However, their role in atherosclerosis with the impact of type 2 diabetes mellitus (DM) as well as their contribution to hallmarks of atherosclerosis is not clear. SUBJECTS AND METHODS: ELISA for serum insulin, high sensitivity C-reactive protein (hsCRP) and GZB levels in atherosclerotic coronary artery diseases (CAD) patients were estimated in comparison to apparently healthy controls, while GZB, PRF and PI-9 mRNA expression levels were quantified by Taqman RT-PCR in both peripheral leucocytes and atherosclerotic tissues. RESULTS: Atherosclerotic patients showed significantly higher insulin, hsCRP and GZB levels than controls. There was a significant increase in GZB mRNA expression and significant reduction in PI-9 mRNA in both patient peripheral leucocytes and atherosclerotic lesions, while PRF mRNA increased significantly only in atherosclerotic tissues. PI-9 mRNA levels were significantly lower in patients with diabetes than patients without diabetes. In contrast to positive modulating effect of GZB, regression analysis revealed negative modulating effect of PI-9 on inflammation and insulin resistance. Circulating PI-9 mRNA was inversely contributed to CAD severity. CONCLUSIONS: GZB and PI-9 could be effective modulators for inflammation and insulin resistance in atherosclerosis.

Plasma granzyme B in ST elevation myocardial infarction versus non-ST elevation acute coronary syndrome: comparisons with IL-18 and fractalkine.

OBJECTIVE: The proapoptotic protein, granzyme B (GZB), was identified as a contributor to the atherosclerotic plaque instability and recently as inflammatory activator. We studied the release kinetics of GZB and other markers of inflammation such as high sensitivity C reactive protein (hsCRP), interleukin 18 (IL-18), and fractalkine (FKN) in the early phase after acute cardiac events in different ACS subgroups. METHODS: Thirty-six nondiabetic patients with ACS were compared to 12 control subjects. According to ACS diagnosis, the patients were classified into 22 patients with ST elevation myocardial infarction (STEMI) and 14 patients with non-ST elevation myocardial infarction or unstable angina (NSTEMI/UA). Blood samples were taken on day 1 (day of onset) and day 3 to measure hsCRP, IL-18, FKN, and GZB by ELISA. RESULTS: Patients with ACS showed significantly higher GZB, IL-18, and FKN levels than the controls. STEMI group showed significantly higher GZB levels than NSTEMI/UA group. On day 3, FKN levels displayed a significant decrease, while GZB levels were significantly increased. IL-18 levels were more or less constant. GZB levels were positively correlated with IL-18 (r = 0.416, P < 0.01) and FKN (r = 0.58, P < 0.001). CONCLUSIONS: Unlike IL-18 and FKN, plasma GZB may be a marker of ACS disease severity.